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dissertation entitled

NICOTINIC CHDLINERGIC INFLUENCES DN SEXUAL
RECEF'TIVITY IN FEMALE RATS

(Rattus Norveqicug)
presented by

David Raymond Weaver

has been accepted towards fulfillment
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NICDTINIC CHOLINERGIC INFLUENCES ON SEXUAL RECEPTIVITY IN
F EHN-E RATS (Baum W)

by

David Raymond Hoavcr

A DISSERTATION

Subnittad to
Michigan Stata Univarsity
in partial fulfillmant of tho raquiramonts
for the dagroa of

DOCTOR OF PHILOSOPHY

Dopartmant of Zoology and Neuroscience Program

1985

Copyright

by

David Raynond Unavar

1985

ii

ABSTRACT

NICOTINIC CHOLINERSIC INFLUENCES 0N SEXUAL RECEPTIVITY IN
FEMALE RATS (emu W)

BY

David Raymond Noavor

'Provious work by Clonons and co-workors has shown that
intracorobral infusions of ouscarinic agonists induco soxual
rocoptivity (lordosis) in ostrogon-prinod ovarioctooizod
(OVX) fooalo rats. Convorsoly, intracorobral in¥usions o‘
ouscarinic antagonists disrupt rocoptivity in ostrogon plus
progostorono prinod DVX rats. Tho purposo oi this thosis
was to oxaoino tho contribution at tho nicotinic cholinorgic
rocoptor in tho rogulation o4 lordosis bohavior.

In agroooont with tho oarlior work oi Fuxo, Evoritt &
Hokiolt tEngcag;g1;_fiiggnln‘__flgn‘¥L 7, 1977, 147-151),
nicotino (50, 100 or 200 lug/kg) facilitatod lordosis
bohavior in ostrogon-prinod OVX rats 5 oinutos attor
intraporitonoal (i.p.) injoction. Protroatnont with tho
nicotinic antagonist nocanylamino (NEDA, 2.5 or 10 ng/kg,
i.p.) cooplotoly provontod tacilitation of lordosis by
nicotino (150 ‘ug/kg). Protroatnont with tho muscarinic
antagonist atropino (30 ng/kg) roducod but did not provont
tho facilitation o¥ lordosis by nicotino; 7.5 mg/kg atropino
was inoftoctivo. Intracorobrovontricular (ICV) infusion of
tho cholinostoraso inhibitor osorino (physostigmino)

facilitatod lordosis in ostrogon-primod OVX rats (Dohanich,

Barr, Nitchor & Clomons, Physio}, Egggxg 32, 1984,

David Raymond Hoavor

1021-1026), and atropino protroatmont cooplotoly provontod
this rosponso. In tho study roportod horo, MEGA
protroatoont (5 or 10 og/kg, i.p.) roducod tho osorino-
inducod {acilitation of lordosis but did not provont it
cooplotoly. NEDA did not disrupt horoono-inducod
rocoptivity whon adoinistorod oithor systonically (5 or 10
og/kg, i.p.) or ICV (5 or io‘ug/cannula, bilatorally).

In conclusion, pharoacological activation of nicotinic
rocoptors can facilitato soxual rocoptivity, but ondogonous
nicotinic transoission appoars to bo rolativoly loss
ioportant than ouscarinic transmission in tho rogulation oi

soxual rocoptivity in fooalo rats.

To Jan

iii

ACKNOWLEDGEMENTS

First, and oost importantly, I would liko to acknowlodgo
tho contributions of oy wiio, Jan. Without hor support,
oncouragooont and pationco I would not havo boon ablo to
cooploto this progoct.

I would also liko to rocognizo tho contributions oi oy
prosont and {oroor colloaguos in tho Hornonos & Bohavior
Laboratory. Undor tho diroction of Dr. Lynwood 6. Clooons,
ioportant rolatod studios havo boon portorood by Dr. Gary
Dohanich, Hissy Barr, David Brighao, Dr. Joff “itchor, Dr.
Bail Richoond, and Thooas Hoyors. Thoso rolatod studios
provido contoxt for intorprotation oi tho prosont rosults.
Both Hoo has boon a coopotont and choorfiul collaborator in
our I‘oouso proJoct' “forts. I would also liko to thank
David Brighao for assistanco in tho proparation o4 figuros
and for rolatod photographic work.

Tho guidanco of oy coonittoo, chairod by Dr. Clooons and
including Drs. Janos A. Ashor, Jr., Antonio A. Munoz, and
Richard H. Roch is also gratotully acknowlodgod.

Nhilo conducting this rosoarch, l was supportod in part

by a National Scionco Foundation prodoctoral followship.

iv

TABLE OF CONTENTS

LIST w TAmB I I I I I I I I I I I I I I I I I I I I I V‘ 1
LIST w FIMBI I I I I I I I I I I I I I I I I I I I Vii‘
IWTIM I I I I I I I I I I I I I I I I I I I I I I I 1

Hormonal and bohavioral cyclicity. . . . . . . . . . .
Horoono-dopondont soxual bohaviors . . . . . . . . . .
Hochanisms of storoid hormono action . . . . . . . .
Approachos to tho hormonal rogulation of rocoptivity .
Bitos of ovarian horoono action . . . . .
Psychopharoacology of lordosis bohavior. .
Honoaoinos . . . . . . . . . . . .
Gamma-amino butyric acid (GABA). . .
Lutinizing horoono-roloasing hormono
Oxytocin and vasoprossin . . . . . .
Dthor poptidos . . . . . . . . . . .
Acotylcholinorgic nourotransoission. .
Psychopharoacology of acotylcholino (ACh)
Btatooont of Purposo . . . . . . . . . .

in:

mm MI I I I I I I I I I I I I I I I I I I I I I51

Subjocts . . . . . . . . . . . . .
Housing and animal caro conditions
Ovarioctomy. . . . . .
Scrooning protost. . .

.51
.52
.52
I53
.54

Bohavioral tosting . . . . .
Statistical analysis . . . .
Hormono and drug solutions .

. .56

. .56
I57
.58
I59

.59

Intracorobral studios. . .
Cannula construction . .
Cannula implantation . . . . .
Intracorobral infusion tochniquo .
Artificial corobrospinal fluid vohiclo
Histological vorification of cannulao loc at

I
I
I
I
i

on

EXPERIMNT 1 I I I I I I I I I I I I I I I I I I I I I I I61

Procwur.I I I I I I I I I I I I I I I I I I I I I I I 61
le t.I I I I I I I I I I I I I I I I I I I I I I I I 65
my. I I I I I I I I I I I I I I I I I I I I I I I 73

EXPERIMNT 2 I I I I I I I I I I I I I I I I I I I I I I I 75

Proc.dur.I I I I I I I I I I I I I I I I I I I I I I I 75
R..u1t.I I I I I I I I I I I I I I I I I I I I I I I I 75
Summary. . .77

EXPERIHENT 3 .

Procoduro.
Rosults. .

suerI I I I I I I I I I I I I I I I I I I I
EXPERIW 4 I I I I I I I I I I I I I I I I I I I
PerdurIo I I I I I I I I I I I I I I I I I I
le t'I I I I I I I I I I I I I I I I I I I I
WYI I I I I I I I I I I I I I I I I I I I
EXPERIW s I I I I I I I I I I I I I I I I I I I
Prxwur.I I I I I I I I I I I I I I I I I I I
le t.I I I I I I I I I I I I I I I I I I I I
“WYI I I I I I I I I I I I I I I I I I I I
EXERIW 6 I I I I I I I I I I I I I I I I I I I
PerdurIo I I I I I I I I I I I I I I I I I I
le t'I I I I I I I I I I I I I I I I I I I I
WYI I I I I I I I I I I I I I I I I I I I
m DIMIM I I I I I I I I I I I I I I I I
WY MD cmuslma I I I I I I I I I I I I I I

LIST OF REFERENCES .

APPENDICES . .

Appondix 1 Individual lordosis quotionts and
‘suooary statistics for ostrogon- primod OVX rats
boforo and 5 and 20 ninutos aftor i.p. injoction
of nicotino (O, 25, 50, 100 or 200 lug/kg)
(Exporioont la) . . . . . . . . . . . . . . .122

Appondix 2 Lordosis quotionts of ostrogon-
primod OVX rats boforo and 5 minuto aftor
nicotino injoction (150 lug/kg): Effoct of
protroatmont with mocamylanino (NEDA, 1 or 5
og/kg), hoxamothoniun (HEX, 8 or 20 mg/kg), or
atropino (ATR, 8 or 20 mg/kg)(Exporimont 1d) 124

Appondix 3 Lordosis quotionts of
ostrogon-primod OVX rats boforo and 5 minutos
aftor nicotino injoction (150‘ug/kg): Effoct of
protroatmont with atropino sulfato (7.5 or 30
og/kg) (Exporimont 3) . . . . . . . . . . . 125

vi

.78

.78
.78
.80
.81
.81
.82
.84
.85
.87
.87
.88
.88
.88
.90
.91
101
103

122

LIST OF TABLES
TABLE 1 Individual lordosis quotionts of OVX, aD-priood

'nonrospondors' boforo and 5 oinutos aftor i.p. nicotino
injoction (Exporioont 1b and 1c). . . . . . . . . . . . . 6B

vii

LIST OF FIGURES
th 1 PFOCIIUFI, EXpr'Imt 1 o o o o o o o o o o o o 63

FIGURE 2 Hoan lordosis quotionts (+l- 8.E.M.) of EB-priood
OVX rats 5 oinutos aftor IfljICtIDfl of nicotino (0, 25, 50,
100 or 200pg/kg, i.p.) (Exporimont 1a). . . . . . . . . 66

FIGURE 3 Hocaoylaoino (MEGA) protroatmont provontod tho
facilitation of lordosis inducod by nicotino (NIB)
‘EXPI'IMt 1d mk 4’ I I I I I I I I I I I I I I I I I I 70

FIGURE 4 Hoxaoothoniuo (HEX) protroatmont roducod but did
not provont facilitation of lordosis by nicotino (Exporimont
1d Wk 5) I I I I I I I I I I I I I I I I I I I I I I I I 7‘

FIGURE 5 Atropino protroatoont roducod but did not provont
facilitation of lordosis by nicotino (Exporimont 1d wook 6.)

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I 72

FIGURE 6 Hocaoylamino protroatmont provontod nicotino
facilitation of lordosis (Exporimont 2) . . . . . . . . . 76

FIGURE 7 Atropino protroatmont roducod but did not provont
facilitation of lordosis by nicotino (Exporioont 3). . . 79

FIGURE 8 Hocaoylamino protroatmont roducod but did not
provont tho facilitation of lordosis inducod by bilatoral
ICV osorino infusion (Exporioont 4). . . . . . . . . . . 83

FIGURE 9 Bystooic troatoont (Tx) with oocaoylaoino did not
inhibit rocoptivity in ED plus P primod OVX rats . . . . 86

FIGURE 10 ICV infusion of oocaoylamino did not inhibit
rocoptivity in ED plus P primod OVX rats. . . . . . . . . 89

viii

WW

Fomalos of most mammalian spocios copulato only during a
rostrictod portion of tho ovarian cyclo (soo Horali & Boyor,
1979). In normal, gonadally intact fomalo rats, thoro is
cyclicity both in tho lovols of ovarian hormonos in tho
plasma and in tho occurronco of soxual rocoptivity.
Romoval of tho ovarios virtually abolishos copulatory
bohavior by romoving tho sourco of thoso ovarian hormonos
(Young, 1961). In cycling fomalo rats, ostradiol lovols in
plasma incroaso slowly, roaching a poak approximatoly 12
hours prior to tho onsot of soxual rocoptivity during
proostus (Butchor, Collins & Fugo, 1974). Progostorono
lovols, in contrast, incroaso rapidly and poak 3-4 hours
boforo tho onsot of bohavioral ostrus (Butchor g;__j1‘,
1974; Fodor, Rosko & Boy, 1968; Fodor, Brown-Grant, Corkor &
Exloy, 1969; Bodorston & Enoroth, 198i). Tho ovary normally
producos this spiko of progostorono, and acuto ovarioctomy
prior to progostorono roloaso provonts tho induction of
rocoptivity (Powors, 1970). Togothor, thoso studios havo
domonstratod that ovarian ostrogon and progostorono aro
rosponsiblo for tho induction of soxual rocoptivity in
normal, gonadally intact fomalo rats. Estrogon troatmont
inducos soxual rocoptivity in ovarioctomizod fomalo rats,
but soquontial troatmont with ostrogon followod by

1

progostorono is moro offoctivo (Boling & Blandau, 1939;
Coach, 1942. soo Young, 1961 for roviow). On tho basis of
hormono roplacomont studios as woll, than, it is possiblo to
concludo that soxual rocoptivity is hormono dopondont, and

tho critical hormonos aro ostrogon and progostorono.

H8CI8nI:IIElnfllni_lllflll_hlhl¥LQCl
During tho poriod of bohavioral ostrus ('hoat'), fomalo

rodonts typically display cortain bohaviors. Aggrossion and
scant marking aro oxamplos of hormono-dopondont bohaviors
whoso froquoncy of occurronco varios with tho ostrous cyclo.
Thoso bohaviors will not bo discussod furthor, although it
is rocognizod that thoy may influonco tho occurronco of
spocific copulatory bohaviors.

Estrus fomalo rodonts aro typically moro attractivo to
malos, moro attractod to malos, and aro moro likoly to allow
tho malo to copulato. Thus, fominino soxual bohavior has
boon concoptually dividod into attractivity, procoptivity,
and rocoptivity (Boach, 1976). 8ohaviorally, tho groator
attraction of fomalos in ostrus towards malos is ovidont by
tho occurronco of "procoptivo" bohaviors. Fomalos rats in
ostrus (oithor naturally or inducod by oxogonous hormono
troatmont) spond moro timo in tho vicinity of malos,
approach thom moro froquontly, and display
"hopping-and-darting" and "oar-wiggling,“ bohaviors which
sorvo to oxcito tho malo and draw his attontion to tho

fomalo.

Rocoptivity, or tho bohavior allowing tho malo to
actually copulato, is froquontly assossod by tho occurronco
of tho lordosis rosponso. Tho lordosis posturo is assumod
by ostrus fomalo rodonts in rosponso to mounting by tho
malo; lordosis consists of arching of tho back, olovation of
tho hoad and porinoum, and latoral dofloction of tho tail
(Komisaruk, 1974; Pfaff, 1980). Lordosis allows tho malo to
achiovo ponilo insortion (intromission) which is obviously
nocossary for intravaginal oJaculation. Bouual rocoptivity
is synchronizod with ovulation, as tho dovoloping folliclos
produco tho hormonos that induco souual rocoptivity. As a
rosult of this synchronization botwoon souual rocoptivity
and ovulation, thoro is also synchronization in arrival of
ova in tho oviducts and sporm in tho vagina.
Hormono-inducod souual rocoptivity is thus critical to
succossful roproduction in rodonts.

Tho rolationship botwoon gonadal hormonos and lordosis
bohavior in rodonts has boon undor ouporimontal
invostigation sinco tho 1920’s. In thoso oarly studios, tho
nocossary rolo of tho ovary in fomalo roproductivo bohavior
was ostablishod, as was tho ability of synthotic ovarian
hormonos to induco bohavioral ostrus in ovarioctomizod
fomalo rodonts (for roforoncos, soo roviow by Coach, 1981).
In tho yoars that havo followod, attontion has focusod on
‘tho'mochanisms of storoid hormono action and tho prociso
malocular spocios of hormonos involvod in tho induction of
somual rocoptivity. Tho major quostions rogarding hormonal

3

rogulation of soxual bohavior havo bocomot
1) 8y what mochanisms do ovarian hormonos act in tho
norvous systom to induco saxual rocoptivity ?
2) In which noural sitos do ovarian hormonos act to induco
soxual rocoptivity 7
Tho following litoraturo roviow will summariza tho

curront litoraturo portaining to thoso quastions.

Winn

Onco in tho systomic circulation (oithor aftor roloaso
from tho ovary or aftor oxoganous iflJICtIIfl), storoid
hormonos aro distributod throughout tho body. Calls which
havo spocific intracollular protains (rocoptors) that bind a
hormono aro rofarrad to as targat calls for that hormono.
8toroid hormonos aro lipophilic, and tharoforo thoy aro
boliovod to antar calls by passivo diffusion. Hithin targot
calls, tho storoid binds to “cytosolic' racoptors (soo
paragraph on torminology bolow). Following activation
(binding) of tho racoptor by tho storoid, tho storoid-
rocaptor complax bacomos moro closoly associatod with tho
chromatin. Tho activatad storoid-racoptor complax is
thought to bind to tho chromatin and altar tho pattarn of
mossangar RNA production (transcription). In this way,
storoid hormonos can influonco tho pattarn of protains
producod by a targat coll (D’Hallay & Haans, 1974).

As indicatod abovo, tho tarm "cytosolic" racoptors may

4

bo misloading. Activatod t'nuclaar“3 racoptors aro saparatod
with tho nucloar fraction of call homogonatas, and aro
tharoforo distinguishad from tho un-activatad (“cytosolic“)
racoptors. Hhilo cytosolic racoptors havo fraquantly boon
assumod to ba cytoolasmic, rocont ovidanco indicatos that
both cytosolic and nucloar ostrogon racoptors rasido in tho
nuclaus in at loast soma tissuos, and that tho racovory of
cytosolic racoptors in tho cytosolic fraction is maroly an
artifact of tho homoganization procoss (King & Groono, 1984;
Halshons, Lioborman & Gorski, 1984).

Hithin tho norvous systom, it is thought that gonadal
hormonos influonco tho pattarn of noural activity in savaral
ways (Boyor, Larsson I: Cruz, 1979). Gonadal hormonos may
affoct noural activity by diract affacts on coll mombranas
(Kally, Moss & Dudloy, 1977a; Kolly, floss, Dudloy & Fawcott,
1977b. Towla & 8za, 1983), and aftor longar latancias by
altaring tho pattarn of protains producod by nourons as
mantionad abova (HcEwon, Davis, Parsons & Pfaff, 1979).
Spocific protoin products inducod or supprassod by storoid
hormono troatmant may includa intrinsic protains of tho call
mambrano (tharoforo influoncing oxcitability), motabolic
anzymas (influoncing anargy availability), mRNA and protoin
cloavago anzymas and kinasos (influoncing tho form of othar
protoin products of tho call), racoptor protains (both for
naurotransmittors and for othar storoid hormonos), and
nourotransmittor-ralatad anzymas. Through tho production or
supprassion of cortain protains, than, gonadal hormonos can

altar tho activity of complox nauronal populations as wall
as of individual nourons. In this way, gonadal hormonos can

ragulato a variaty of hormona-dapandont bohaviors.

