A BEHAwoRAL mums. or ' muucmoemc DRUGS Bissefiatiosi for the Degree of Ph. D. , MSGH‘éGAN SYATEUNEVERSITY WiLLEAM JAMES MARQUfiS 1974 ' IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIOLIIII I . LIBRARY 3 1293 10472 Michigan State University This is to certify that the thesis entitled #WWWE presented by ‘4/ // 5". _ . , ;),,v;l ' has been accepted towards fulfillment of the requirements for P1 D. degree in .2 Zigzag/cf; flak/W571 7;” MI, WM 0-7 639 fixASU iRARr' I «I “ st; 1’ 7*? fLZce— -"’ fie“ _ ”929'“ ABSTRACT A BH-IMIIOML ‘MLYSIS OF HALLUGINOGDIIC DRUGS By Willie! J ales Marquis the results free these studies indicate that operant conditioning paradips can be a useful tool for characterizing hallucinogenic properties of psychoactive drugs as well as for differentiating agents within the hallucinogenic drug class. Furthermore. these schedules provided a practical means for assessing tolerance phenuena and cross-tolerance relation- ships between hallucinogenic drugs since the results derived from these experiments with rats as experimental subjects correlated well with data derived free human studies. Finally. the utilisation of these schedules for drug inter- action experiments provided data that may well be useful for ascertaining the mechanius of action of hallucinogenic drugs. Since these techniques yielded unique behavioral profiles for hallucinogens they should prove useful in psychiatric research for testing endogenous compounds that are potentially instru— nental in initiating naturally occurring psychosis. The results free Section I indicate that nar. a cate- cholanine-like hallucinogenic agent could be differentiated behaviorally true the indoleanine type hallucinogens. LSD and psilocybin. The behavioral profiles induced by am on URL. ’1 and Sidman-lvoidance paradigms resembled those seen following gee-phetnaine over a wide dose range. it the highest dose tested in URL and II paradigns. om resembled 1.51) and psilocybin. Additional behavioral similarities between m4 and 93amphetamine were noted in Section II. The development of a unidirectional cross-tolerance between these agents on both PR and URL paradigms further confinmed the likelihood that they shared to some extent common mechanisms of action in the central nervous system. Finally. it was demonstrated in Section III that the stumulation of Sidman-Avoidance re- sponding induced by either our or g—amphetamine was identically attenuated by IMP? pretreatment. These findings and the fact that an?! pretreatment failed to attenuate the pause induced by M on an FR. whereas cinanserin ( a 5-HT receptor blocking agent) did, indicated that the amphetamine-like stimulation induced by non was probably mediated by catecholamines. whereas the hallucinogenic behavioral depression is more likely due to an interaction with a serotonergic mechanism. Studies investigating the effects of repeated administration of hallucinogens revealed that LSD and mescaline produced a rapid and complete tolerance formation on an F3940 schedule. whereas peilocybin. non. nMT’and gramphetamine produced varying degrees of tolerance development and only over a longer period of daily injections. Drug dosage proved to be an important variable as larger doses of hallucinogenic agents consistently prolonged tolerance developent. In addition. the utilisation of different schedules in tolerance assessment confined a previously reported finding that an animal will only develop tolerance if this develollent enhances the likelihood of meeting reinforc-ent requiruents. Thus. in these studies. tolerance develoxment to drug-induced disruptions was evident on URL and FR paradips. whereas tolerance was not manifested for drug- indaoed stimulation on the shock avoidance schedule. The tolerance and cross-tolerance data suggest that the disruption of operant behavior induced by various hallucino- genic agents has a canon basis in acting upon sale central discriminatory function. more are likely to be several points of attack on this overall systu. however. since a complete cross-tolerance was not duonstrable for all combinations tested. the assumption that the hallucinogenic action is exerted through some cos-on pathway. regardless of the specific agent examined. was fortified by the finding that cinanserin is an effective antagonist of mescaline. mr. LSD. non and psilocybin for the hallucinogenic pause in as performance. Since cinanserin is a specific blocker of 5—HT receptors. it follows that the canon factor for the hallucinatory effects would relate to increased activity at central serotonergic receptors. me one-my cross-tolerance relationships for not when tested with other agents. however. indicates that perhaps this agent has a wider spectrum of action in the central nervous syst- than other hallucinogens and probably involves catecholnine mechanisms as well. A working hypothesis of the