Tho importanca of hormono-inducod protoin synthosis in
tho induction of soxual bohavior has boon domonstratad by
savoral workors using drugs which provont protoin synthosis
(soo Haisal & Pfaff, 1984, for critical roviow). Bystamic
traatmont with tho RNA synthosis inhibitor actinomycin-D
intarfaras with ostrogon priming if administarod prior to,
concurrant with or up to 12 hours aftor ostrogon inJoction
(Cuadagno, Hough, Ochs, Ronnar & Bast, 1980; Guadagno,
8hryna & Gorski, 1971; Tarkol, 8hryno & Gorski, 1973;
llaalan, Gorzalka, DoBold, Ouadagno, Ho a Hough, 1974);
actinomycin-D doas not appaar to intarforo with tho
synargistic affoct of progostorono aftor a normal poriod of
ostrogon priming (Cuadagno .;_.1‘, 1971, .1971) Rasults
with intracarabral application of actinomycin-D support
thoso conclusions (Ho, Ouadagno, Cooka & Gorski, 1973/4;
Madagno m 1971, 1990; Tarkol 1:41.... 1973; Uhalan
gt__‘1‘, 1974). 8ystomic injactions of tho protoin
synthosis inhibitor anisooycin intarfaras with both ostrogon
and progostorono induction of rocoptivity (Parsons, Rainbow,
Pfaff & HcEwon, 1982; Rainbow, Davis & McEwon, 1980a). Hhan
takan togathar, thoso and othar studios (soo aitgg_ g1_
Qxgc1;n___flgclgnl___figgign_ soction) domonstrata that
hormono-inducod altorations in gono oxprassion loading to

6

altorations in tho pattarn of protoin synthosis aro
nocossary for tho induction of saxual rocoptivity. Tho
apparantly discrapant rosults with actinomycin failing to
block progostorono-inducod rocoptivity aftor ostrogon
priming has lad to tho suggostion that ostrogon and
progostorono act by slightly diffarant mochanisms, a.g.,
progostorono may act primarily at tho translational lovol,
whilo ostrogon may involvo both transcription and
translation. This possibility is supportod by tho shortar
latancy to progostorono affacts on lordosis ralativo to
ostrogon (a.g., Glasar, Rubin & Barfiold, 1983; Parsons,

HacLusky, Kroy, Pfaff & HcEwan, 1980).

W

Ovarian hormonos act within spocific sitos in tho
cantral norvous systom (discussad in tho noxt soction) to
induco saxual rocoptivity. Attampts to undarstand tho
rolationship botwoon hormonos and bohavior at tho
naurotransmittar laval havo takan two ganaral approachas,
naurochamistry and psychopharmacology.

Using tho naurochamical approach, ona can administar
hormonal troatmonts which aro known to induco saxual
rocoptivity and than oxamina a variaty of noural sitos for
changas in naurochamical paramatars. In this way it is
possiblo to domonstrata hormono-inducod altorations in
naurotransmittar synthotic and dagradatory anzymas, racoptor
lovols and transmittar turnovar ratas. A graat doal of

7

rasaarch has boon conductad using this approach, but it is
not possiblo by this approach alono to domonstrato that a
givan naurochamical changa is actually rolatod to tho
bohavior boing studiad. For axamplo, altorations in
hypothalamic muscarinic racoptors inducod by ostrogon havo
boon doscribod by savaral groups (Assivar, Egozi &
Sokolovsky, 1981; Dohanich, Hitchar, Haavar & Clamans, 1982;
Mayors & Clamans, 1985; Rainbow, DoGroff, Luino & HcEwan,
1980), but this changa has boon intarpratad to ba rolatod to
sakual bohavior by soma invastigators and to gonadotropin
sacration by othars, dopanding on tho intarost of tho
authors. Furthormora, standard naurochamical assays involvo
grind-and-bind mothods, which can obscura within-sita
hotoroganoity in transmittar modulation by storoids. In
this way, a bahaviorally rolavant altoration in
naurochamical paramatars can ba ovarlookod bacauso of
“dilution“ of tho changa in soma nourons by surrounding
tissuo in which thoro is no altaration. Tho naurochamical
approach can only provido supporting avidanca for tho
involvomant of a givan transmittar in spocific sitos in
rogulating a givan bohavior. As a rosult, rolativoly littlo
amphasis will ba placod on this approach in this litoraturo
roviow.

Tho sacond approach to tha hormona- naurotransmittar-
bohavior rolationship is to administar drugs which altar
naurotransmission and subsaquantly to datarnino thair affoct
on bohavior. This psychopharmacological approach has boon

naurotransmittars on saxual bohavior. This thasis is
concornod with nicotinic cholinorgic psychopharmacology and
sauual bohavior; it is tharoforo appropriato to roviow tho
litoraturo on tho psychopharmacology of souual bohavior.
First, howovar, it is nocossary to considar tho
nauroanatomical substratos important in tho hormonal

activation of saxual rocoptivity.

W
8ovaral tochniquas havo boon usad to implicata tho

involvomont of spocific noural sitos in hormona-activatad
roproductivo bohavior. Sitas of hormono action in tho
rogulation of saxual rocoptivity havo boon implicatad by
storoid autoradiography, alactrophysiology (stimulation and
racording), brain lasions, and intracorabral applications of
hormonos, protoin synthosis inhibitors, naurotransmittars
and othar drugs. A dascription of tho storoid-concontrating
calls in tho fomalo rat brain follows as an introduction to
tho sitos that may bo important for hormono-activatad
bohaviors. An ovarviaw of tho proposad noural pathway for
lordosis (which combinos information from a variaty of
tachniquas) will than ba prasantad. Nhila intracorabral
microinfusion of naurotransmittar-rolatod drugs has boon
usad in this and othar laboratorias to implicata spocific
intracranial sitos in tho rogulation of soxual rocoptivity
(Dohanich & Clamans, 1981), moro racant avidanca has
indicatod that this mothod is not always sito-spocific

9

(Clamans, Dohanich & Barr, 1983; Dohanich, Barr, Hitchar a
Clamans, 1984). Similarly, Haisal & Pfaff (1984) havo
proposad that sproad of infusod actinomycin-D from tho
praoptic araa (FDA) to tho vantromadial hypothalamus (VHH)
is rosponsiblo for tho bohavioral affactivanoss of POA
infusions in disrupting lordosis, as powdorad actinomycin-D
application to tho POA is not affoctivo. Duo to
rasarvations about tho powor of microinfusion tachniquas in
implicating spocific sitos in tho rogulation of lordosis
bohavior, tho psychopharmacology of saxual bohavior will ba

discussad in a saparato saction.

Staroid autoradiography has boon usad to idontify sitos
which concantrata ovarian hormonos. In tho rat brain,
tritiatod ostradiol bacomas concantratad most roliably in
calls in tho hypothalamus and limbic systom following
systomic inJaction into ovarioctomizod (OVX) adults (Pfaff &
Koinar, 1973). Spocifically, diancaphalic sitos which
concantrata ostradiol aro locatad in tho madial praoptic
araa, madial antarior hypothalamus, vantromadial and arcuato
nuclai, and tho vantral pramammilary nuclaus. In tho
taloncophalon, tho madial and cortical nuclai of tho
amygdala bacomo dansaly labolad; tho lataral saptum,
olfactory tubarcla, bad nuclaus of tho stria torminalis,
hippocampus, diagonal band of Broca, antorhinal cortox and
propyriform cortax aro also roliably labolad, although loss
intansoly. In tho midbrain, tha aasancaphalic cantral gray

10

(HCG) also contains astradiol-concantrating calls. Labollad
calls waro obsorvad olsawhoro in tho norvous systom, but in
ganaral thoso calls waro not labolad consistantly from
animal to animal and waro not haavily labolad. Stumpf
(1970) found assantially similar rosults, with tho oxcaption
that soma of tho lass intonsaly labolad araas of Pfaff a
Kainor (1973) waro considarad to ba unlabolad by Stumpf
(a.g., antorhinal cortax). In addition, Stumpf notad
laballing of tho organum vasculosum of tho lamina tarminalis
and tho subfornical organ, which aro circumvantricular
structuras outsida of tho blood-brain barriar.

As discussad by Pfaff & Koinor (1973), many of tho brain
ragions which aro labolad following systomic inJoction of
labolad ostradiol aro rolatod to tho rogulation of
gonadotropin sacrotion, mating bohavior, or both.
Unfortunatoly, it is impossiblo to toll which calls aro
involvod in which functions from autoradiography. Losion
and hormono implant studios havo implicatad savaral of thoso
araas in tho rogulation of saxual bohavior. Furthormora,
thoro aro anatomical connoctions botwoon many of thoso
araas, which supports tho idaa of functionally rolatod
astrogon-concantrating “systoms' in tho rat brain.

Pfaff & Kainar (1973) and HcEwan & Pfaff (1973) havo
doscribad tho pathways connacting ostrogon-concantrating
ragions as comprising fivo groups: 1) savaral araas
(propyriform and antorhinal cortax, olfactory tubarcla,
modial and cortical amygdala) racaiva input from tho

11

olfactory or accassory olfactory bulbs; 2) tho saptum,
olfactory tubarcla, and diagonal band of Broca aro connoctod
to aach othar and to tho madial forabrain bundlo; 3) tho
madial and cortical amygdala progact via tho stria
torminalis to tho bad nuclous of tho stria torminalis,
modial praoptic araa, madial antarior hypothalamus,
vantromadial nuclous, and tho vantral pramammilary nuclous;
vantral hippocampal nourons DPOJICt via tho madial
corticohypothalamic tract to tho madial antarior
hypothalamus and tho arcuata nuclous; tho hippocampus is
raciprocally connoctod to saptum and tho diagonal band of
Broca; and tho bad nuclous of tho stria torminalis and
saptum projact to tho madial praoptic araa; 4) antorior
hypothalamic and praoptic araas progact caudally to tho
vantromadial nuclous; 5) tho praoptic hypothalamic ragion
connocts to tho HCG via parivantricular fibors and tho
madian forabrain bundla. "any of thoso araas, and
connoctions botwoon tham, havo boon implicatad by othar
mathods as boing important for tho display of
hormono-activatad saxual rocoptivity.

M not-d in th- datum—MW
saction of this INEBQQUQILQH, ostrogon followod by
progostorono is tha most affactiva hormonal traatmont for
tho induction of saxual rocoptivity in rats. It should bo
obvious that sitos which accumulata progostorono ara
potantial sitos for hormonal actions on bohavior. Savoral
authors havo lookad at tho distribution of progostorono

12

binding sitos in rat brain. Using tho synthotic progostin
R5020 as a ligand, for oxampla, Uarambourg (1978) has
domonstratad a high laval of progostin binding in tho
praoptic araa, tho madiobasal hypothalamus, and tho antarior
pituitary. Tho induction of progostin racoptors is
ostrogon-dopondont in thoso araas (Roy, HacLusky a HcEwan.
1979). Hhalan and Luttga (1971) havo prosantad avidanca.
that tritiatad progostorono is also takan up by calls in tho

midbrain.

Thus, on tho basis of data from a variaty of tachniquas,
soma sitos important for hormono-inducod saxual rocoptivity
havo boon idantifiod. Additional anatomical studios havo
axaminad connoctions botwoon thoso sitos in an attampt to
construct a noural pathway for lordosis bohavior. Tho
following paragraphs roviow tho .critoria for idantifying
sitos, tho proposad influonco of soma of thoso sitos, and
thair connoctions. It should bo roalizad that soma portions
of tho ”pathway" aro still highly spaculativa.

Lordosis bohavior occurs in rosponso to stimulation by
tho malo. Tho tactilo information from tho flanks and
parinaum of tho fomalo is carriad by tho pudondal norvos and
asconds in tho antarolataral columns of tho spinal cord
(Kow, Hontgomary & Pfaff, 1977). Tho location of torminals
of thoso ascanding antarolataral fibors coincida with tho
location of nourons that rospond to lordosis-rolavant
somatosansory stimuli (Halsbury, Kallay & Pfaff, 1972;

13

Hahlar, 1969); thoso nourons aro in tho "CG and surrounding
subtactal ragions. Carrar (1978) has suggastod that ono of
thoso othar midbrain sitos is tha paripaduncular nuclous
(PPN). It is possiblo, howovor, that tho PPN also contains
fibors or nourons which sand fibors to tho HCG.

On tho offaront sido of tho noural circuit controlling
tha lordosis raflax, it is known that tho motonourons of tho
axial musculaturo rocoivo input from roticulospinal nourons
(Brink, Hodianos & Pfaff, 1981). Thoso roticulospinal
nourons originato in tho modullary roticulum and aro
involvod in tho control of lordosis (Hodianos & Pfaff, 1976,
1979). Naurons in tho HCG progact to tho modullary coro,
prasumably modulating its activity (Sakuma a Pfaff, 1980a,
1980c). Tho circuitry nocossary far axacution of tho
lordosis roflas is tharoforo complata at tho laval of tho
midbrain in that affaront and offaront pathways convarga in
tho HCG (Sakuma a Pfaff, 1979a; Pfaff, 1980). Tho HCG is
thus thought to bo an araa of intagration botwoon tho
diancaphalic ostrogon-concantrating araas (which influonco
HCG activity via doscanding pathways as Just discussod) and
tho sansory and motor pathways involvod in tho lordosis
roflox (Pfaff, 1980). Losions of tho HCG also disrupt
hormona-activatad lordosis bohavior, as would ba axpoctad if
it is an intarfaco botwoon facilitativo doscanding
influoncos and tho actual roflaxivo componants of tho noural
circuitry for lordosis bohavior (Sakuma & Pfaff, 1979b). Of
particular noto is tho finding that HCG stimulation producos

14

a vary short-latancy facilitation of lordosis, and tho
facilitation disappoars with cossation of tho stimulation
(Sakuma & Pfaff, 1979a). This aay indicata (in support of
tho suggastion of Pfaff/Sakuma) that tho "CE is a part of
tho “final common pathway” loading to tho spinal mochanisms
diroctly rosponsiblo for tho lordosis roflox. In
contradiction to tho apparantly consistant modal prasantad
by Pfaff and co-workors, Arandash & Gorski (1983) havo
racontly raportad that alactrical stimulation of tho HCG
supprassas lordosis bohavior. Tho roason for this
difforanca in rosults is unclaar.

Tho activity of HCG nourons is in turn influoncad by
ostrogon diroctly and also by doscanding influoncos from tho
forabrain. In particular, tho HCG racoivos input from tho a
variaty of staroid-concantrating araas known to bo involvod
in tha rogulation of lordosis bohavior. Host notablo among
thoso aro tho praoptic araa (FDA) and tho vantromadial
nuclous (VHN) (Sakuma & Pfaff, 1980 b, c). Tho anatomical
connoctions botwoon tho hypothalamus (VHN and FDA) and HCG
havo boon cloarly ostablishod (Conrad & Pfaff, 1976a,b;
Kriogar, Conrad & Pfaff, 1979).

Intagrity of tho connoctions botwoon tho VHN and tho
midbrain aro important for tha axprassion of
ostrogon-plus-progastarona activatad lordosis bohavior
(Lopoz & Carror, 1982; Edwards & Pfoiflo, 1981). It has
boon proposad that tho bad nuclous of tho stria torminalis
and tho lataral amygdala aro rolay stations botwoon tho

15

paripaduncular nuclous (PPN) and VMN (Lopoz A Carrar, 1982).
Tho PPN may ho a rolay point for information ascanding via a
lataral pathway to tha VHN; doscanding information also
travols from VHN toward PPN in this sama lataral pathway.
Edwards A Pfoifla (1981) havo shown that disruption of
fibors that pass from tho VHN through tho paripaduncular
ragion to tho HCG producos daficits in hormona-activatad
lordosis bohavior. Asymmatrical damago to this lataral
pathway (parasagittal knifa cut on ona sido, PPN ragion
losion on tho othar) also disruptad hormonal activation of
lordosis. Honogua, Kow A Pfaff (1980) havo also
domonstratad that disruption of tho connoctions botwoon VHN
and pariaquoductal gray producos daficits in
hormona-activatad lordosis bohavior.

Lasions in cortain forabrain araas disrupt
hormono-activatad lordosis bohavior, prasumably by ramoving
a facilitativo input to tho midbrain circuitry (a.g.,
vantromadial nuclous of tho hypothalamus IVHN, Carrar, Asch
A Aron, 1973; Kannady, 1964; Hathaws A Edwards, 1977;
Hathows, Donovan, Hollingsworth, Hutson A Dvorstraot, 1983;
Pfaff A Sakuma, 1979a; Sakuma A Pfaff, 1980c), tho habanula
[Hodianos, Hitt A Floxman, 1974; Hodianos, Hitt A Popolow,
1975], tho antarodorsal hippocampus ICamoron, Gaga, Hitt A
Popolow, 1979] and tho antarior portion of tho madial
amygdaloid nuclous [fiasco A Carror, i980]. Tho facilitativo
rolo of thoso araas is also supportod by tho finding that
alactrical stimulation of tho VHN (Pfaff A Sakuma, 1979b) or

16

madial amygdaloid nuclous (fiasco A Carrar, 1980) will
incroaso soxual rocoptivity. It has boon proposad that tho
bohavioral affoct of stimulation of tho VHN is duo to a VHN
stimulation-inducod incroaso in oxcitability of HCG nourons
as has boon domonstratad alactrophysiologically (Sakuma A
Pfaff, 1980b,c). Consistant with this suggastion is tho
finding that stimulation of tho HCG itsolf loads to a
dramatic incroaso in lordosis roflox scoros in
ostrogon-primod famalas (Sakuma A Pfaff, i979a).
Furthormora, HCG lasions disrupt lordosis bohavior, whothor
activatad by hormonos alono or by alactrical stimulation of
tho VHN following ostrogon priming (Sakuma A Pfaff, 1979b).

On tho basis of olactophysiological avidanca, it appaars
oxtromoly unlikoly that thoso forabrain araas involvod in
hormono-inducod saxual rocoptivity (a.g., VHN) aro involvod
diroctly in tho roflax circuit (Pfaff A Sakuma, 1979a).
Instaad, thoso araas modulato tho oxcitability of tho
midbrain lordosis raflox circuit. On tho basis of a variaty
of studios, it has baan suggastod that “tho rolo of tho
vantromadial nuclous of tho hypothalamus can bo doscribad as
a tonic ostrogan~dapandant facilitation of supraspinal
mochanisms which control lordosis and aro locatad moro
caudally in tho brain stam“ (Honogua, g; 31,, 1980, p.
277).

Tho hormono-dopondanco of this facilitativo input has
boon axaminad by othar workars. Using tho logic that a sito
which is involvod in tho rogulation of soxual bohavior

17

should also rospond to hormono following rostrictod
intracranial application, tho hypothalamic VHN has boon
idantifiad as a sito of hormono action in tho rogulation of
ostrus bohavior (soo Barfiold, Glasar, Rubin A Etgon, 1984,
for roviow). Barfiold A Chan (i977) and Rubin A Barfiold
(1980) domonstratad that ostradiol implants in tho VHN waro
affactiva in priming tha animals so that thoy bocamo
rosponsivo to tho bohavioral affocts of systomically
administarod progostorono. This affoct is spocific for tho
VHN and thoso implants appaar to oxposa only tho modiobasal
hypothalamus to ostrogon, as ravoalad by autoradiography
(Davis, HcEwan A Pfaff, 1979; Davis, Kriagar, Barfiald,
HcEwon A Pfaff, 1982). Thus tho VHN has boon shown to bo an
important sito of ostrogon action.

Using tho sama mothods, tho VHN has also boon shown to
bo an important sito for progostorono action following
ostrogon priming. Progastarona implants in tho modiobasal
hypothalamus/VHN affactivoly activato saxual rocoptivity in
ostrogon-primod fomalo rats (Powors, 1972; Rubin A Barfiald,
1983b, 1984). As with ostradiol, tho sproad of tritiatod
progostorono from tho implant sito was rostrictod to tho VHN
(Rubin A Oarfiold, 1983a). Tho VHN has also boon indicatod
as a sito important for tho progostorono-inducod saquantial
inhibition phonomanon (Rubin A Barfiald, 1984).

Using a similar approach, Glasar A Barfiold (1984) and
Rainbow, HcGinnis, Davis A HcEwan (1982) domonstratod that
application of tho protoin synthosis inhibitor anisomycin to

18

tha VHN provontod tha induction of rocoptivity by systomic
ostrogon plus progostorono traatmant. Thoso rosults
domonstrato that tho VMN is an important sito of
progostorono action in tha induction of soxual rocoptivity,
and that protoin synthosis in tho VHN is roquirad for
progostorono-inducod soxual rocoptivity in ostrogon-primod
fomalo rats.

Evidanca concarning tho bohavioral affoct of
progostorono application to tho midbrain is contradictory.
Ross, Claybaugh, Clamons A Gorski (1971) raportad that
progostorono implantad into tho masancaphalic roticular
formation (HRF) facilitatad lordosis bohavior in
ostrogon—primod OVX rats. In this study, ostrogon priming
could ba accomplishad through systomic injaction of
ostradiol banzoato (E8) or diract implantation of EB into
tho HRF. In famalas primod with systomical injactions of
a3, HRF application of oithar progostorono or E8 offactivoly
inducod rocoptivity. Thoso rosults indicata tho "RF is a
bahaviorally important sito of action for both ostrogon and
progostorono. It is intarosting to noto that VMH implants
of progostorono waro found to bo inaffactivo (but soo
Barfiald and othars abova). In contrast, othars havo found
hormono traatmonts of tho HRF to bo bahaviorally inaffactivo
(Powors, 1972; Rubin A Barfiold, 1983b, 1984). Furthormora,
application of tho protoin synthosis inhibitor.anisomycin to
tho intarpoduncular araa of tho MRF did not provont
hormono-inducod rocoptivity. Thoso rosults, in conflict

19

with thoso of Ross g;_‘LL, indicata that hormono action
within tho HRF is not critical for hormonal induction of
rocoptivity.

It is unclaar how hormono oxposura to a singlo sito, tho
VHN, can induco saxual rocoptivity. Cortainly,
hormono-inducod saxual rocoptivity involvas tho VHN. It is
still somowhat surprizing that activation of a singlo
'modulatory' sito can activato astrous bohavior. Tho VHN
must bo a particularly critical sito, as its influonco on
tha HCG must ovarcoma tho absanca in activation in othar

portions of tho systom.

In contrast to tho facilitativo rolo of tho VHN and
othar sitos discussad so far, an inhibitory rolo has boon
proposad for savaral othar diancaphalic and toloncaphalic
araas. This proposal is basad on tha finding that lasions in
thoso araas facilitata tho axprassion of astrogon-activatad
lordosis. This ignoros tho possibility that a losion may
load to raorganization instaad of a simpla loss of function
(Clamans, 1978). Araas idantifiad in this way includa tho
madial praoptic araa (HPOA, Powors A Valanstain, 1972),
lataral saptum-bad nuclous of tho stria torminalis (Gorzalka
A Gray, 1981; Nanca, Shryna A Gorski, 1975; McGinnis A
Gorski, 1980), olfactory bulbs (Lumia, Hoisol A Sachs,
1981), and tho postarior portion of tho lataral amygdaloid
nuclous (Hasco A Carror, 1980). Eloctrical stimulation in
soma of thoso araas supprassod hormono-activated rocoptivity

20

(saptum, Zasorin, Halsbury A Pfaff, 1975; "FDA, Napoli,
Powors A Valanstain, 1972; Sakuma A Pfaff, 1979b; lataral
amygdaloid nuclous, fiasco A Carror, 1980), furthor
indicating thair inhibitory rolo. Finally, rovorsiblo
”lasions" can bo producod by blocking protoin synthosis in
localizod brain araas. Infusions of cyclohakimido into tho
lataral saptum, cortical amygdala, or madial praoptic araa
producos facilitation of lordosis in ostrogon-primod OVX
rats (Ronnar, Bast, Purcoll A Ouadagno, 1981); crystallino
application of anisomycin to tho POA also facilitatas
lordosis (Hoisol A Pfaff, 1983). As suggastod by Haisal A
Pfaff (1984), it appaars that gonadal hormonos may dapross
protoin synthosis in soma (lordosis-inhibiting) brain araas
in ordor to bring about soxual rocoptivity. Tho rola of tho
POA in sokual rocoptivity has tharoforo boon doscribad as an
inhibitory modulator, rathar than a primary affactor, of
storoid-inducod saxual rocoptivity (Ronnar g;_g1‘, 1981).

This intorprotation is similar to that of Pfaff A Sakuma

(alroady doscribad).

21

W2:

Honoaminas

Tho oarliast raports of monoaminargic psychopharmacology
and saxual bohavior domonstratad that monoaminos waro
involvod in saxual rocoptivity, but tho drugs usad
(monoamina oxidasa inhibitors and rouptaka inhibitors) woro
not solactivo for ona or tho othar of tho monoaminos
(sarotonin, dopamina, norapinaphrino, and opinaphrina). It
was novortholass possiblo to concludo that olovation of
brain monoaminos through blocking rouptaka or dagradation
roducod lordosis bohavior in ostrogon plus progostorono
primod fomalo-rodonts (Hoyorson, 1964, 1966). Tho studios
that havo followod havo triad to idantify tho contribution
of individual monoamino transmittars involvod in tho
rogulation of saxual rocoptivity through tho usa of moro
solactivo pharmacological tools.

An inhibitory rolo of sarotonin (5-hydroxytryptamino, or
5-HT) in tho rogulation of fominino saxual bohavior was
proposad ovor 2O yoars ago (Hoyorson, 1964), but this
suggastion ramains controvorsial (Ahlanius, Engol, Erikkson,
Hodigh A Sodarstan, 1975; Cartar A Davis, 1977; Clamans,
1978; Crowlay A Zamlan, 1981; Hoyarson, Palis A Siatniaks,
1979). Sorotonorgic transmission has boon manipulatad at
tho lovol of synthosis, storago, roloaso, racoptors, and
dagradation in attampts to moro cloarly dafina tho rolo of
sarotonargic transmission in saxual rocoptivity.

22

Lordosis bohavior is facilitatod in ostrogon-primod
fomalo rats by systomic inJaction of tho sarotonin synthosis
inhibitor, para-chlorophonylalanino (pCPA; Ahlonius It.
gL., 1975; Evaritt, Fuxa A Hokfolt, 1974, 1975a; Evaritt,
Fuxo, Hokfolt A Jonsson, 1975b, 1975c; Hayarson A Lawandor,
1970; 1amlan, Hard, Crowlay A Hargulos, 1973. This affoct
of pCPA may bo indapandont of its action on cantral
sarotonargic naurotransmission, howovor. PCPA is convortad
to pCPEA (p-chlorophonylothylamino); pCPEA producos a
transitory doplotion of catacholaminos and diroctly
stimulatos lordosis bohavior (Nilson, lonnoy, Evorard,
Parrott A Nisa, 1982). Tho doplotion of catacholaminos
following pCPA traatmant corralatos with tho short-latancy
of pCPA to facilitata lordosis (Ahlanius, Engal, Eriksson,
Nodigh A Sodarstan, 1972) and not with tho long latancy
raquirod for sarotonin doplotion. Furthormora, bansarazido,
which provonts convarsion of pCPA to pCPEA, provonts both
pCPA-inducod rocoptivity and tho pCPA-inducod doplotion of
NE, whilo not provonting 5-HIAA doplotion (Hilson gg__.L.,
1982). It has boon suggastod that pCPEA also causas a briof
roloaso of 5-HT, and that this is rosponsiblo for tho
short-tarm facilitation of lordosis by pCPA (Nilson It.
‘1‘, 1982).

In addition to facilitating lordosis bohavior, pCPA has
boon raportad to dacraaso lordosis rosponding in ED plus P
primod sosually racoptivo famalas whon givan rapaatadly or
at longor intarvals ( > 24 hours) boforo priming (Emory A

23

Larsson, 1979; Gorzalka A Hhalan, 1975; Sagal A Hhalon,
1970; Singar, 1972). This typo of ragiman is most affactivo
in roducing brain 5-HT lovols. Hilson g;_.1‘_ (1982) and
othars havo suggastod that sarotonin has biphasic affocts on
aauual bohavior; tho initial incroaso in sarotonin roloaso
facilitatas lordosis bohavior, whilo sustainad olovation or
doplotion inhibits lordosis.

To furthor complicata mattars, thoro is avidanca that
pCPA may stimulato tho roloaso of progostorono from tho
adranal gland (Nilson g§___.1., 1982). Thus, tho
adranal-darivod progostorono may bo rosponsiblo for tho
pCPA-inducod facilitation of lordosis. Adranalactomy should
than provont tho PCPA facilitation of lordosis, and this has
boon obsorvad by soma (Eriksson A Sodarstan, 1973; Gorzalka
A Nhalon, 1975) but not all (Evoritt g;_g1., 1974, 1975b,
1975c; Zamlan g;_gL‘, 1973) invastigators.

Thus, studios of pCPA and saxual rocoptivity havo
indicatod that pCPA can daplata sarotonin, daplata NE and DA
briofly, facilitata lordosis with an intarmadiato latancy
(1-8 hr), and inhibit lordosis with long latancy ( > 24
hours). Adranal progostorono may also provido a
non-naurochamical ouplanation for tho facilitativo influonco
of pCPA on lordosis bohavior.

Rasults with othar daplators of 5-HT havo boon no loss
confusing. Tho drug pCA (p-chloroamphotamino) is both a
doplotor of sarotonin in tho long-tarm and an indiract
short-torm sarotonin agonist bacauso it causas roloaso of

24

5-HT. Lordosis was inhibitod by pCA 30 minutas aftor
inJoction in fomalo rats mada racoptivo with an plus P '
priming (Yamanouchi, Hatanabo, Okada A Arai, 1982). Othor
invostigators havo found an inhibitory affoct of pCA in
ostrogon-plus-progastorona primod famalas, whilo it was
without affoct in animals primod with ostrogon alono
(Sodarstan, Bargo A Hola, 1978; Zomlan, Trulson, Howoll A
Hoabol, 1977).

Chamically-inducad 5-HT danarvation of tho hypothalamus
by inJaction of tho nourotouin 5,7-DHT into tho madial
mosancophalic 5-HT bundlos facilitatas lordosis in
ostrogon-primod famalas (Evaritt, Fuxo A Jonsson, 1975d).
This facilitation was waak, howovor, and was obsorvad only
100 days aftor losion (and not at somo aarliar timo points
aftor lasion). In anothar study (Sodorstan gg_.L;, i978),
5,7-DHT chomical lasions waro inaffactivo in facilitating
lordosis. A moro rocant study (Luina, Frankfurt, Rainbow,
Biagon A Azitia, 1983) has domonstratad tho “rapid, dramatic
and roliabla incroaso in lordosis bohavior whon 5,7—DHT is
appliod diroctly within tho hypothalamus“. In this study,
famalas with 5,7-DHT lasions woro moro racoptiva following
an priming than tho control animals in tosts 9 to 14 days
postrlasion. Thoso authors suggastod that tho lasions in
tho othar studios may havo boon inaffactivo bacauso thoy
sparod an important midbrain-hypothalamic sarotonargic
projoction, or altornativoly that tho important sarotonargic
progaction is intrahypothalamic. Ragardlass of tho roason

25

for tho difforancas in rosults botwoon thoso studios,
intorprotation of thoso rosults is difficult. Nhilo 5,7-DHT
lasions may facilitata lordosis bohavior by ramoving an
inhibitory sarotonargic influonco, it is also possiblo that
thoso lasions induco danarvation suporsansitivity to 5-HT.
This lattar intorprotation would indicata a facilitativo
rolo of 5-HT; racoptor assay data aro nocossary to rulo out
this possibility. Luino g:__.1‘, ouaminod imipramino
binding to maasuro 5-HT torminals; whilo prasynaptic
torminals woro roducod, thoso authors mada no maasuramants
of postsynaptic racoptor lovols.

Using 5-HT racoptor agonists, both stimulatory and
inhibitory affocts on lordosis havo boon raportad, and tho
affoct saoms to bo dosa-rolatod (sao Crowlay and Zamlan,
1981). For auampla, in ostrogon-primod fomalo rats, LSD
(5-20 uglkg) facilitatod lordosis bohavior, whilo low and
high dooas (1 and 404ug/kg, raspactivoly) waro inaffactivo
(saa Evoritt g§__.L., 1975c). In ostrogon-progostorono
primod rocoptivo famalas, howovor, 5-HT agonists such as
LSD, psilocybin, dimathyltryptamina, p-chloroamphatamino,
alpha mothyl tryptamina and fanfluramina supprass lordosis
bohavior (Eliasson A Hoyorson, 1977; Espino, Sano A wads,
1975; Evaritt A Fuxa, 1977b; Evaritt g;_.L;, 1974, i975b,
1975c; Hichanok A Hoyorson, 1977; Yamanouchi, Natanaba,
Okada A Arai, 1982). It has boon suggastod that low dosas
of agonist proforantially activato tho prasynaptic
autoracaptors loading to a dacraaso in 5-HT roloaso (and

26

facilitation of lordosis), whilo highor dosas activato
postsynaptic racoptors (and inhibition of lordosis
pradominatas).

Intracorobral infusion of 5-HT itsalf was inaffactivo in
facilitating lordosis in astrono-primod fomalo rats, but
5-HT did inhibit lordosis in modarataly rocoptivo famalas
primod with a highor dosa of astrono (Foraman A Boss,
1978b). Tho inability to produco facilitation of lordosis
with 5-HT apparantly contradicts tho proposal by Hilson It.
‘1‘,(1982), that sarotonin is nocossary for lordosis.
This contradiction rosults only if ona assumos that tho
infusions by Foraman A floss into NPOA and
arcuata-vantromadial hypothalamus dafinitoly oxposod tho
critical nourons to 5-HT, and that tho singlo dosa of 5-HT
infusod producod tho propar drug concantration at thoso
nourons for facilitation. Thoso assumptions aro not
warrantad on tho basis of currontly availabla avidanca.

Disruption of sarotonargic transmission with tho
racoptor antagonists mothysargido and cinansarin facilitatod
lordosis, and tho facilitation is indopandont of tho adranal
gland (Evaritt 83.11;: 1974, 1975b; Foraman A floss, 1978b;
Honrik A Gorall, 1976; Hard, Crowlay A Zamlan, 1975; Zamlan
mm-

In summary, thoro is avidanca, albait somawhat confusing
and contradictory, to support tho proposal that sarotonin
inhibits fominino saxual bohavior. Tho data aro also
consistant in damonstrating that low dosas of agonists

27

facilitata lordosis. This has lad to tho suggastion that
thoro is solactivo activation of autorocaptors at low
agonist dosas, which raducas andoganous 5-HT and causas an
incroaso in lordosis bohavior. Tho multiplo affocts of soma
drugs that havo boon usad (a.g., pCPA) has also addod to tho
confusion. Tho possibility that adranal staroids modiato
tho sarotoninargic facilitation of lordosis has boon largoly
aucludod in savaral paradigms, aspacially in tho casa of

antagonists.

Norapinaphrina (NE) has boon suggastod as a transmittar
that facilitatas lordosis bohavior (Evoritt g;_.1., 1975b,
1975c), but tho rolo for adranargic transmission is
novortholoss unclaar (Crowlay A Zoolan, 1981). Soma of tho
confusion may bo duo to tho multiplo racoptor typos for NE
and opinophrino, and tho varying soloctivity of drugs for
ono or tho othar of thoso typos of sitos. In addition,
savaral of tho drugs usad to study tho adranargic rogulation
of samual rocoptivity also affoct tho othar monoaminos,
dopamino and sarotonin. Thus, drug studios using
alpha-mathyl-para-tyrosina (a tyrosino hydroxylasa
inhibitor), amphataminos (which roloaso catacholaminos) and
rasarpino (which disrupts rouptaka) ara not as solactivo as
is nocossary for a dotailad pharmacological analysis.
Similarly, rosults discussad aarliar with pCPA and pCPEA
suggost that raduction in hypothalamic NE and/or DA may bo

28

involvod in tho facilitation of lordosis by thoso drugs
(Nilson gt_gl‘, 1982), but it is difficult to saparato
thoso affocts from thoso on sarotonin systoms. Tho approach
of tamporally corrolating tha naurochamical affocts of a
drug with its bohavioral affocts and proposing a spocific
rolo for a givon transmittar on that basis is waak,
aspacially for drugs with multiplo actions.

Studios using NE itsalf havo also yialdod conflicting
rosults rogarding tho rogulatory rolo of NE on saxual
rocoptivity. Third vontricular infusion of NE roducod
lordosis bohavior in OVX, 88 plus P primod famalas as wall
as in ED + pCPA traatad famalas (Hilson g;__‘L‘, 1982).
Caldwoll (1983) has also raportad that infusion of NE into
tho HPOA inhibitod lordosis bohavior in 88 plus P primod
rocoptivo fomalo rats, and this inhibition was ravarsad by
simultanaous infusion of tho alpha-2 adranargic blockar
yohimbina (but not by tho alpha-1 antagonist phontolamina).

Clonidino (an alpha-2 agonist) and apinaphrino waro also
found to inhibit lordosis in Caldwoll’s (1983) study.
Clonidino had proviously boon raportad to inhibit lordosis
with short latancy following intracorabral infusion (Davis A
Kohl, 1977). Foraman A floss (1978a) also found clonidino to
inhibit lordosis. Tho clonidino (and NE) supprassion of
lordosis may ba duo to activation of prasynaptic alpha-2
racoptors, as tho clonidino affoct was blockad by yohimbino,
a prasynaptic (alpha-2) blockar, but not by
phanoxybonzamino, a postsynaptic (alpha-1) blockar.

29

Furthormora, Evaritt g;_.LL, (1975b, 1975c) raportad that
tho alpha-2 blockars yohimbina and piparoxano facilitatod
lordosis. Thus it appaars that activation of alpha-2
racoptors supprassas lordosis bohavior, whilo alpha-2
blockada facilitatas lordosis. Tho suggastion that tho
alpha-2 sitos madiating tho adranargic inhibition of
lordosis aro prasynaptic has boon challangod, as not all
alpha-2 racoptors ara prasynaptic (sao Caldwoll, 1983, for
discussion).

If tho lordosis-supprassing affoct of alpha-2 racoptor
acivation is duo to actions at a prasynaptic autorocaptor,
than this indicatos that a raduction in NE outflow
supprassas lordosis, a.g., lordosis is facilitatod by NE.
Caldwoll (1983) axaminad this possibility diroctly, and
found NE did not facilitata lordosis aucapt at a high dosa
(20 ug) which ha considarad dabilitating to tho animals. As
alroady notod, Hilson “—31” (1982) also found an
inhibitory affoct of NE infusion on horaono-activatad
lordosis bohavior. Thus, from thoso studios tho rolo of NE
appaars to ba inhibitory rathar than facilitativo.

In anothar study, howovor, NE microinfusion into tho POA
or VHH facilitatod lordosis in ostrogon-primod fomalo rats
105 minutas aftor infusion (Foraman A floss, 1978a). This
facilitativo affoct of NE was mimickad by tho bata racoptor
agonist isoprotaranol. Hhilo tho proposal of a facilitativo
rolo of bata racoptor activation is strongly supportod by
tho finding that infusion of tho bata blockar propranolol

30

roducod lordosis in ostrogon-primod famalas, it also
diroctly contradicts tho aarlior finding that bata blockars
facilitata lordosis (Hard gL_gL., 1975). Tho bohavioral
affocts of adranargic drugs obsorvad by Foraman A floss had a
long latancy (105 minutas to poak affoct) and roquirod
rapaatad matings to occur. Thoso lattar factors raisa tho
possibility of adranal storoid madiation of this affoct. In
ganaral, paradigmvdopandont and long-latancy affocts of this
sort cannot raasonably bo attributad to a
naurotransmittar-dopondant machanism. Tho contradictions
botwoon onparimontars, who aach usa thair own hormono
priming ragimons, drug dalivary locations and routas, and
bohavioral tosting schadulos aro outramoly difficult to
rosolvo. Finally, soma oxporimanal ragimons which usa
ropaatad tasting and long latancios to tasting do not
adaquataly control for tho possibility of roloaso of adronal
staroids, which could potantially facilitata lordosis
bohavior in astogan-primod famalas.