mechaniu of hallucinogenic drug action as developed based on the drug interaction studies (Section III): “me drugs induce. directly or indirectly. an emessive activation of 5-HT receptors on the serotonergic raphe neurons projecting to the limbic forebrain and thereby markedly suppress the firing rate of the raphe cells. theories purporting a 5-HT receptor antagonist role for hallucinogenic drug action were not supported by these studies. no tolerance develcpent to the 1'3 impairment induced by hallucinogms (LSD and mescaline in this study) was not de- pendent upon contiguous presentation of the drug action and the specific behevioral measuruent. Presumably. the tolerance development progresses independently of experiential inter- actions. If LSD and like agents result in marked and pro- longed activaticn of receptors on raphe neuronal cell bodies. a desensitization may one about which would result in the reduction of the drug effect and subsequent tolerance fonation. A WVIORAL AMLYSIS OF HAILUGDDWIC DRUGS 8! William James Marquis A HISSERTA HON mhitted to Michigan State University in partial fulfillment of the requiruents for the degree of mom 0? nummnnr Deparhent of Pharmacology 1971; AOWHLEDWTS me author wishes to convey his gratitude to Dr. mohard H. M for his intellectual and mactioml support thrcuyaout the preparation of this thesis. It has indeed been a priveledge and rent-ding experience to work under his direction. He also appreciates the generous assistance provided by m. 8.1. Tilson. Finally. he wishes to thank Dr. TM. Brody. m- OoL. abhor. Dr. TM. Tobin and Dr. R. Raisler for their helpful suggestions while serving on his guidance cmittee. nun 0F WNTDJTS FAG mmL IHWNCHO’OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO 1 SECTION I nose-mm arms 01‘ n-AMPHETAMINE. M4. PSILDCIEIN AID LSD ON OPRAH? BEAVIORAL PARAlIIGlS. moss. 53 DISCUSSION 85 sacnoun MC AWNISTRATION 01' HALLUCINOMIC DRUGS. CROSS- 10mm: mummrs AND HWNISiS OF “ELEANOR. INTRONC‘I‘ION......................................... 88 METHODS.............................................. 91+ WIS.............................................. 96 DISCUSSION........................................... 1'41 $6110}! III DRUG-INTEAC’I'ION MRS INVOLVING HALLUCIMMC DRUGS. INWWC‘I’ION........................................ M8 moweeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee 15° 118311.13...”....................................... 1.53 DISCUSSION.......................................... 175 mnr‘nn ”ml! mNCLUSONSeeeeeeeeeeeeeeeeeeeee 18“ mmommYO000......OOOOOOOOOOOOOOOOOOO00.0.0.0... 189 l. 2. 3. 1+. 5. 1. 2. 3. lb. 5. 1. LIST OF TABLES FAG MON I Control drl responding during various phases of 59 the experimmt. The Effects of Various Doses of LSD and g. 70 amphetamine on Continuous Avoidance Responding The Effects of Various Doses of Psilocybin and 72 non on Continuous Avoidance Responding. Response rates during consecutive 15 second 75 sepente of II 60 seconds responding under NaCl control conditions. Dose-related effects on the slope of the 76 regression line for n responding. sorrow II he mini-u effective dose of various hallu- 99 cinogenic drugs that will induce a pause in Flt-1&0 responding. ‘me time-course of tolerance formation for l02 various hallucinogenic drugs on M. ‘me effects of chronic. daily drug admini- ion straticn on the hallucinogeMc pause. Cross-tolerance relationships between various 122 hallucinogenic drugs based on pause durations. Cross-tolerance relationships between various 125 hallucinogenic drugs based on responding rates. ”ZION III Iffect of cinanserin on the disruption of 171+ Flt-30 responding by various hallucinogens. l. 2. 1. 2. lb. 5. 6. 7. 8. l. 2. LIST OF mamas MEAL INTMDUC‘EION Ordeal structures of one hallucinogenic drugs mosynthetic pathways involved in neurotransmitter production: potential pathways leading to hallu- cinogenic compounds. SECTION I in. dose-response effects of g-amphetamine and non on drl-18 second response patterns. Sample cumulative records depicting response patterns of Rat 3-2 on drl-18 induced by various doses of g-amphetamine. Sample cumulative records depicting response patterns of Rat 8-2 on drl-18 induced by various doses of psilocybin. “the dose-response effects of LSD and psilocybin on drl-1.8 response patterns. The rate-dependent effects of various doses of III! on 11-60 responding. ’me rate-dependent effects of various doses of g-amphetaaine on 3-60 responding. me rate-dependent effects of various doses of psilocybin on FI-60 responding. m rate-dependent effects of various doses of LSD on lit-60 responding. SECTION II Representative response patterns (cumulative records) for 15D and g-smphetsmine on M. The effects of repeated. daily injections of g. amphetamine on Flt-30 responding. PAGE 63 65 67 79 81 83 100 107 3. 5. 6. 7. 8. 9. 10. 12. 1. 2. 