In summary, tho usa of racoptor subtypa-solactiva
agonists and antagonists has lad to tha proposal that
activation of alpha-2 racoptors inhibits lordosis. Othor
suggastions havo also boon mada, but tha rolo of tho alpha-2
racoptor saoms to ba tho only point on which thoro is soma
agroomant. It can bo disputad whothor thoso alpha-2
racoptors aro prasynaptic, rosulting in a dacraaso in NE
outflow, or postsynaptic, rosulting in NE-liko agonistic
actions. As a rosult, thoro is still confusion ovor tho

31

rolo of NE, dospito tho fact that tho action of ono class of
racoptor agonists is agraad upon. Evary possiblo
combination of alpha-1, alpha-2, and bata racoptors with
inhibitory and facilitativo rolas has boon proposad. Tho
rolo of adranargic transmission in tho rogulation of saxual

rocoptivity is obviously unclaar.

Dopamina (DA) has boon suggastod to ba inhibitory to
sasual rocoptivity. This suggastion is supportod by tho
finding that DA agonists supprass lordosis, whilo DA
antagonists activato lordosis (citations bolow).

DA racoptor stimulants (a.g., apomorphina, ET 495)
supprass lordosis in ostrogon plus progostorono primod
fomalo rats (Evaritt ML... 1974, 1975b, 1975c; Hayorson,
Carrar A Eliasson, 1974). Amphatamino, a roloasar of
catacholaminos, also supprassos lordosis, although this
affoct is not cloarly rolatod to DA alono (Eliasson,
Hichanok A Hoyorson, 1972; Hoyarson, 1968; Hichanak A
Hayarson, 1977). Tho affocts of agonists havo boon
doscribad as biphasic or dosa-dopondont, howovar; low dosas
of agonist facilitata lordosis in ostrogon primod fomalo
rats, and highor dosas disrupt rocoptivity in ostrogon plus
progostorono primod famalas (Evaritt A Fuxa, 1977a;
Hamburgar-Bar A Rigtor, 1975). This dosa-dapandancy is
thought to bo duo to tho activation of prasynaptic
”autorocaptors“ by low dosas of agonist, which results in
docroasod DA roloaso and hence 3 facilitation of lordosis.

32

Highar dosas aro thought to act diroctly at tho postsynaptic
racoptors to inhibit lordosis. Littlo has boon dona to
rigorously tost this sita-of-action hypothasis for tho
dosa-dapandont affocts of dopaminorgic drugs.

Consistant with tho proposad inhibitory rolo of DA aro
studios damonstrating that DA antagonists (pimozido,
spiroporidol) activato lordosis in ostrogon-primod fomalo
rats (Evaritt gg_.L‘, 1974, 1975b, 1975c). Tho finding
that intravantricular infusion of tho catacholamino
naurotox i n , 6-hydrokydopami no, i ncraasad l ordosi s bohavi or
is also consistant with tho proposad inhibitory rolo of DA
(Caggiula, Horndon, Scalon, Groanstona, Bradshaw A Sharp,
1979; Horndon, Caggiula, Sharp, Ellis A Radgata, 1978).
This tochniquo is not prociso or solactivo anough to allow
ona to concludo with cartainty that tho obsorvad bohavioral
affoct is duo to dastruction of DA nourons alono, howovor.

Using intrahypothalamic (HPOA or ARC-VHH) infusion of DA
or tho DA agonist apomorphina, Foraman A Moss (1979)
domonstratad a facilitation of lordosis in astrono-primod
OVX fomalo rats. Infusion of tho DA antagonists haloparidol
and alpha-flupanthixol to thoso samo araas daprossad
lordosis bohavior in famalas mada rocoptivo with a high dosa
of astrono. This study, which damonstratas a long-latancy
facilitativo rolo of DA on lordosis bohavior, may diffar
from othars bacauso of sita-spocificity in tho rosponso;
a.g., tho rosults of systomic traatmant may diffar from
intrahypothalamic infusion. It is also impossiblo to

33

comparo tho systomic and intracorabral dosas to soo if tho
infusions produca “low“ dosas of agonist which would act
proforantially at tho autorocaptors. Thoso authors havo
proposad that DA facilitatas lordosis, and that DA doas so
by stimulating lutainizing hormona-raloasing hormono (LHRH)
roloaso. (Tho psychopharmacology of LHRH will bo discussad
latar in this soction.) LHRH is in turn dapandant upon
dopaminorgic nourons for its affactivanass, suggasting a
positivo foodback loop rolationship. It saoms unlikoly that
tho facilitativo affoct of DA on lordosis could ba madiatod
by LHRH, as LHRH takos savaral hours longor than DA to
produca its bohavioral affocts in tho hands of Ross and
co-workars. Tho affocts of LHRH as doscribad by thoso
workars raquiro a long latancy and rapoatad tasting,
although it has boon shown that thoy aro indopandont of tho
adranal and pituitary glands. Othor workars (a.g., Pfaff,
soo LHRH discusssion, balow) sao moro rapid, moro roliabla
and moro robust facilitation of lordosis by LHRH.

In summary, DA and DA agonists appaar to inhibit
lordosis bohavior in most studios, although tho
dosa-rosponso is biphasic. Soma studios citad in suppport
of an inhibitory rolo of DA aro not solactivo anough for DA
nourons or racoptors, although tho moro racant trand saoms
to bo toward improving this soloctivity through tho usa of

moro solactivo drugs. DA antagonists facilitata lordosis.

34

Gamma-aminobutyric acid (GAGA)

HcGinnis, Gordon A Gorski (1980) axaminad tho affocts of
altorations in GAGA transmission on hormono-dapandant
lordosis bohavior. Picrotouin, a GAGA antagonist, and
hydrazinopropionic acid (HPA), a drug which alovatos
andoganous GAGA lovols by inhibiting tho dagradatory anzyma,
GAGA transaminasa, waro usad. Picrotoxin infusion into tho
substantia nigra roducod rocoptivity in 88-primad famalas
with saptal lasions. Intranigral HPA facilitatod lordosis
in EG-primod sham animals. Thoso rosults aro consistant
with tho suggastion that GAGA facilitatas lordosis in OVX
fomalo rats. Giochamical avidanca prasantad in tho samo
papor indicatod that this affoct may ba oadiatod by
dopamino; auoganous intranigral GAGA raducas turnovar of
dopamino, and DA (from nigra and othar mosancaphalic araas)
inhibits lordosis (saa abova), so GAGA facilitatas lordosis
by roducing DA activity. Tho incroasad bohavioral
sansitivity of animals with saptal lasions to ostrogon may

bo duo to losion-inducad daprossion of DA lovols.

Lutainizing hormono-ralaasing hormono

Tho hypothalamic nauropaptida lutainizing hormono
ralaasing hormono (LHRH; also callad gonadotropin ralaasing
hormono, or GnRH) has boon shown to facilitata lordosis
bohavior following systomic injaction in ostrogon-primod OVX
rats (Moss A HcCann, 1973; Pfaff, 1973). In thoso first

35

studios, this ostrus-facilitating action was shown tov bo
indopandont of tho pituitary. Hora racont studios havo
domonstratad that intracranial application of LHRH also
facilitatas lordosis bohavior with short latancy, with tho
most affactiva sitos boing tho vontromadial-arcuato araa of
tho modiobasal hypothalamus, tho praoptic-antarior
hypothalamic araa, and tho HCG (Hoss A Foraman, 1976; Sakuma
A Pfaff, 1980, 1983; Rodriguaz-Siorra A Komisaruk, 1982;
Riskind A Ross, 1979, 1983). Tho spinal cord has also boon
indicatod as a potantial sito of LHRH action
(Sirinathsingh51, 1982). Considoring tho racont avidanca
from this laboratory concarning tho possiblo bohavioral
affocts rosulting from movomont of infusod substancos up tho
cannula tracks (Dohanich gt_gL‘, 1984), it appaars that
sits spocificity of rosponso may not ho a roalistic
aupactation.

Indapandanca of tho lordosis-facilitating affoct of LHRH
and rogulation of tho pituitary havo boon cloarly
domonstratad not only by tho usa of hypophysactomy, but also
by oxamining tho affactivanass of LHRH analogs to influonco
saxual rocoptivity and LH sacrotion. Studios of this typo
havo cloarly indicatod soloctivity difforancas botwoon tho
racoptors rogulating LHRH affocts on roproductivo bohavior
and LH sacrotion (Kastin, Coy, Schally A Zadina, 1980;
ladina, Kastin, Fabro A Coy, 1981; Sakuma A Pfaff, 1983;
Dudloy, Valo, Rivior A Moss, 1981). LHRH antisara havo also
boon usad, but tho rosults havo not boon consistant.

36

Infusion of LHRH antisorum disrupts astrogon-activatod
lordosis following infusion into tho HCG (Sakuma A Pfaff,
1980d, 1983) and tho third vantriclo (Kozowski A Hostottar,
1978), whilo third vontriclo infusions into naturally
cycling proastrus famalas waro inaffactivo (Coopar, Sappala
A Linnoila, 1984), parhaps bacauso of synargism botwoon E
and P in tho intact famalas. Intracorobral application of
LHRH antisora into tho vontromodial-arcuata ragion (Dudloy
IL_.L,, 1981) and tho madial praoptic araa (Coopar It.
gL., 1984) waro inaffactivo in disrupting
astrogon-activatad lordosis bohavior, parhaps indicating
that LHRH nouromodulation/ naurotransmission in thoso sitos
is not as important as it is in tho midbrain for tho
ouprassion of lordosis bohavior. Altarnativaly, variation
botwoon tho antisora usad could ba rosponsiblo for tho
discrapancy botwoon sitos axaminad in difforant

laboratorias.

Okytocin and vasoprossin

Oxytocin and vasoprossin aro poptidos producod primarily
by colls in tho supraoptic and paravontricular nuclai of tho
hypothalamus. Thoso nourons proJact to tho postarior
pituitary and roloaso thair poptidos into tho circulation
thoro. Additional projactions and sitos of origin of
ouytocinorgic and vasoprossinorgic calls within tho brain
havo racontly boon doscribad (Caffa A van Laouwan, 1983;
Sofroniaw A Hoindl, 1981; Van Loouwan A Caffo, 1983),

37

raising tho possibility that thoso poptidos also function as
nauromodulators or nourotransmittors in tho cantral norvous
systom. Accordingly, thoso poptidos havo racontly boon
invostigatad for affocts on hormona-dapondant saxual
bohavior.

Intracorobral oxytocin traatmant facilitatas soxual
rocoptivity in ostrogon-primod fomalo rats (Caldwoll,
Podarsan A Pranga, 1984). Duo to tho fairly high laval of
8D priming usad, howovor, tho control animals also showod an
incroaso in lordosis ovor timo aftor infusion. Hhilo tho
ouytocin traatmont incroasod lordosis abova tho laval soon
in tho vohiclo controls, tho possiblo affoct of rapoatad
tasting was not controllod. It is novartholoss quita
apparant from this study that oxytocin can facilitata
lordosis bohavior.

Sodarstan, Hanning, Holin A Ludin (1983) havo racontly
shown that ICV ingoctions of vasoprossin (1 to 10 ng) can
inhibit saxual rocoptivity in rocoptivo rats. This affoct
was indopandont of altorations in blood prassura and its
spocificity was domonstratad by blocking it with

protroatmont with antisorum to arginino vasoprossin.

Othor poptidos
Sovoral othar hypothalamic and pituitary poptidos havo
also boon oxaminad for thair influonco on saxual
rocoptivity. Systamic injaction of alpha-NSH has boon
raportad to both potantiato and disrupt lordosis bohavior in
38

ostrogon plus progostorono primod fomalo rats, with tho
diroction of tho affoct dopanding on tho initial laval of

rocoptivity (Thody Hilson A Evorard, 1979, 1981; Hilson,
Thody A Evorard, 1979). In famalas primod with ostrogon
alono, HSH facilitatod lordosis in non-rocoptivo famalas but
did not inhibit rocoptivity in rocoptivo famalas.
Intracorobrovontricular infusions of HSH or ACTH‘-‘° also
facilitata but do not inhibit lordosis in E8 plus P primod
famalas.

Thoso studios aro plaguad with mathodological problams,
not tho loast of which is tha fact that NEH
inJaction/infusion occurs 4 to 6 hours boforo bohavioral
tosting. Hith such long latancy to drug affocts, tho
potantial for indiract (a.g., adranal) mochanisms for tho
activation of lordosis incroasos. Animals waro also
comparad for lordosis rosponsivanoss in rosponso to priming
(plus drugs) across succossivo waoks, without
countarbalancing tho drug ordor and without damonstrating
that rosponsos woro consistant from wook to wook. Finally,
tho division of animals into rocoptivo and non-rocoptivo
groups for analysis holps statistically, but it obscuras tho
largo variability in rosponso to tho priming ragiman usad in
control tasts. This highly variabla basalina may confound
or “produca“ drug affocts. Thus, whilo HSH has boon
raportad to influonco lordosis bohavior, tho dosa-dapondancy
and I"rata--dapandancy" of tho drug affoct maka this proposal
loss than compalling.

39

Adranocorticotrophic hormono (ACTH) stimulatos soxual
rocoptivity in ostrogon-primod fomalo rats whon administarod
systomically (do Catanzaro A Gorzalka, 1980; Fadar A Ruf,
1969), but thoso authors havo pointad out tho potantial for
an indiract mochanism involving activation of adranal
staroidoganasis and storoid sacrotion by ACTH. This
criticism is supportod by tho study of do Catanzaro, Gray A
Gorzalka (1991), in which ovx and OVX-adronalactomizod
ostrogon primod fomalo rats waro inJoctad systomically with
ACTH"’“. Adranaloctomy provontod tho facilitation of
lordosis obsorvad 120 minutas aftor ACTH“’* inJaction. No
facilitation occurrod in a tost 20 minutas aftor ACTHf-tf
inJoction. Systamic ACTH*-’4 tharoforo inducos saxual
rocoptivity by a long-latancy, adranal-dopandont mochanism
which is thought to roly on adranal sacrotion of progostins.
Tho proposal of a naurotransmittar or nauromodulator rolo
for ACTH is not nocossary to axplain tho facilitation of
lordosis following systomic administration.

In contrast to tho paripharal affocts of systomically
administarod ACTH"", intracorabrovontricular infusion .of
ACTH"" inhibitod rocoptivity in ostrogon-primod CV! and
adranalactomizad-OVX rats. This short-latancy (20 minutas),
contral affoct was indopandont of tho adranal glands. Thus,
it appaars that cantral ACTH can supprass lordosis bohavior
(do Cantanzaro gg_31,, 1981).

40

Data-ondorphin, anothar pituitary paptido from tho
proopiomolanocortin procursor moloculo, also influoncos
lordosis bohavior. Liko ACTH, bata-ondorphin has boon found
to raduco rocoptivity following intracorabral infusion;
affactiva sitos aro tho third vantriclo (Hoisnor A floss,
1984) and tho flCG (Girinathsinghgi, Hittington, Audsloy A
Frasar, 1983; Sirinathsinghji, 1984). In support of an
inhibitory rola of andoganous opiatos, intracorabral
nalouona infusion was found to facilitata lordosis in ona of
thoso studios (Sirinathsinghji ggdgL., 1983). Hhilo ona
study indicatos that systomic administration of an opiata
antagonist will facilitata lordosis (Allan, Ronnar A Luino,
1985) anothar study did not confirm this (Hoisnor A floss,
1984).

In summary, a variaty of poptidos havo racontly boon
shown to influonco lordosis bohavior. Evidanca is quits
consistant in indicating a facilitativo rolo of LHRH, which
is particularly intarosting sinco oxtrahypothalamic LHRH
contant appaars to bo modulatad by ostrogon (Shivars,
Harlan, floroll A Pfaff, 1983). It is tharoforo possiblo
that LHRH is an andoganous transmittar involvod in tho
ouprossion of hormona-dapondant fominino saxual bohavior.
Oxytocin also facilitatas lordosis, whilo vasoprossin
inhibits it. Systamic administration of alpha-flSH or ACTH
can facilitata lordosis, but intracorabral ACTH supprassos
rocoptivity. Gota ondorphin also suppresses rocoptivity,

41

and data using opiata antagonists indicata that andoganous

opiatas may normally inhibit lordosis bohavior.

65W

Tho influonco of acotylcholino on lordosis bohavior is
currontly tho main focus of savaral workars in tho Hormonas
and Gohavior Laboratory at flichigan Stats Univsrsity; ons
aspsct of cholinorgic function in tho rogulation of souual
rocoptivity is tha topic of this thasis. In ordor to
provido background matarial for tho discussion that will
follow, it is nocossary to includa a moro dotailad
dascription of cholinorgic transmission than was providod
for tho othar transmittars that havo boon discussad.

Acotylcholino was tho first naurotransmittar to bo
idantifiad, and it was among tho first to bs charactarizod
pharmacologically (sss flcGaor, Ecclos A flcGosr, chaptors 3
and 5 for roviow). Early work on tho autonomic norvous
systom idantifiad a sat of affocts which could bo attributad
to tho action of acotylcholino. Boss of thoso affocts of
acotylcholino waro found to bo mimickad by tho alkaloid
muscarino, whilo othar actions waro mimickad by nicotino.
Soma drugs, such as tho bolladonna alkaloids (atropinics)
waro found to solactivaly block tho “muscarinic“ affocts.
Othor drugs blockad I'nicotinic" affocts of acotylcholino and
nicotino. As tho pharmacology of acotylcholino davalopod,
so did tho concopt of two typos of racoptors, muscarinic and

42

nicotinic, which madiatod saparato subsots of tho affocts of
acotylcholino.

flora racont work has oxtandad tho muscarinic-nicotinic
dichotomy to tho control norvous systom. Soma bohavioral
affocts of acotylcholino havo boon analyzad
pharmacologically, and it has boon possiblo to attributs
soma affocts to muscarinic racoptors, whilo othar affocts
sasm to bo duo to nicotinic racoptors (a.g., Guccafusco A
Grozonoff, 1980; Schachtar A Rosacrans, 1971). Diract
avidanca for saparato populations of nicotinic and
muscarinic racoptors in norvous tissuo has boon providod by
racoptor assays. fluscarinic racoptors aro soloctivsly
labolad by radioactivo muscarinic antagonists (a.g.,
atropino, scopolamino, quinuclidinyl banzilata, N-mathyl
4-piporidyl banzilato) and agonists (cis
msthyldioxolano)(sas Kloog A Sokolovsky, 1978; Girdsall A
Hulmo, 1976 for citations). Tho addition of unlabolad
nicotino or macamylamina (a nicotinic antagonist) to tho
incubation sodium doas not raduco binding of tho labolad
muscarinic ligand, indicating that muscarinic racoptors do
not bind nicotinic drugs (Ehlart, Dumont, Roaska A Yamamura,
1980; Kloog A Sokolovsky, 1978; Yamamura A Snydar, 1974).
In contrast, unlabolad muscarinic agants raduco binding of
tho radioligand, indicating that muscarinic drugs compsta
with tho labolad ligands for muscarinic binding sitos.
Similarly, spocific nicotinic racoptors havo boon idantifiad
in binding studios with radiolabalod acotylcholino in tho

43

prssoncs of unlabolad atropino or with labolad nicotino
itsalf (Clarka, Schwartz, Paul, Port A Part, 1984; Rainbow,
Schwartz, Parsons A Ksllar, 1984; Romano A Goldstain, 1980;
Schwartz, flchs A Kollar, 1982). Rasults of compotitivo
binding studios indicata that thoso sitos aro solactivo, and
do not bind muscarinic agants with high affinity (Schwartz
IL 11., 1982; Romano A Goldstain, 1980). Ono aucoption

to this ganaral rulo is carbachol, which may bo liks
acotylcholino in binding both muscarinic and nicotinic
racoptors (Schwartz g1,gLL, 1982; Romano A Goldstain,
1980). flany oarly studios usad alpha-bungarotoxin as a
nicotinic racoptor ligand, but racont avidanca has indicatod
that alpha-bungarotoxin may not bind to tho sass population

of sitos as nicotino and acotylcholino (a.g., Clarko gt_
‘1‘, 1984).

WWW
Tho first studios analyzing tho influonco of tho

cholinorgic systom on saxual rocoptivity in rats usad
systomic drug troatmonts and wars parformad by Lindstrom
(1970, 1971, 1973, 1975; and Linstrom A floyarson, 1967).
Initial studios domonstratad an oarly (10 to 30 minuts
latancy) inhibitory affoct on lordosis aftor injaction of
muscarinic cholinorgic agonists, which was blockad by tho
muscarinic antagonist atropino. Tho inhibition of lordosis
by cholinorgic agonists was potantiatsd by protroatmont with
44

monoamino oxidasa inhibitors (pargylins, nialamids, or
dosmothylimipramino), and it was blockad by protroatmont
with monoamino daplators (pCPA, rasarpino, or
totrabonazins). Thoso lattar rosults suggastod an
intoraction with monoaminorgic systoms; sarotonin was
thought to ba involvod bacauso protroatmont with pCPA
blockad tho pilocarpins-inducsd inhibition of rocoptivity,
but tho tyrosino hydrouylasa inhibitor alpha-asthyl-
para-tyrosino did not. Considoring tho confusion rogarding
tho mochanism of action of pCPA, this conclusion saoms
promaturs.

Facilitation of lordosis by systomic traatmant with
cholinorgic agonists has also boon raportad (Lindstrom,
1975). Tho muscarinic agonist okotramorina was found to
incroaso lordosis bohavior in an primod OVX rats, and tho
facilitation was blockad by atropino. This cholinorgic
facilitation of lordosis was oliminatad by adranalactomy or
hypophsactomy (Lindstrom, 1973), howovor, indicating that it
may bo madiatod by adranal sacrotions. Consistant with a
facilitativo rolo of muscarinic cholinorgic transmission,
Singar (1968) domonstratad that atropino supprassas lordosis
in hormono-primod fomalo rats.

Thus, from thoso systomic studios it appoarod that
muscarinic cholinorgic drugs could oithar facilitata or
inhibit lordosis, and muscarinic antagonists inhibitod
rocoptivity.

Tho contribution of tho nicotinic racoptor in tho

45

rogulation of soxual rocoptivity was first assossod by Fuxo,
Evaritt A Hokfolt (1977). Thoso authors domonstratad that
systomic ianction of nicotino facilitatod lordosis bohavior
in EG-primad OVX rats 5 minutos aftor inJoction.
Pratroatmant with tho nicotinic racoptor antagonist,
macamylamina, complotoly provontod tho nicotino-inducod
facilitation of lordosis. In tho ramaindor of this study
and in a sariss of studios which followod, Fuxo gg__gL.
wars moro intarostad in tho possiblo intoractions of
nicotino with dopaminorgic systams than in tho cholinorgic
systom. As a rosult, thoy did not pursua tho potantial
influonco of othar nicotinic cholinorgic drugs on ssxual
rocoptivity.

A sariss of studios from this laboratory havo
domonstratad that intracorabral pharmacological stimulation
of cholinorgic racoptors stimulatos saxual rocoptivity in
ostrogon-primod OVX rats. This short-latancy, transisnt
affoct is ostrogon-dopondont, progostorono indopandont, and
indopandont of tho adranal glands.

Estrogan-dapondancy has boon domonstratad by showing
that cholinorgic agonists aro moro affactiva in facilitating
saxual rocoptivity aftor ostrogon priming, avan with vary
low dosas of ostrogon. Progastarona-indapondanco has boon
domonstratad by showing that tho cholinorgic facilitation of
lordosis occurs at lovols of ostrogon priming which aro
inaffactivo in facilitating lordosis in combination with
progostorono (Clomans g§__gLL, 1981). Only a singlo

46

progostorono dosa was usad in this study, howovor. Furthor
avidanca for progostorono—indapandanca comas from studios
damonstrating that cholinorgic agants can facilitata
lordosis Abshavior in ostrogon-primod animals which aro
bahaviorally insansitivo to progostorono. Spocifically,
malos (Haavar, 1982; Hsavar A Clamans, 1983) and famalas
mada unrasponsivs to progostorono-inducod facilitation of
lordosis oithar by a progostorono antagonist (Richmond A
Clamans, 1985b) or by saquantial or concurrant inhibition
paradigms (Garr, flsyars A Clamans, 1984) novartholoss
rospond to intracorabral infusion of a cholinorgic agonist.

Tho cholinorgic agonists which havo boon usad to
facilitata lordosis in ostrogon-primod fomalo rats includa
carbachol, bothanachol, oxotramorina and pilocarpina
(Clamans g§_gLL, 1983). Hhilo thoso drugs aro primarily
muscarinic in thair actions, carbachol and bathanachol may
stimulato nicotinic racoptors (oithar diroctly or through
stimulating roloaso of andoganous ACh). Tho
acatylcholinastoraso inhibitor osorina (physostigmino) also
facilitatas lordosis following intracorabral infusion to
ostrogon-primod OVX rats, oithar whon infusod alono or in
combination with ACh (Clamans g;_‘LL, 1983).

In addition to tho facilitativo affoct of
pharmacological stimulation of tho cholinorgic systom on
lordosis, othar studios havo domonstratad that muscarinic
transmission is roquirod for hormono-inducod soxual
rocoptivity. Intracorobral infusion of a cholins uptaks

47

inhibitor, hamicholinium-3, which raducas andoganous ACh
formation, disrupts rocoptivity in ED plus progostorono
primod famalas (Dohanich A Clamans, 1980). Furthormora,
infusion or application of muscarinic cholinorgic
antagonists (atropino and scopolamina) also disrupts EG plus
P inducod sawual rocoptivity (Clamans g;__‘1,, 1983;
Dohanich A Clamans, 1980; Kaufman, Pfaff A flcEwan, 1984).
Thoso studios havo indicatod that thoro is activation of tho
cholinorgic systom in hormono-inducod rocoptivity, and
disruption of cholinorgic transmission will disrupt
rocoptivity.

Giochaoical analysis of sitos known to ba important for
sakual bohavior has shown that cholinorgic anzymas and
racoptor lovols can ba altarad by hormono troatmonts.
Hhsthar thoso hormono-inducod altorations in cholinorgic
nourochsmistry aro causally rolatod to tha induction of
sowual rocoptivity is unclaar, howovor. Thus, whilo
ostrogon troatmont incroasas muscarinic cholinorgic racoptor
numbsr in tho modiobasal hypothalamus of OVX fomalo rats
(Rainbow g;__g1‘, Dohanich g;__gL,, 1982; flsyars A
Clamans, 1985), tho functional significanca of this incroaso
is unclaar. flals rats, which rospond with lordosis bohavior
in a mannor not difforant from famalas to both ostradiol
troatmont and ostradiol plus cholinorgic infusion (Haavar A
Clamans, 1983), do not show altorations in hypothalamic
muscarinic racoptors following ostrogon troatmont (Dohanich
g§_gL;, 1982). In addition, dosas of ostrogon which do

48

not significantly altar muscarinic racoptors in fomalo rat
hypothalamus aro affactiva in potantiating tho rosponso to
infusion of muscarinic cholinorgic drugs (floyors A Clamans,
1985). In tho abssnca of conclusiva avidanca that
cholinorgic drugs act in tho modiobasal hypothalamus, tho
rolovanca of flGH muscarinic racoptors to saxual rocoptivity
is unclaar. Similar criticisms can ba mods for othar
proposad sitos.

Similarly, hormono-inducod sito-spocific altorations in
cholinorgic anzymas havo boon domonstratad. It is possiblo
that storoid hormonos induco sauual rocoptivity by anhancing
cholinorgic transmission through supprassing acotylcholino
dagradation or anhancing acotylcholino synthosis. Tho
activitios of cholins acotyltransfarasa, (tho onzyms for ACh
synthosis), and acatylcholinastoraso (tho snzyms which
braaks down ACh) in hypothalamus aro altsrad by ostrogon
troatmont (Luina A flcEwon, 1983; Luino A Rhodos, 1983;
Luina, Khylchovskaya A flcEwon, 1974, 1975). floyors and
Clamans (parsonal communication) havo similarly domonstratad
that ostrogon troatmont rasultod in appropriato changas in
cholinastarasa activity in carobrospinal fluid,
hypothalamus, and flCG. Tho nocossity of thoso naurochamical
changas for tho induction of rocoptivity aro unclaar,
howovor. Hhilo thoso sitos havo boon implicatad as
important for tho rogulation of fominino saxual bohavior by
othar mothods, thoso sitos aro not particularly high in
cholinorgic markars and tharoforo may not ba tho sitos

49

important for tho cholinorgic facilitation of lordosis. On
tho othar hand, losion studios havo domonstratad that tho
flCG is an important sits in tho madiation of tho cholinorgic

facilitation of lordosis (Richmond A Clamans, 1985a).

Wm
As raviawad abova, a graat doal of avidanca indicatos

that cholinorgic transmission is important for tho
rogulation of saxual rocoptivity in fomalo rats.
Considoring tho oxistonco of two typos of racoptors for
acotylcholino, it is roasonabla to ask whothor this affoct
is madiatad by muscarinic or nicotinic racoptors, or both.
Hhilo it appaars that tho antira facilitativo affoct of
cholinorgic agants on lordosis can bo blockad by tho
muscarinic antagonists, atropino and scopolamino, tha
facilitation of lordosis by nicotino inJaction raisss tho
possibility that nicotinic transmission is also important.
Tho six axparimonts raportad in this thasis havo boon
parformad to moro pracisaly charactariza tho nicotinic
contribution to tho rogulation of soxual rocoptivity in
fomalo rats. To accomplish this, comparison of tho
bohavioral affocts of nicotinic and muscarinic agonists and

antagonists and thair intoractions havo boon assossod.

50

m

Fomalo Sharman strain rats (Camm Rosoarch Industrios,
Inc., Hayna, NJ) waro usad in all axporimants raportad hora.
Animals waro racoivad whon 60-70 days of ago (190-215 grams)
and allowod to acclimato to tho laboratory for at loast ons

wook boforo any manipulations waro parformad.

Winds

Animals wars housad in pairs in stainlass stool hanging
cagas (30 x 23.8 x 23.8 cm) from tho timo thoy waro
racoivad; animals that subsaquantly undarwant staraotaxic
surgsry (Exparimants 4 and 6) wars singly housad at tho timo
of starootaxic surgsry. Tho animals in Exporimant 1 wars
singlo housad aftor tho third drug tast (Hook 3) and
romainad singly housad throughout tho ramaindor of tho
oxpsrimsnt. Animals in tha othar systomic drug studios
(Exparimsnts 2, 3, and 5) wara housad in pairs throughout
tho oxparimont.

Tho colony room was maintainad on a 14:10 ravarso
light-dark cyclo, with lights off at 11:00 local timo (EST
or EDT). Tamporatura was controllad automatically at 70
dsgroos Faranhoit. Rod and dim whita lights waro usad by
axparimantars in the colony room during tho dark phasa of
tho light cyclo.

Food (Tsk-lad mouso/rat dist, Hinfiold IA) and tap watar

51

waro availabla at all timas. Tho animals for Exparimant 1
wars givan totracyclino (Profassional Votarinary
Laboratorias, flinnaapolis, flN; 1/2 toaspoon par 250 cc
distillod watar) in placo of drinking watar from tho timo of
arrival until 3-5 days aftor ovarioctomy (a.g., a total of

13 days).

Mission
Savon to tan days aftor arriving in tho laboratory, all

famalas waro ovarioctomizod undor Kotamina anosthssia
(Vatalar, Parks-Davis Co., florris Plains, NJ).
Ovariactomias waro parformad using bilataral flank
incisions; tho stump of tho ovarian vasculatura was ligatod
with silk (Champion numbsr 0), ths musclo of tho body wall
suturod with gut (Ethicon 4-0), and tho skin ovor tho
incisions was closad with wound clips (Justrito, Clay Adams,
Parsippany, NJ) .

Ovariactomy rsmovos tho primary sourca of andoganous
hormonos which affoct soxual bohavior (ostrogon and
progostorono) and tharoforo allows tha axparimantar control

ovor tho hormonal status of tho animals.

Wm

Following ovarioctomy, all famalas wars scrasnad to
assass for normal rssponsivanass to axogsnous gonadal
hormonos. This scraaning pratast occurrod 7-12 days aftor

52

ovarioctomy and was procadad by hormonal priming. Each
fomalo was inJoctad with ostradiol banzoato (EG, 0.5 ‘ug/
animal! day, i.m.) 72,-48 and 24 hours boforo bohavioral
tasting and also racoivad a singlo injaction of progostorono
(P, 0.5 mg/ animal, i.m.) 4 to 6 hours boforo bohavioral
tasting. This saquantial troatmont with ostrogon and
progostorono mimics tho saquanca of hormono sacrotion from
tho ovarios during tho astrous cyclo (Gutchar .g__.1.,

1974) and normally inducos high lovols of ssxual rocoptivity
in all famalas. This laboratory has usad tho critsrion that
an animal must achiavo a lordosis quotiant (sas Gshavioral
Tasting soction) of 70 or moro in ordor to bo considarad
normally rosponsivo to axogsnous hormonos; animals which
failod to most this critsrion waro okcludad from subsoquant
oupsrimsntation. Of tho 151 famalas scrasnad for usa in tho

6 ouparimsnts raportad hora, l was oxcludad bacauso of this

critsrion.
Wasting
Gshavioral tasts for saxual rocoptivity waro

administarod at varying timas boforo and aftor oxporimontal
troatmonts. In all casas, bohavioral tasts waro conductad
undor dim rad illumination in small rooms IdJICIflt to tho
main colony room. Tosts waro conductad during tho first
half of tho dark phasa of tho light cyclo, but novor loss
than 1 hour aftor lights-out (a.g., normally 12:30 - 4:00
pm).

53

Each bohavioral tost consistad of scoring tho rosponso
of tho tost fomalo to aach of 11 mounts by a saxually
vigorous Long-Evans strain “stimulus“ malo. Tho stimulus
malo was allowsd to adapt to tho tasting arana (45 x 50 x 58
cm, Plowiglas, with Sanicol bodding) for at loast 5 minutas
boforo introduction of tho tast fomalo. In tho avont that a
stimulus malo bocams sakually inactivs prior to complotion
of a bohavioral tast, tho tsst fomalo switchsd to anothar
tasting arsna with a difforant malo. Tho rosponso of tho
fomalo to aach mount by tho malo was scorsd on tho intansity
scala doscribad by Hardy A DoGold (1971) and rosponsos
scorsd as 1, 2, or 3 waro considarad lordosis. A lordosis
quotisnt was calculatad for aach fomalo aftor owclusion of
tho rosponso to tho first mount, so that L8 - 0 lordosas/ I

mounts N 100, with tho numbsr of mounts always boing 10.

W

Lordosis quotionts ars scoros on a scala of 0 to 100,
with tho scors of an individual animal actually boing a
multiplo of 10 botwoon 0 and 100. Gacauso of tho intarval
natura and non-normal distribution of thoso data, paramatric
statistics aro not appropriato. All data havo tharoforo
boon analyzad using non-paramatric statistical procoduras as
doscribad by Siagal (1956). To comparo rolatod groups
(a.g., individuals ovor savaral timo points) tho Friadman
two-way analysis of varianca, Hilcoxon matchod-pairs
signsd-ranks tast, and sign tost waro usad. For unralatad

54

groups, Kruskall-Hallis analysas of varianca, flann-Hhitnoy U
tasts, and Chi-souara tasts waro usad. Tho abbraviation
‘ANOVA' will bo usad for “analysis of varianco'. Tho
critsrion for statistical significanca was sat at p < .05;

tasts waro two-tailod unloss othrwiza notad.

W

Estradiol-17Gata-3-bonzoata (I, Sigma Chamical Co., St.
Louis, flO) and progostorono (P, Sigma) wars dissolvod in
sasams oil (Sigma) and administarod by intramuscular
ingoction into ths thigh. InJaction volumo for hormonos (SD
and P) was 0.10 cc par animal axcapt in Exparimsnt 1, whsro
tho SD dosas wars administarod on a‘ug/kg basis by adjusting
tha volumo of ianction at tho rats of .4 cc I kg.

Ssvsral drugs wars inJactad intraporitonoally in salina;
control injactions of tho salino vohiclo alono wars also
mada. In ordor to accommodata for difforancas in body
woight, systomic drug troatmonts wars administarod on a
mg/kg basis. Drug solutions wars mada up to bs administarod
at tho rats of 0.8 cc/ kg, so that tho “avaraga” 250 gram
rat would rocoivo a 0.2 cc inJaction. Tho inJaction volumo
was adjustad for individual body woights moasurad aarlior
tha sams day. Tho following drugs for systomic inJaction
waro obtainad from Sigma Chamical Company; nicotino (froo
bass), macamylamina hydrochlorido, atropino sulfato, and

hoxamsthonium bromida.

Win

In Exporimsnts 4 and 6, intracorabral microinfusions of
drugs wars parformad. Tho following soctions doscribs tho
mothods for intracorabral cannula construction,

implantation, infusion and histological vorification.

Cannula construction

Cannulaa assamblias waro constructad from stainlass
stool tubing (Small Parts Inc., fliami Florida). Two 12 mm
long ”guida cannulao“ (HTX-23 thin-wallad) woro fusad with
dsntal acrylic so that thoy wars 2 mm apart and parallol to
ona anothar. Thoso guida cannulao assamblias waro
psrmanontly implantad into tho brain as doscribad bolow.
: Romovabls ”occluding insarts“ waro constructad from a
short piacs (3-5 mm) of HTX-23 gaugo tubing crimpod around
ono and of a longor piacs (17-20 mm) of HTX-27 gaugo tubing.
A 13 mm shaft of HTX-27 tubing thus axtondad from tho HTX-23
piacs. Hhan ths HTX-27 portion of an occluding insart is
insartad into a psrmanontly implantad HTX-23 guida cannula,
tho HTX-23 gaugo and of tho insart only allows it to ba
lowsrsd 13 mm into tho guida. In this way, tho occluding
insart torminatas ono mm past tho and of tho guida cannula.
Hhan in placo, tho insart oxtonds 1 mm past tho and of tho
guida.

Infusion insarts waro constructad of HTX-27 or HTX-28

56

gaugo stainlass stool tubing attachad to 20 gaugo tubing
(PE-20; Clay Adams, Parsippany NJ) so that 13 mm of HT!
tubing outandad out of tho PE tubing. In this way, tho PE
tubing would allow tho HTX infusion insart to ba insartad
only 13 am into tho guida, a.g., so that tho infusion insart
torminatad 1 as past tho and of tho guida cannula in tho

sams spot that tho occluding insart had torminatad.

Cannula implantation

Animals for soma sxpsrimants undarwant staraotaxic
surgsry for tha implantation of intracorabrovontricular
(ICV) cannulao 1 to 12 days aftor tho scrasning protost.
Surgsry was parformad undor Kstamina anosthssia
(approximatsly .14-.18 cc par animal). Following
anasthotization, tho hsad was shavod and tho animal was
placad in tho starootaxic instrumant (David Kopf
Instrumants, Now York). Using blunt oar bars and with tho
incisor bar at intaraural zaro, bilataral guida cannula
assamblias (doscribad abova) waro implantad. Tho assamblias
waro placad on a 27-gauga carriar and diroctad at tho
lataral vsntriclas by orionting tho assambly ovor Grogma
(A-P), and cantaring tho two cannula ovor tho sagittal
sutura (aach was than 1 mm lataral to tho sagittal sutura).
Holos waro drillod in tho skull with a dsntal drill, and tho
assambly was lowsrsd 2.7- 2.8 mm from tho laval of dura.
Tho guida cannula assambly was sacurad to tho skull by
placing dsntal acrylic ovor tho bass of tho assambly and

57

ovor 4 small scrows proviously drillad into tho skull. Tho
dsntal acrylic was allowad to dry, tho carriar assambly was
romovsd, and tho guida cannulao waro fittod with rsmovablo
occluding insarts. Finally, tho skin ovor tho skull was
closad using matal wound clips. Following ramoval from tho
storaotaxic instrumant, animals wars allowad to racovor from
tho anosthssia undor obsorvation boforo boing placad

individually into matal cagas.

Intracorobral infusion tochniquo

To parform an intracorabral infusion, tho PE tubing
attachad to tho infusion insart was first fillad with tho
appropriato solution for infusion. Tho occluding insarts
waro romovsd, and tho solution was dolivorod through tho
infusion insart into tho lataral vantriclo using a
raciprocal microinfusion pump (Harvard Apparatus, flillis
flA). Ths infusions waro parformad bilatarally, with aach
occluding insart boing raplacad immadiatoly aftor ramoval of
tho infusion insart.

Tho volumo of solution dolivorod was ragulatad not by
maasuring tho amount of timo at a givan pump satting, but
rathar by watching tho movamant of a bubblo drawn up into
tho infusion tubing. Tho bubblo also sarvad to saparato tho
CSF and drug solutions. Tho bubblo mothod was usad bacauso
tho rats of flow through an infusion insart can bo altarad
by movamant of tho animal boing infusod, by movamant of tho
infusion insart within tho guida cannula, by tho tissuo

rasistanco, and by tho hoight of tho animal ralativo to tho
i nf usi on pump (parsonal obsorvati ons and porsonal
communications from Drs. Gary Dohanich and Gail Richmond).
On avarags, infusion of .5 microlitsrs took 15-45 ssconds at
tho pump sattings usad.

Infusion insarts (both tho PE and HT! tubing portions)
waro usad for a singlo drug only to avoid cross-
contamination. Infusions waro parformad undor dim whita
illumination in tho colony room. Tho animals waro gantly
rostrainod by holding tham against ths infusar's chost (lab
coat raquiradt); this mothod allows infusion of

unanosthatizsd animals with minimal strass to oithar party.

Artificial carobrospinal fluid vohiclo

flacamylamins (Exparimsnt 6) and osorina (Exparimsnt 4)
(Sigma Chamical Co.) waro dissolvod in an artificial
carobrospinal fluid (CSF) vohiclo immadiatoly boforo
intracorabrovontricualr infusion; in Exporimant 6 tho CSF
vohiclo was also infusod alono as a control. Tho CSF
vohiclo consistad of 130 mfl NaCl, 25 mfl NaHCOs, 0.5
“CzPOA, 3.0 mfl KCI, 0.8 mfl flgClz, and 1.3 mfl CaC12 in
doubls distillod watar, IIJUItId to pH 6.8. Tho CSF was
allowad to warm to room tamporaturo for approximatoly 1 hour

prior to dissolving drugs in it.

Histological vorification of cannulao location
Following complotion of infusion studios, tho animals

59

waro anosthstizad with pontobarbital (15 mg/ animal, i.p.)
and parfusod transcardially with 0.9% salino followod by 10%
phosphata buffarod formalin. Following parfusion, intact~
skulls waro placad in 41 formalin for storaga for savaral
days; tho brains waro than rsmovad from tho skulls and
roturnad to 41 formalin for savaral moro days. Tho brains
waro rsmovad from tho formalin, rinsad in 1001 othanol,
blockad, and frozon sactionad at 50 microns. Tho cortox on
ono sido of tho brain was oftsn notchsd to aid in
distinguishing right from loft in tho soctions. Sactions
containing portions of tho cannulao tracks waro placad on
slidos proviously coatad with 3% gal and allowod to dry.
Staining of tho tissuo and covarslipping was not parformad,
as thoso procoduras waro not nocossary to datarmina whothor
tho cannulao torminatad in tho vantriclos. Tho soctions
waro oxaminad by proJaction and tho sito of tormination of
tho cannulao was dstarminod indopandontly by two obsorvars
(tho author and David A. Brigham). Only thoso animals for
which both obsorvars dstarminod that both cannulao wars in
tho vantriclas havo boon includad. Tho sat of coordinatss
usad placad tho majority of cannulao in tho lataral
vantriclas (bilatarally) at a laval aquivalant to Figuro 17
in tho atlas of Konig A Klippol (1963). Tho rango of
raprasantativo soctions spans Figuras 15 to 18 in Konig A
Klippsl. A soction botwoon Platos 14 and 15 in tho atlas of
Paxinos and Hatson (1982) would also closoly raprasont tho
typical soction containing tha cannulao tracks.

60

W14.

As notod in tho litoraturo roviow portion of tho
LNIBQDHQILQu_soction, Fuxo 81.11; (1977) havo raportad
that systomic injoction of nicotino facilitatas lordosis
bohavior in ostrogon-primod ovarioctomizod (OVX) rats.
Exporimants 1, 2, and 3 wars parformad to raplicato thoso
oxparimonts (with slight modifications in tho mathods) and

to sktand tho pharmacological analysis of nicotino action.

mm

Goginning ona wook aftor thair scrasning protost, 24 OVX
Sharman strain rats waro tsstod at ono wook intarvals for
lordosis bohavior. Each wooks’ tasting consistad of a
sariss of bohavioral tasts boforo and aftor pharmacological
troatmonts. Each waokly tsst sariss was procadad by
inJactions of EB (.5‘ug/ kg) 72, 48, and 24 hours boforo
bohavioral tasting. For clarity, tho axporimont will ba
discussad in four parts, rofarrad to as Exparimants 1a
through 1d. Figura 1 is a schamatic diagram of tho
procoduro for Exparimont 1.

Exparimant 1a. For aach of tho first two waokly tasts,
tho IUbjICtI waro randomly assignad to ona of fivo dosas of
nicotino (0, 25, 50, 100 and 200 ‘pg/ kg). Tasts for
lordosis bohavior waro conductad boforo (protost, PT) and 5
and 20 minutas aftor nicotino ianction. Tho rosults of

61

FIGURE 1 Procaduro, Exparimont 1. Prior to

sariss of lordosis bohavior tasts, tha animals
with ostradiol banzoato (EB, 0.5 ug/kg x 3).

1a, 1b, 1c, and 1d aro indicatod.

62

aach waokly
waro primod

Exparimants

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345$”. azmuxum .x>o

F EmEtmaxm

63

thoso first two wooks havo boon poolad to provido a
dosa-rosponso curvo for nicotino on lordosis bohavior in
EB-primsd OVX animals.

Expsrimsnt 1b. On tho third wook, all animals waro
EB-primad and givan a singlo nicotino inJoction (200‘pg/kg).
Gshavioral tasts wars conductad boforo (PT) and 5 minutas
aftor nicotino ianction.

For tho subsaquant wooks of tasting, tho animals waro
dividod into two groups basad on tho rosults of thoso first
thrao wooks of tasting. It appoarod that soma animals wars
rosponding to nicotino in;action, whilo othar animals wars
not on thass first tasts. Groups of raspondars and
non-rospondas wars tharoforo dofinad and thoy procaodsd
through tho naxt savaral wooks on difforant schadulas
(Exparimants 1c and 1d). Animals which had lordosis
quotionts of loss than 40 on wook 3 waro dasignatad as
non-raspondars.

Exparimsnt 1:. In ordor to datarmina whothor animals
that had boon idantifiad as non-raspondars waro consistantly
non-raspondars to nicotino injaction, thoy racoivad nicotino
ianctions of incroasing dosago ovor wooks 4-6. Gshavioral
tasts occurrod boforo (PT) and 5 minutas aftor inJoction of
nicotino. Tho nicotino dosa was incroasod from 200 ,ug/kg
(Hook 4) to 300‘ug/kg (Hook 5) to 400‘pg/kg (Hook 6). Of
tho 9 animals dasignatad as non-raspondars, 6 complotsd
tasting. Tho othar thrao animals diad boforo complotion of
tho sixth tost; thoso daaths did not saam to ba rolatod to

64

tho drug troatmonts.

Exparimant 1d. In ordor to obtain pilot data on which
to bass subsaquant oxpsrimontation, tho l‘raspondar" group (n
. 15) undarwant tasts to datarmina tho ability of savaral
cholinorgic antagonists to block tho facilitation of
lordosis by nicotino. Thus, ”raspondars“ waro randomly
assignad to ona of thrao pro-troatmont groups for aach of
tho naxt thrao wooks. Each wook, aach animal was EB primod
(.5pg/ kg x 3), protostad for lordosis bohavior, and
pratroatad with oithar salino, a low dosa of antagonist, or
a highor dosa of antagonist. All animals subsoquontly
racoivad nicotino (200 ,ug/kg, 45 minutas aftor
protroatmont), and lordosis bohavior was assossod 5 minutos
lator. Tho nicotinic antagonists macamylamina (1 and 5 mg/
kg, wook 4) and haxamsthonium hydrobromido (8 and 20 mg/kg,
wook 5), and tho muscarinic antagonist, atropino sulfato (8
and 20 mg/kg, wook 6) waro usad. A savanth bohavioral tast,
which was idantical in dasign to wook 3, was also conductad.
Tho EB-primod animals waro simply tsstod for lordosis
bohavior boforo and 5 minutas aftor nicotino (200 ,ug/ kg)
injoction. Tho data from Exporimonts 1c and 1d should bo
considarad praliminary data bacauso of tho low numbsr of
animals usad and bacauso tho animals racoivad savaral

difforant drugs ovor timo (Exparimant 1d).

Banana

Exparimant 1a. Tho rosults of tho first two wooks of

65

SYSTEMIC NlCOTlNE FACILITATED LORDOSIS

Snmiisst
EB dose; 0.5 ug/kg x 3

LORDOSIS ouonENT

 

0 2 5 50 ICC 200

NICOTINE DOSEipg/kg)

FIGURE 2 floan lordosis quotionts (+l- S.E.fl.) of EB-primad

OVX rats 5 minutas aftor inJoction of nicotino (0, 25, 50,

100 or 200,uglkg, i.p.) (Exparimant 1a). Tho stars indicata

significant incroasos from protast (PT) lordosis quotionts

(LO’s) for tho 50, 100 and 200,ug/kg nicotino dosas. Numbar

of tasts for aach moan is 9-10 as indicatod.

tasting aro prasantad in Appandix 1 and Figura 2. An
ovsrall affoct of dosa at tho 5’ tost was domonstratad in
that tho proportion of animals showing lordosis bohavior
aftor troatmont variad botwoon nicotino dosas (Chi-squars
tast, X2-17.9, 4 dograas of fraodom, p < .01). Nicotins at
dosas of 50, 100 and 200 ug/kg producod a significant
incroaso in lordosis quotionts (LO's) 5 minutas aftor
inJaction (sign tasts, PT vs 5 minuts tsst Ip-.031, .004,
and .016, for dosas 50, 100, and 200,ug/kg, raspactivoly)).
By 20 minutas aftor inJoction, LO’s had roturnad to low
lovols.

Exparimant 1b. Tho rosponso to a singlo nicotino dosa
(200 ug/kg) was quits variabla. Tho avarago 5 minuts tost
LO was 49.5 (standard orror . 6.6). Tho moan LO for tho
raspondars (n - 15) was 72.1 +/- 4.2, whilo tho
non-raspondars (n - 9) avaragad 16.7 +/- 4.4.

Exparimant 1c. Tabla 1 shows tho bohavior of tho
non-raspondars to nicotino injaction ovor wooks 3-6.
Statistical analysis domonstratad that ”non-raspondars” is a
poor tsrm for this group, as thara actually was a
significant facilitation of lordosis by nicotino on aach
wook 3-5 (PT vs 5-minuta LO, p - .031, sign tast). Tharo
was no affoct of nicotino on wook 6, possibly bacauso this
dosa of nicotino (400‘pg/kg) producod dobilitation in soma
animals. It is claar from axamination of Tabla 1 that
animals salactod as non-raspondars in wook 3 aro capablo of
showing induction of rocoptivity by nicotino injoction. Tho

67

TABLE 1 Individual lordosis quotionts of OVX, EG-primod
“non-raspondars“ boforo and 5 minutos aftor i.p. nicotino
inJaction (Exparimants 1b and 1:). Animals salactod as
nonrospondors to 200‘ug/kg NIC on wook 3 racoivad subsoquont
tasts with 200, 300 and 400‘ug/kg NIC.

NIC
dosa; 200 pg/kg 200 jig/kg 300 jig/k9 400 pg/kg
Hook 3 Hook 4 Hook 5 Hook 6
.L BIL—.5; Li; Ell—.5; U
162 0 20 10 60 0 50 10 30
163 0 30 10 70 0 70 0 30
169 0 0 0 0 0 60 0 10
174 0 20 0 100 0 60 10 0
181 0 10 0 10 10 10 0 0
1.8.1 9__19. L19. 9.__9. 9._9.
flEAN 0 15.0 3.3 45.0 1.7 41.7 3.3 6.7
SEfl - 4.3 2.1 15.7 1.7 11.9 2.1 4.9

68

failuro of animals to rospond on wook 3 was also apparantly
not duo to insufficiancy in dosa, as most animals raspondad
moro strongly to tho sams dosa of nicotino (200 ‘ug/kg) on
wook 4.

Exparimant 1d. Tho rosults of wooks 4-7 for tho
rosponding group of animals aro prasantad in Appandix 2 and
Figuras 3-5. Nicotins injaction rasultod in a significant
facilitation of lordosis in tho salino pratroatad animals
aach wook (PT vs 5-minuto tast, sign tast, p I .031 for aach
wook 4-6).

In Hook 4, thoro was a significant affoct of
protroatmont on lordosis bohavior in tho 5-minuta tasts
(Kruskal-Hallis ANOVA; sao Figura 3). Pratroatmant with tho
tartiary nicotinic racoptor antagonist macamylamina (flECA, 1
or 5 mg/kg) complataly blockad tho rosponso to nicotino
(flann-Hhitnay U-tost, p - .004 for aach flECA dosa vs.
salina; PT vs 5-minuta tast not significantly difforant,
sign tost).

Ovorall, haxamsthonium (HEX) protroatmont did not
significantly affoct lordosis bohavior in tho 5-minuta tasts
aftor nicotino injaction (Kruskal-Hallis ANOVA, p > .05; soo
Figura 4). Two animals in tho 20 mg/kg haxamsthonium group
had high protost scoros, howovor, and so it saoms moro
appropriato to usa tho difforanca scoros (5-minuta tost LO -
protost LO) for tho analysis of tho data from wook 5. (For
tho othar wooks, tho difforanca scoros and tho 5-minuts
scorad waro vary similar, and using oithar scora producod

69

100

0.5 ug/kg E8 1: 3

   

80 ‘
200 ug/kg NICOTINE
n 8 5/ Group
60
40
20
o _ t — '
PT 5' PT 5' PT 5'
SALINE MEGA MEGA
+ [1.0 wig/kg] [5.0 rig/kg]
NICOTINE NICOTINE NICOTINE

FIGURE 3 flocamylamino (flECA) protroatmont provontod tho
facilitation of lordosis inducod by nicotino (NIC)
(Exparimant 1d, wook 4). Tha triangla indicatos a
significant incroaso from protost LO's. Stars indicata
significant raductions in 5-minuta LO scoros ralativa to tho

control group (salino + nicotino).

70

100

 

      

80 0.5 ug/kg EB x 3
200 ug/kg NlCOTlNE
n: 5/ Group
60
40
20
o I
PT 5' PT 5‘ PT 5‘
SALINE HEX . HEX
+ [8.0 dig/kgl [20 ".19/ kgl
NlCOTlNE 'NICOTINE NICOTINE

FIGURE 4 Hoxamothonium (HEX) protroatmont roducod but did
not provont facilitation of lordosis by nicotino (Exparimant
1d, wook 5). Tho trianglas indicatos a significant incroaso
from protost LO's. Hollow stars indicata significant
raductions in L9 difforanca scoros (5’-PT) rslativo to tho

control group (salino + nicotino).

71

100

0.5 ug/kg EB x 3
200 ug/kg NICOTINE
n: 5/ Group

   

PT 5' PT 5' ' PT 5'
SALINE ATROPINE ATROPINE

4, l80t19/kgl 120 .../kg:
NICOTINE NICOTINE NICOTlNE

FIGURE 5 Atropino protroatmont roducod but did not provont
facilitation of lordosis by nicotino (Exparimant 1d, wook
6.) Trianglas indicata a significant incroaso from protost
LO’s. Stars indicata significant raductions in 5-minuts LO

scoros rslativo to tho control group (salino + nicotino).

72

ths sams statistical conclusion).

Analysis of difforanca scoros ravoalod a significant
affoct of haxamsthonium protroatmont (Kruskal-Hallis ANOVA,
p < .05). Subsaqusnt pairwizs comparisons of tho salino and
haxamsthonium protroatmont groups showod that haxamsthonium
protroatmont significantly roducod tho facilitation of
lordosis by nicotino as moasurad by tho difforanca scora
(flann-Hhitnoy U-tast, p < .048 for 8 mg/kg HEX and p < .016
for 20 mg/kg HEX vs salino protroatmont). Dsspits tho
raduction in nicotino-inducod lordosis bohavior by
haxamsthonium, thoro was still a significant facilitation of
lordosis in tho 20 mg/kg HEX group (sign tast, p I .031) but
not in tho I mg/kg group.

Hhilo atropino protroatmont also significantly roducod
lordosis bohavior inducod by nicotino inJaction (wook 6),
thoro was still a significant facilitation of lordosis in
atropino-pratroatad animals (soo Figuro 5; PT vs. 5-minuta
tast, p - .031, for both atropino dosas). Atropino (20
mg/kg) roducod 5-minuto tast LO’s rolativo to salino
protroatmont (flann-Hhitnay U tost, p < .008); protroatmont
with tho lowsr atropino dosa did not significantly affoct
ths 5-minuta tast scoros.

In wook 7, tho LC of tho raspondars avoragod 49.3 (+/-

8.4) in rosponso to 200,ug/kg nicotino.

SUI-IL!

Tho rosults of Exparimant 1a domonstrato that nicotino

73

troatmont can indaod facilitata lordosis in EB-primod fomalo
rats. Tho division of animals into raspondars and
non-raspondars basad on tho rosponso to a singlo inJoction
of nicotino (Exparimant 1b and 1c) was inaffactivo in
idantifying a rosponsivo population of subjacts, as tho
rosponso of individual animals was not consistant ovor
trials. Tho subsaquant pharmacological analysis of nicotino
rssponsivanass (Exparimant 1d) indicatos that tho affoct of
nicotino on lordosis bohavior is madiatad by tho nicotinic
racoptor, as tho nicotino-inducod facilitation of lordosis
was complataly blockad by tho nicotinic antagonist
macamylamina. This agraos with tho publishad rosults of
Fuxs g3__gl‘, (1977). Hoxamothonium and atropino
protroatmonts also roducod tho magnitudo of tho
nicotino-inducod lordosis, but a significant facilitativo
affoct of nicotino was novartholoss soon in all but tho 8
mg/kg haxamsthonium group.

As notod aarlior, tho rosults from Exparimant 1d waro
considarad pilot data. In ordor to moro fully axamina tho
pharmacology of nicotino-inducod lordosis bohavior, tho
affocts of protroatmont with macamylamina and atropino waro
salactod for furthor analysis in saparato oxparimonts,

Exporimonts 2 and 3.

74

W

Exparimant 2 was dasignad to confirm tho praliminary
rosults of Exparimant 1d, wook 4. Spocifically, tho affoct
of protroatmont with tho nicotinic antagonist macamylamina

on nicotino-inducod rocoptivity was axaminad.

EEQSIOHCI

Twalvs Shorman strain fomalo rats waro OVX and scrasnad
as doscribad in tho fiEflEBfiL_flEIflQnfi_soction. Thrao tost
sariss wsrs administarod at waokly intarvals, with tho first
tsst sariss ons wook aftor tho scrasning protost. Each
animal was EG-primod (0.13,ug EB at -72, -48, and -24 hours)
boforo aach waokly tost sariss. For aach tast sariss, tho
animals waro protostad for lordosis (PT), injactad with
macamylamina (flECA, 2.5 or 10 mg/kg, i.p.) or tho salino
vohiclo, and 30 minutas latar injactad with nicotino (150
,ug/kg). Thay wora than ratsstod for lordosis bohavior 5
minutas aftor nicotino. In this way, tho ability of
macamylamina protroatmont to provont tho nicotino-inducod
facilitation of lordosis was assossod. Each animal racoivad
all thrao possiblo protroatmonts ovor tho thrao wooks of

tasting; tho ordor of protroatmonts was countarbalancad.

83min
As axpactad, nicotino inJaction (1501ug/kg) producod a

statistically significant facilitation of lordosis in tho

75

NICOTINE ANTAGONIST (MECAM‘YLAMINE) PREVENTED
NICOTINE FACILITATION OF , LORDOSIS

 

,_ loo

2

SE

*5 80

D

O

1, so

(I)

8

a: 40

O

a

z 20

< .

U

2 0
PT 5' PI 5' PT 5'
SALINE MECAMYLAMINE MECAMYLAMINE
4. (25mm) (lOmg/kql .

+ +

NICOTINE , NICOTINE NICOTINE

FIGURE 6 flocamylamina protroatmont provontod nicotino
facilitation of lordosis (Exparimant 2). Tho triangla
indicatos a significant incroaso from protost LO's. Stars
indicata significant raductions in 5-minuta LO scoros
rolativo to tho control (salino + nicotino) tsst for thoso

12 animals.

76

Balino + Nicotino group (PT vs. S-oinuto tost, Hilcoxon
oatchod-pairs signod-ranks tost, p < .05). As illustratod
in Figaro 6, oocaoylaoino protroatoont (2.5 or 10 og/kg)
cooplotoly provontod tho facilitation of lordosis by
nicotino (iso‘pg/kg). This offoct of protroatoont on tho
S-oinuto tost scoros was statistically significant (Friodoan
two-way ANOVA, p < .001) followod by Hilcoxon oatchod-pairs
signod-ranks tost to cooparo salino vs oach HECA wook,
ono-tailod, p < .005). In nono of tho tosts with
oocaoylaoino-protroatoont did an anioal show an incroaso in
L0 following nicotino troatoont, whilo thoso saoo anioals
all showod an incroaso in L9 in rooponso to nicotino

injoction following tho salino vohiclo protroatoont.

EHIIIEX.

ln agroooont with tho prolioinary rosults froo
Exporioont l and with tho publishod rosults of Fuxo .1_.LL
(1977), oocaoylaoino was found to provont tho
nicotino-inducod facilitation of lordosis. This indicatos
that nicotino is acting at nicotinic rocoptors to facilitato

lordosis.

77

W

Exporioont 3 was porforood to oxtond tho pharoacological
charactorization of tho nicotino-inducod facilitation of
lordosis. Spocifically, Exporioont 3 was dosignod to assoss
tho ability of tho ouscarinic antagonist. atropino, to block
tho nicotino-inducod facilitation of lordosis in EB-priood

fooalo rats.

Ems-m

As in Exporioont 2, DVX, scroonod Shoroan strain rats (n
I 10) woro tostod for lordosis bohavior in 3 tost sorios
spacod ono wook apart. Tho first tost sorios was ono wook
aftor tho scrooning protost. Each wook, oach fooalo was
priood (.13 ‘pg EB x 3), protostod for lordosis (PT),
1HJICt0d with a protroatoont, and 30 oinutos lator inJoctod
with nicotino (150 ‘pg/kg, i.p.). Each animal was thon
rotostod for lordosis 5 oinutos aftor tho nicotino
inJoction. Tho protroatoonts woro systooic injoctions of
atropino (7.5 or 30 og/kg) or tho salino vohiclo; oach
anioal rocoivod all throo protroatoonts and tho ordor of

protroatoonts was countorbalancod.

m

Tho rosults of Exporinont 3 aro prosontod in Figuro 7
and in groator dotail in Appondix 3. Using within-animal
cooparison of tho rosponso ovor tho throo wooks (Friodman

78

100

80

60

4O

20.

.13 09 EB x 3
150 ug/kg NICOTINE
n: 10/ Group

   

      

_ —_
PT 5' PT 5' PT 5
SALINE ATROPINE ATROPINE
... I25 "lg/Ital I30 «lg/kgl

NICOTINE NICOTINE NICOTINE

FIGURE 7 Atropino protroatoont roducod but did not provont
facilitation of lordosis by nicotino (Exporinont 3).
Trianglos indicato a significant incroaso from protost Ln's.
Tho star indicatos a significant roductions in S-ninuto LO
scoros rolativo to tho control (salino + nicotino) tost for

this group of 10 anioals.

79

two-way ANOVA), atropino protroatmont was found to bo
without offoct on nicotino-inducod lordosis bohavior
(calculatod X2 I 4.55 < critical valuo for significanco,
X3 I 5.99 with two dogroos of froodon, p > .05).

Pro-plannod cooparisons botwoon tho rosults of tho salino
wook vorsus oach of tho two atropino protroatmont wooks
indicato that high doso atropino (30 ng/kg) protroatmont
significantly roducos lordosis rosponding 5 ninutos aftor
nicotino rolativo to tho salino-protroatod tost (Hilcoxon
natchod-pairs signod-ranks tost, T I 6.5 is loss than 8, tho
critical valuo for 10 pairs at p < .05). Protroatoont with
tho lowor doso of atropino (7.5 ng/kg) did not significantly
roduco lordosis bohavior in rosponso to nicotino injoction
rolativo to tho tosts procoodod by salino protroatmont (p >
.05, as tho calculatod T I 10 oxcoods tho critical valuo of

T I 8 for 9 pairs).

Sunnacx
Protroatmont with tho highor doso of atropino (30 mg/kg)

roducod tho facilitation of lordosis bohavior inducod by
systooic injoction of nicotino (150 ‘ug/ kg). Tho lowor
atropino doso (7.5 mg/ kg) was inoffoctivo.

Atropino, a muscarinic antagonist, would not bo oxpoctod
to block an offoct of nicotino modiatod by tho nicotinic
rocoptor, as tho nicotinic facilitation of lordosis is. Tho
potontial mochanisms for this offoct of atropino will bo

considorod in tho fiEflEBflL_Dl§§y§§19fl soction.
80

W

Exporioonts l, 2, and 3 oxaoinod tho nicotino-inducod
facilitation of lordosis and its pharoacological basis.
Thoso studios cloarly indicato that nicotinic rocoptor
stioulation can facilitato lordosis. Tho work of othors in
this laboratory has indicatod that intracorobral infusion of
agonts which stioulato ouscarinic rocoptors will facilitato
lordosis in EB-priood OVX rats, and infusion of agonts that
disrupt ouscarinic cholinorgic transoission disrupts ongoing
EB plus P-inducod soxual rocoptivity (soo
Wm suction of th-
LNIBQDHQILQH, Booo of tho agonts which havo boon usod to
stioulato ouscarinic rocoptors also say rosult in
stioulation of nicotinic rocoptors. Tho
acotylcholinostoraso inhibitor osorino (physostigmino) is an
oxaoplo. By blocking tho onzyoatic dogradation of
acotylcholino, osorino producos an incroaso in synaptic
acotylcholino which could potontially stimulato both
ouscarinic and nicotinic rocoptors. Tho prosont oxporioont
was dosignod to assoss tho contribution of nicotinic

rocoptors to tho osorino-inducod facilitation of lordosis.

EEQEIQHEI

A total of 51 Shornan strain rats woro DVX, scroonod,
and inplantod with cannulao which woro lator dotorminod to
toroinato bilatorally in tho latoral vontriclos. Two

81

lordosis tost sorios woro administorod; tho first tost
sorios was ono wook aftor storootaxic implantation of tho
intracorobral cannulao, and tho socond tost sorios was ono
wook lator. Prior to oach wookly tost sorios, oach fooalo
was priood with EB (.13‘ug x 3). Animals woro protostod for
lordosis bohavior boforo any troatoonts (PT), inJoctod with
a protroatoont (oocaoylaoino or salino), and infusod with
osorino (5‘pg/ 0.5‘ul/ sido, bilatorally) 30 ninutos lator.
Tho anioals woro rotostod for lordosis bohavior i5 oinutos
aftor ICV osorino infusion. Twonty-four anioals rocoivod
oocaoylaoino protroatmont at 5 og/ kg, i.p., ono wook and
tho salino vohiclo tho othor. Anothor group of anioals (n I
27) rocoivod a highor doso of nocaoylaoino (10 og/kg) ono
wook and tho salino vohiclo tho othor. Each anioal thus
rocoivod two osorino infusions spacod ono wook apart; ono
wook tho osorino was procodod by ono of tho two dosos of
oocaoylanino and tho othor wook osorino was procodod by tho
salino vohiclo. Ordor of tho protroatmonts was

countorbalancod within oach group of animals.

8mm

Esorino infusion rosultod in a significant facilitation
of lordosis in control tosts with animals rocoiving salino
protroatmont (soo Figuro 8). Following mocamylamino
protroatmont (oithor doso), osorino infusion still producod
a statistically significant facilitation of lordosis (PT vs
15 ninuto tost, Wilcoxon signod-ranks matchod-pairs tost,

82

MEAN LORDOSIS QUOTIENT

 

 

 

 

 

          

.0 EB dou- .l3pg x 3
Esorino do“ - {mg/mode Icv

so

40

20 5535335

o _,
PT 5' PT 15‘ PT us‘ PT 3‘
SALINE moustache) I SALINE MECMIOmo/koI

+ f i + f

essama eseame E ESERINE ESERINE

"=24 u=27

FIGURE 8 Mocamylanino protroatmont roducod but did not
provont tho facilitation of lordosis inducod by bilatoral
ICV osorino infusion (Exporimont 4). Trianglo indicato a
significant incroaso from protost LD's. Stars indicato
significant roductions in l5-minuto LO scoros rolativo to

tho control (salino + osorino) tost within oach group.

83

p < .05). A comparison within animals across the two wooks,
howovor, indicatod that mocamylamino protroatmont roducod
tho osorino-inducod facilitation of lordosis (15’ tosts
cooparod within animal for salino vs HECA wook, Hilcoxon
matchod-pairs tost, p < .05). Thus, mocamylamino
protroatmont roducod but did not provont tho induction of

rocoptivity by ICV osorino troatmont.

85m
Tho finding that osorino facilitatos lordosis bohavior

in EB-primod fomalo rats agroos with provious rosults from'
this laboratory (Clomons g; .1,, 1983). Hhilo

mocamylamino protroatmont roducod tho osorino-inducod
facilitation in this oxporimont, MECA did not complotoly

provont tho facilitativo offoct of osorino.

B4

W

whilo tho oxporimonts doscribod to this point havo
domonstratod that pharmacological stimulation of nicotinic
rocoptors can influonco lordosis bohavior in rats, nono of
thom has addrossod tho quostion of whothor nicotinic
rocoptor stimulatiion is nocossary for soxual rocoptivity.
Exporimonts 5 and 6 woro dosignod to ask oxactly that
quostion, by assossing tho offocts of tho nicotinic rocoptor
blockor, mocamylamino, on hormono-inducod soxual
rocoptivity. In oxporimont 5, HECA was administorod

systomically, whilo in Exporimont 6 it was infusod ICV.

EIQEIIHLI

Ton DVX, scroonod Shorman strain rats sorvod as
subjocts. Throo tost sorios woro administorod ono wook
apart, with tho first tost sorios occurring ono wook aftor
tho scrooning protost. Prior to oach wookly tost sorios,
oach fomalo was primod with EB (.5‘pg x 3) plus P (.5 mg) in
ordor to induco high lovols of soxual rocoptivity on tho day
of tosting. Tho animals woro tostod for lordosis bohavior
boforo (PT) and 15, 45 and 90 minutos aftor i.p. inJoction
of MEGA (5 or 10 mg/kg) or tho salino vohiclo. Each fomalo
rocoivod all throo troatmonts, with troatmont ordor

countorbalancod.

SYSTEMIC TREATMENT WITH momma ANTAGONIST (MECAMYLAMINE)
DID NOT IN-IIBIT LORDOSIS '

Hormone Tx= .5pg E8 1: 3 + .qu ‘Prog
I00

'O‘
+
..—

80

60

40

LORDOSIS QUOTIENT

20

 

.PT I5 45 . PT IS 45 . PT Is 45 min
SALINE MECAMYLAMINE MECAMYLAMINE
(5mg/kg) (IOmg/kg)

FIGURE 9 Systomic troatmont (Tx) with mocamylamino (NEDA)
did not inhibit rocoptivity in E8 plus P primod DVX rats.
Ton animals rocoivod oach of tho throo systomic troatmonts
in throo bohavioral tost sorios at wookly intorvals. Thoro

was no offoct of mocamylamino troatmont at oithor doso.

86

Bllflltl
Bystomic inJoction of tho nicotinic rocoptor antagonist
mocamylamino was inoffoctivo in disrupting tho hormono-

inducod rocoptivity (soo Figuro 9; Friodman two-way ANOVA of
I5-minuto tost LD’s or delta-15 LQ’s [8 L015 - Lap?)

across troatmonts within animals, p > .05). Only tho
i5-minuto tost scoros and dolta-15 scoros woro oxaminod, as

tho poak “offoct” was obsorvod 15 minutos aftor inJoction.

8mm

Systomic mocamylamino troatmont did not disrupt soxual
rocoptivity in E8 plus P primod fomalos at dosos which do
block nicotino-inducod lordosis and which roduco ICV

osorino-inducod lordosis bohavior.

87

W

In Exporimont 6, tho ability of ICU infusion of HECA to

disrupt EB plus P-inducod rocoptivity was assossod.

EEQSIIHCI.

Fourtoon OVX, scroonod, Bhorman strain rats with
bilatoral ICV cannulao (histologically vorifiod aftor
complotion of tho oxporimont) woro usod as IUbJICtI. Each
rat undorwont two tosting sossions spacod ono wook apart,
with tho first of thoso occurring ono wook aftor tho
storootaxic surgory for implantation of tho intracorobral
cannulao. Prior to oach of tho two tosting sossions, oach
animal was primod with EB (0.5‘ug/ day x 3) plus P (0.5 mg)
in ordor to induco high lovols of soxual rocoptivity on tho
day of bohavioral tosting. Animals woro tostod boforo (PT)
and i5, 45 and 90 minutos aftor infusion. Tho animals woro
randomly dividod into two groups (nI7 oach), ono of which
rocoivod an infusion of a high doso of MEGA (10 ‘ug/ .5ul/
sido, bilatorally) ono wook and tho CSF vohiclo tho othor
wook; tho othor group rocoivod a lowor doso of NEDA (5 ,ug/
.591! sido) ono wook and CSF tho othor wook. within oach

group, tho ordor of infusion troatmonts was countorbalancod.

mm
Bilatoral infusion of HECA did not significantly affoct

loo ‘ o—O

 

s‘w.~.-_. o i /
.\ \o
°\‘./ 0’
80
3 so
:2
:5 4o
2
20
HORMONE REGIMENT .Spq EB a: Body: + .5mg Frog
0
PT 1545 90 PT1545 90, PT15 45 90
C S F M E C A M EC A
0.5ullside. ICV 5.0 ug/side 1O ug/side

FIEURE 10.1CV infusion of mocamylamino did not inhibit
rocoptivity in E8 plus P primod OVX rats (Exporimont 6).
For oach MEGA doso, sovon animals rocoivod MEGA ono wook and
tho CSF vohiclo tho othor wook. Tho CSF tosts from tho two

groups havo boon combinod for clarity in this figuro.

89

LO’s in E3 plus P primod fomalo rats (Uilcoxon matchod-pairs
signod-ranks tost on 15 minuto scoros or dolta-l5 LO’s,
comparing CSF and HECA wooks within animal, p > .05). Tho
CSF tosts from tho two NEDA doso groups havo boon poolod for
clarity in Figuro 10, which shows tho rosponso ovor timo

following infusion of mocamylamino and CSF.

Bin-ac!

Intracorobral infusion of mocamylamino was inoffoctivo
in antagonizing hormono-inducod rocoptivity at tho dosos

usod.

9O

W

Exporimont 1a domonstratod that nicotino troatmont could
facilitato lordosis in EB-primod fomalo rats as roportod
proviously (Fuxo g;__gLL, 1977). Tho nicotino-inducod
facilitation of lordosis was complotoly blockod by tho
nicotinic antagonist mocamylamino (Hook 4 of Exporimont 1,
Exporimont 2), also confirming tho rosults of Fuxo .;_.L.

Hoxamothonium protroatmont roducod tho magnitudo of tho
nicotino-inducod lordosis, but a significant facilitativo
offoct of nicotino on lordosis was novortholoss soon in tho
20 mg/kg HEX protroatmont group (Hook 5 of Exporimont 1d).
Atropino protroatmont was also found to roduco nicotino-
inducod rocoptivity, but not to provont it complotoly (Hook
6 of Exporimont 1d, and Exporimont 3).

Bystomically administorod mocamylamino protroatmont
roducod tho induction of rocoptivity by ICV osorino infusion
(Exporimont 4). Bystomic HEOA was inoffoctivo, howovor, in
roducing rocoptivity in E8 plus P primod fomalos (Exporimont
5). ICV infusion of MEGA was also inoffoctivo in disrupting

hormono-inducod lordosis bohavior (Exporimont 6).

Tho nicotino-inducod facilitation of lordosis obsorvod
in Exporimonts 1, 2, and 3 agroos with tho rosults of Fuxo
I£__ILL (1977) dospito mothodological difforoncos.
Spocifically, thoso difforoncos includo tho strain of
animals usod (Fuxo: Spraguo-Dawloy vs. our uso of tho
Shorman strain) and tho EB priming rogimon (Fuxo: 1

91

pg/animal/day x at loast 5 days, vs. our 0.5 pg /kg, or
approximatoly 0.13‘ug/animal/day x 3). Tho tosting protocol
also difforod (Fuxo g;_gLL_did not protost thoir animals
boforo administration of nicotino) as did tho form of
nicotino (Fuxos tartrato form, vs. our uso of froo baso).

In ostrogon-primod OVX rats, any drug can potontially
facilitato lordosis by stimulating roloaso of progostorono
from tho adronal gland. Thoro aro two roasons that this
potontial hormonal mochanism is unlikoly. First, tho offoct
of nicotino is vory rapid and transiont, occurring within 5
minutos and doclining by 20 minutos aftor injoction. Diroct
intravonous injoction of progostorono itsolf roquiros 30
minutos to facilitata lordosis (Glasor, Rubin & Barfiold,
1983), so tho offoct of nicotino could not bo modiatod by
progostorono. Bocond, tho ostrogon doso usod in this study
is bolow tho lovol roquirod for dovolopmont of sonsitivity
to tho bohavioral offocts of progostorono (Olomons I;_.LL,
1981).

Tho division of tho population of animals usod in
Exporimont 1 into rospondors and non-rospondors soomod
nocossary in attompting to scroon tho subjoct population.
Tho rosponso of animals to nicotino inJoction is not
consistont ovor trials, howovor, making it impossiblo to
assign an animal to ono of thoso catogorios basod on a
singlo tost. Tho inoffoctivonoss of tho classification usod
is illustratod in Tablo 1. Soloctod non-rospondors did
rospond strongly to nicotino injoction (Tablo 1), and

92

soloctod rospondors occasionally did not rospond to nicotino
(Exporimont 1d, Hook 7, individual data not shown). Tho
variability botwoon animals is apparontly not duo to
consistont individual difforoncos in suscoptibility.

Protroatmont with tho nicotinic antagonist mocamylamino
complotoly blockod nicotino-inducod lordosis bohavior, whilo
hoxamothonium and atropino woro loss offoctivo. This
indicatos that tho bohavioral offocts of nicotino aro duo to
an action on tho nicotinic rocoptor.

Tho lowor offoctivonoss of tho nicotinic antagonist,
hoxamothonium, to block nicotino-inducod facilitation of
lordosis rolativo to mocamylamino may bo duo to structural
difforoncos botwoon thoso two compounds. Both mocamylamino
and hoxamothonium aro nicotinic antagonists, but
hoxamothonium has a quatornary nitrogon (and is thoroforo
chargod at physiological pH) whilo mocamylamino has an
unchargod tortiary nitrogon. Duo to its chargo,
hoxamothonium would havo poor accoss to tho brain from tho
systomic circulation duo to tho blood-brain barrior (Goodman
& Gilman, 1975). Tho partial offoctivonoss of hoxamothonium
to roduco nicotino-inducod facilitation of lordosis may
indicato that at loast part of nicotino’s offoct is duo to
stimulation of poriphoral nicotinic rocoptors.
Altornativoly, tho brain aroas in which nicotino acts to
induco lordosis bohavior may bo poorly protoctod by tho
blood-brain barrior. Circumvontricular organs and tho
hypothalamus would bo indicatod as important sitos for

93

nicotino action by such a proposal. On tho basis of tho
data on hand, it is impossiblo to distinguish botwoon thoso
altornativos.

Tho antagonism of nicotino by atropino, a muscarinic
antagonist, was unoxpoctod. Thoro aro, howovor, sovoral
possiblo oxplanations for this offoct. If ono assumos that
nicotino facilitatos lordosis only by binding to nicotinic
rocoptors, thon throo possibilitios oxist. First, 'atropino
may act as a nicotinic antagonist by compoting with nicotino
for nicotinic binding sitos. Such a possibility is not
supportod by biochomical data, howovor, as atropino doos not
displaco nicotino from nicotinic binding sitos in vitro (soo
1H1392fl§119fl,for citations). A socond possibility is that
atropino roducos nicotino-inducod rocoptivity by provonting
activation of muscarinic rocoptors by nicotino. In this
schomo, it is proposod that nicotino's bohavioral offoct is
in part dopondont upon indiroct_activation of an ondogonous
muscarinic mochanism. Atropino roducos tho offoct of
nicotino by acting ”downstroam“ in tho lordosis-facilitating
noural circuit activatod by nicotino. No assumption of
intoraction at a singlo sot of rocoptors or within a singlo
noural sito is roquirod. Tho potontial for this typo of
intoraction may bo ono of tho roasons that tho litoraturo on
tho psychopharmacology of soxual bohavior is so full of
contradictory offocts and nourotransmittor intoractions.
Finally, and most likoly, atropino may antagonizo tho
bohavioral offoct of nicotino in a non-spocific manor. At

94

tho high doso usod (30 mg/kg), it is possiblo that atropino
has non-spocific offocts not limitod to tho muscarinic
rocoptor. Tho doso of atropino which roducod
nicotino-inducod rocoptivity is cortainly highor than should
havo boon nocossary: tho lowor (7.5 mg/kg) doso is
sufficiont for most spocific offocts of atropino. This
lowor doso, whilo inoffoctivo in antagonizing tho nicotinic
induction of rocoptivity, is sufficiont to block tho
induction of rocoptivity by intracorobral infusion of
muscarinic drugs (soo Clomons .3_.1,, 1983 for roviow).
Othor possiblo oxplanations for tho antagonistic offocts
of atropino and nicotino on lordosis bohavior involvo
assuming that nicotino doos not act strictly at nicotinic
rocoptors. Antagonism botwoon atropino and nicotino would
bo okpoctod if nicotino actod as a muscarinic agonist,
oithor diroctly or indiroctly. A diroct agonist rolo of
nicotino is unlikoly, as nicotino is not a ligand \for
muscarinic rocoptors (soo INIBQDHQIIQN)- Indiroct rolos
aro also possiblo. Nicotino could potontially roloaso
ondogonous acotylcholino or to dolay tho broakdown of
acotylcholino, although I aam unawaro of any biochomical
data to support oithor suggostion. Eithor of thoso actions
would bo oxpoctod to facilitato lordosis bohavior duo to tho
rosulting stimulation of muscarinic rocoptors. On tho basis
of othor work in this laboratory, it appoars that nicotino
probably doos not facilitato lordosis by an indiroct action
involving ondogonous ACh. Atropino protroatmont at 2 mg I

95

animal, i.p. (approximatoly oqual to tho bohaviorally
inoffoctivo lowor doso usod in Exporimont 1d and Exporimont
3) complotoly provonts tho facilitation of lordosis inducod
(by intracorobral infusion of carbachol, osorino, or
acotylcholino plus osorino. Thoso compounds stimulato
lordosis bohavior by stimulating muscarinic rocoptors
diroctly or indiroctly; if nicotino also stimulatos lordosis
by a muscarinic rocoptor modiatod mochanism, thon tho lowor
doso of atropino should havo complotoly provontod tho
facilitation of lordosis by nicotino.

On tho basis of tho discussion to this point, it is
posiblo to concludo that tho most likoly mochanism of action
of nicotino on lordosis bohavior is through tho stimulation
of nicotinic rocoptors. Tho most likoly mochanisms by which
atropino could intorforo with that facilitation is to block
muscarinic rocoptors 'downstroam" from tho sito of nicotino
binding or as a rosult of non-spocific actions of tho high
doso usod. It appoars from othor work in this laboratory
that thoro is an important muscarinic cholinorgic link in
tho noural circuit for lordosis bohavior (soo
Lulagnugllgu). Disruption of this atropino-sonsitivo link
in tho noural pathway loading to nicotino-activatod lordosis
bohavior disrupts tho bohavioral rosponso to nicotino. A
partial bohavioral rosponso to nicotino porsists, porhaps

duo to activation of othor transmittor systoms by nicotino.

Tho finding that ICV osorino facilitatos lordosis bohavior

96

in EB-primod fomalo rats agroos with provious rosults from
this laboratory (Clomons g§_.LL, 1983). Hhilo systomic

mocamylamino troatmont was found to roduco this facilitation
1n Exporimont 4, it did not complotoly provont it. This
indicatos that stimulation of muscarinic rocoptors can
rosult in facilitation of lordosis, ovon if nicotinic
rocoptors aro blockod. As notod abovo, howovor, tho
convorso is not truo, as Clomons g;_gLL,(19G3) havo shown

that atropino protroatmont complotoly provonts tho
facilitation of lordosis by osorino or osorino plus
acotylcholino infusion. This pattorn of rosults is not
consistont with tho nicotino data, howovor. Hhilo tho
bohavioral offoct of nicotino inJoction is blockod by
mocamylamino and roducod by a high doso of atropino, tho
bohavioral offoct of osorino infusion is blockod by atropino
and roducod by mocamylamino. Tho facilitation of lordosis
by osorino is apparontly modiatod primarily by muscarinic
rocoptors, although nicotinic rocoptor activation may
contributo. As concludod oarlior, tho bohavioral offoct of
nicotino is most likoly duo to activation of nicotinic
rocoptors, which ovontually rosults in tho activation of an
atropino-sonsitivo pathway. Thoso rosults, whon takon
togothor, suggost that thoro is a common muscarinic
mochanism to tho facilitation of lordosis by both nicotino
and osorino. It appoars that nicotino may facilitato
lordosis through pharmacological activation of tho
ondogonous muscarinic mochanism, and that thoro is not

97

roally a ”nicotinic mochanism” for lordosis bohavior.

This proposal is strongly supportod by tho rosults of
Exporimonts 5 and 6. In thoso oxporimonts, systomic or
intracorobral troatmont with mocamylamino did not disrupt
soxual rocoptivity in ED plus P primod fomalos. If thoro
woro an ondogonous nicotinic mochanism rolovant to
hormono-activatod soxual rocoptivity, thon disruption of
nicotinic transmission should havo disruptod rocoptivity.
This was not obsorvod, ovon at dosos which aro bohaviorally
offoctivo in othor systoms. Tho dosos of mocamylamino
administorod systomically had oarlior boon found to provont
nicotino-inducod lordosis and to roduco osorino-inducod
lordosis bohavior (Exporimonts 1d, 2, and 4). whilo wo havo
no bohavioral data of our own rogarding tho dosos of
mocamylamino administorod intracorobrally, Brozonoff &
Jondon (1970) showod that 5 ‘ug mocamylamino complotoly
blockod a dolayod prossor rosponso producod by carbachol
whon both drugs woro infusod (soquontially) into tho floor
of tho fourth vontriclo. Tho dosos of mocamylamino usod
thoroforo should havo boon offoctivo in disrupting nicotinic
transmission.

Hhilo mocamylamino is inoffoctivo in disrupting lordosis
bohavior in hormono-primod animals, administration of a
muscarinic antagonist in tho samo paradigms doos intorforo
with soxual rocoptivity. Systomic troatmont with tho
muscarinic antagonist scopolamino (dosos) significantly
roducos rocoptivity in E8 plus P primod fomalo rats

98

(Richmond & Clomons, 1965a). Similarly, ICV infusion of
scopolamino roducos lordosis quotionts in E8 plus P primod
fomalo rats (Clomons .1__.LL, 1983). It appoars that
blockado of muscarinic rocoptors disrupts hormono-inducod
lordosis bohavior, but blockado of nicotinic rocoptors doos
not. Onco again, an ondogonous muscarinic cholinorgic
mochanism is indicatod.

Pharmacological stimulation of nicotinic rocoptors can
facilitato lordosis, but stimulation of nicotinic rocoptors
is not ossontial for hormono-inducod soxual rocoptivity. In
contrast, whilo pharmacological stimulation of contral
muscarinic rocoptors also inducos soxual rocoptivity,
stimulation of muscarinic rocoptors is critical for
hormono-inducod soxual rocoptivity. In conclusion,
muscarinic cholinorgic transmission is moro important than
nicotinic transmission in tho rogulation of lordosis
bohavior. In fact, wo havo no ovidonco to indicato that tho
bohavioral offocts of nicotino troatmont aro actually
rolatod to tho control of lordosis bohavior by ondogonous
nicotinic transmission. Tho bohavioral offocts of nicotino
may roprosont a rocoptor-modiatod pharmacological artifact,
as thoso offocts may havo nothing to do with tho rogulation
of soxual rocoptivity by a nicotinic mochanism. It
thoroforo doos not soom fruitful to attompt to dotormino tho
sitos of nicotino action, as this offort may bo ono of
studying tho bohavioral pharmacology of nicotino rathor than
studying tho nourochomical control of soxual rocoptivity.

99

On tho othor hand, tho study of tho sitos of tho
muscarinic mochanism is vory important to tho undorstanding
of lordosis bohavior. It is possiblo to proposo that tho
muscarinic cholinorgic mochanism boing discussod roprosonts
tho “final common pathway” to tho oxprossion of
hormono-activatod lordosis bohavior. If this muscarinic
mochanism is as important as it appoars to bo on tho basis
of tho data currontly availablo, thon muscarinic antagonists
should disrupt lordosis activatod by any of a largo numbor
of hormonal or pharmacological mothods. Only thoso agonts
which facilitato lordosis via activation of an altornato
(non-muscarinic) routo or via simultanoously activating
parallol routos should facilitato lordosis in tho prosonco
of atropino or scopolamino.

An altornato suggostion is that pharmacological
troatmonts which facilitato lordosis do so by prosynaptic
modulation of acotylcholino roloaso. If this is tho caso,
thon muscarinic antagonists should provont tho bohavioral
offoct of any of tho agonts which facilitato lordosis by
incroasing acotylcholino roloaso. Convorsoly, muscarinic
agonists should ovorcomo tho inhibition of lordosis inducod
by agonts which aro prosumod to act by roducing
acotylcholino roloaso. Tho possibility that nicotino
facilitatos lordosis by stimulation of acotylcholino roloaso
has alroady boon discussod, and it sooms unlikoly to this

author.

100

SUHHARY AND CONCLUSIONS

Bystomic nicotino injoction facilitatod lordosis
bohavior in ostrogon-primod OVX rats, and this facilitation
was provontod by protroatmont with tho nicotinic antagonist,
mocamylamino. Hoxamothonium, a nicotinic antagonist with
poor accoss to tho brain, was loss offoctivo. Hoxamothonium
roducod but did not provont tho nicotino-inducod
facilitation of lordosis. Similarly, tho muscarinic
antagonist atropino roducod but did not provont
nicotino-inducod rocoptivity.

ICV infusion of tho cholinostoraso inhibitor, osorino
(physostigmino) facilitatod lordosis; this offoct was
roducod but not provontod by mocamylamino protroatmont.

ICV infusion or systomic inJoction of mocamylamino did
not roduco soxual rocoptivity in OVX rats mado highly
rocoptivo with ostrogon plus progostorono priming.

Proviously publishod work from this laboratory has
domonstratod that muscarinic antagonists (atropino and
scopolamino) disrupt soxual rocoptivity whon administorod
systomically or intracorobrally in tho samo paradigm
(Clomons .;_‘LL, 1980, 1983; Richmond & Clomons, 1985a).

By comparing tho ability of mocamylamino to roduco or
provont soxual rocoptivity in sovoral paradigms with tho
offoctivonoss of muscarinic antagonists in thoso samo
paradigms, it appoars that thoro is a critical muscarinic

lOl

link in tho noural circuit rosponsiblo for tho induction and
maintonanco of soxual rocoptivity. In contrast, thoro doos
not appoar to bo a comparablo nicotinic link. In fact, tho
lordosis-facilitating offoct of systomically administorod
nicotino may bo largoly a pharmacological offoct without
rolation to tho normal nourochomical rogulation of soxual

rocoptivity.

102

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120

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121

APPENDICES

APPENDIX 1: Individual lordosis quotionts and summary
statistics for ostrogon-primod OVX rats boforo (PT) and 5 and
20 minutos aftor i.p. inJoction of nicotino (0, 25, 50, 100,
or 200‘pg/kg) (Exporimont 1a).

 

Nic Lordosis Ouotiont
.1_.Iisols___nau ET 4’ 493.
162 i 0 0 0 0
163 2 0 0 0 0
165 1 0 0 0 0
166 1 0 0 0 0
167 2 0 0 0 0
168 1 0 0 0 0
176 2 0 0 0 0
179 2 0 0 0 0
1a1 1 .9. .9. .9. .9.
MEAN (nI9) 0 0 0 0
162 2 25 0 0 0
167 1 25 0 0 20
171 2 25 0 0 0
173 1 25 0 0 0
178 1 25 0 0 0
178 2 25 0 0 0
182 1 25 0 10 10
184 2 25 0 0 0
121 2 .2: .9. ..9. .L
MEAN (nI9) 25 0 1.1 3.3
161 1 50 0 0 0
161 2 50 0 0 0
165 2 50 0 20 10
168 2 50 0 100 20
170 1 50 0 0 0
174 1 50 0 0 0
176 i 50 0 20 0
179 1 50 0 0 0
181 1 50 0 90 0
1.82 1 .52 .9. 99.. .9.
MEAN (nI10) 50 0 31 3
164 2 100 20 100 90
169 2 100 0 0 ’ 0
171 1 100 0 20 0
172 2 100 0 40 0
173 2 100 0 0 0
175 1 100 0 40 20
177 1 100 0 50 0
180 1 100 0 10 0
180 2 100 0 30 0
la; 1 19.9 .9. 19. .L
MEAN (nI10) 100 2 33 11

122

Appondix 1, continuod

 

Nic Lordosis Ouotiont
Link—Mas ET 3’
163 1 200 0 0
164 1 200’ 0 90
166 2 200 0 90
169 1 200 0 0
170 2 200 0 0
172 1 200 0 60
174 2 200 0 0
175 2 200 0 80
177 2 200 0 70
181 2 292 ..L :9.
MEAN (nI10) 200 0 44

Summary statistics, Exporimont 1a.

Hia_Dass.
0 #O/I‘O
25 119/k9
50 uo/ko
100 119/kg

200 pg! kg

10
10

10

3F38°°°°38°E

Moan Lordosis Ouotiont (S.E.M.)
Brain:

0 N O O O

(2)

2.1.1.11...
o
1.1 (1.1)

31.0 (13.2)
33.0 (9.3)

44.0 (12.6)

123

W
o

3.3 (2.4)
3.0 (2.1)
11.0 (9.0)

10.0 (5.2)

APPENDIX 2: Lordosis quotionts of ostrogon-primod OVX rats

boforo (PT) and 5 minutos aftor

nicotino

injoction (150

‘ug/kg): Effoct of protroatmont with mocamylamino (MECA, 1 or 5
mg/kg), hoxamothonium (HEX, 8 or 20 mg/kg), or atropino (ATR,
8 or 20 mg/kg). (Exporimont 1d).

Hook 4 :

Mocamylamino (MECA)

ni coti no-i nducod lordosi s

8:118 81 ii

 

Sal 20 30
Sal 0 80
Sal 0 80
Sal 0 90
Bai...._19...129.
MEAN 6 76
SEM 4 12

 

 

protroatmont provontod
EnaTx PT .51. Ecol: PT :1
MECA 1 0 0 MECA 5 0 0
MECA 1 0 0 MECA 5 0 0
MECA 1 0 0 MECA 5 0 0
MECA i 0 0 MECA 5 10 0
baaa.i....9.....9. naaa.:...19L...J&l
0 0 4 2
- - 2o‘ 2

Hook 5 : Hoxamothonium (HEX) protroatmont roducod but did not
provont nicotino-inducod lordosis

8:118. PT 4:;

 

Sal 0 40
Sal 0 70
Sal 0 70
Sal 0 80
811......9...199.
MEAN 0 72
SEM - 9.7

Hook 6 : Atropino

EEIIX.. PT §L_.

 

HEX e o o
HEX a 0 so
HEX a o co
HEX a o 60
HEL.E.....9....aQ

o 46

- 11.7

(Atr) protroatmont

provont nicotino-inducod lordosis

8:113. PT .QL

 

Sal 0 60
Sal 0 70
Sal 0 80
Sal 10 80
Sai......9...129
MEAN 2 78
SEM 2 6.6

8:115 PT I§L_

 

Atr 8 0 10
Atr 8 0 10
Atr 8 0 60
Atr 8 0 60
63:..5L...9...192

0 48

- 17.1

124

Baal: #81 .5;
HEX 20 0 1o
HEX 20 o 10
HEX 20 o 20
HEX 20 so 90

16 42
10.3 17.7

roducod but did not

 

EcaIx ET :1
Atr 20 o 10
Atr 20 0 1o
Atr 20 o 40
Atr 20 0 so
612.22...JQ...482

o 34
- 10.3

APPENDIX 3: Lordosis quotionts of ostrogon-primod OVX rats
boforo (PT) and 5 minutos aftor nicotino injoction (150,ug/kg):
Effoct of protroatmont with atropino sulfato (7.5 or 30 mg/kg).
(Exporimont 3).

Protroatmont (30 minutos boforo nicotino)

Animal Salino Atropino (7.5) Atropino (30)
may... LT. ET—JI; ELL—.2.
288 0 30 0 0 0 10
289 0 30 0 50 0 0
291 0 40 0 20 0 10
292 0 100 0 50 0 30
293 0 20 0 70 0 10
294 0 50 0 0 20 10
295 0 0 0 0 0 10
297 30 80 0 70 0 0
298 0 20 0 0 0 50
.Zfi 9__.fl 9__9. 9__l.Q
MEAN 3 46 0 26 2 14
SEM 3 10.6 - 9.9 2 4.8

125