3. b. FAQ The effects of repeated. daily injections of 109 d-amjhetuine on M responding. me effects of repeated. daily injections of non 111 on drl-18 behavior. The effects of repeated. daily injections of a 111; depressing dose of mm on drl-18 response patterns. The effects of repeated. daily injections of 116 g—amphetsmine on Sims-Avoidance behavior. The effects of repeated. daily injections of 118 nor on Sidman-Avoidance behavior. Cross-tolerance relationships between mm and 128 mescaline on M0. Cross-tolerance relationships between LSD and 130 1141' on Flt-#0. Cross-tolerance relationships between non and 133 g-uphctsmine on drl-18. Cross-tolerance relationships between g-smphe- 135 thine and non on drl-18: Importance of drug order. The lack of effect of conditioning factors in 138 the developaent of tolerance to mescaline on IVE-30. SECTION III The effects of lowering 5-HT on the behavioral 19. response to I!!! and mescaline on Flt-30. The effect of lowering catecholamines on the 156 behavioral response to g-smpnetuine on Sid-an- Avoidance. The effect of lowering catecholamines on the 158 behavioral response to 1114 on Sidman-Avoidance. The effect of lowering catecholamines on the 162 behavioral response to M on mac. 5. 6. 7. 8. 9. 10 . 'flhe effects of pretreatment agents on the behaviora1.disruption induced by non on IR responding. The effects of cinanserin pretreatment on the behavioral disruption induced by nnT’and seesa- line on PRpBO responding. The~effect of cinanserin pretreatment on the behavioral disruption induced by LSD on tRp30 responding. The effect of cinanserin pretreatment on the behavioral disruption induced by peilocybin on £3.30 responding. The effect of cinanserin pretreataent on the behavioral disruption induced by'gralphetanine on FRpSO responding. schematic representation of hallucinogen-raphe interactions. RAGE 16b 170 172 133 GENERAL INTRODUCTION A consciousness revolution has permeated our society. People utilising such diverse techniques as meditation. hypnosis. yoga. ingestion of psychoactive drugs. sensory deprivation. biofeedback. etc.. are discovering and explor- ing new states of awareness quite different and apparently infinitely more exciting and meaningful than those experienced during nomal. everyday activity. Although this revelation is a fairly recent phenomenon in our society. primitive cultures have long recognized the significance of altered states of consciousness for spiritual development as well as physical and mental healing. Advocates hold out hope that. at a time when so much seems wrong in our world. a change of consciousness might help to reduce the problems. prejudices and inhumanities which prevail and provide an environment for the development and realization of man's true potentials. ‘ It is important to appreciate the evolution of the limited awareness state which dominates our ordinary con- sciousness. It is both biologically and culturally con- ditioned for the purpose of selecting only those stimuli in our envirorment that have biological and psychological survival value. The central nervous system expands a large amount of energy screening out irrevelant stimuli. Thus. from the plethora of potential sensory data. both external and internal. only a small proportion reaches consciousness. Our perception of reality is thus constricted under normal circumstances through a very limited sampling of our environment. One can readily appreciate the significance of efficient and selective sensory screening in biological evolution. for one would be overwhelmed. confused and diverted from survival tasks if exposed to a total onslaught on the senses. This would certainly be disastrous for an animal whose very existence depended on its ability to detect predators. However. humans in their comparatively safe environment can probably afford to let down their "perceptual screens" and sample the wide spectrum of sensory data previously unknown. In this manner. human consciousness may progress beyond its present lhmitation to reveal the intimate nature of the mind and its vast potentialities. Of course. more conservative views emphasize the possible dangers of an “open" psyche to the emotional stability of the individual and to the maintenance of established social and cultural systems. Because of the current widespread experimentation with altered states of consciousness by so many members of our society and because of the potential usefulness of these states. it is imperative that multidisciplinary scientific research efforts be carried out in order to understand their biological mechanisms. psychological consequences and possible medical applications. Hope- fully. objective scientific scrutiny and reporting will dissipate some of the mystery. uncertainty and emotionalim that seems to exist concerning the subject. William James. the eminent psychologist and pioneer of the consciousness movement. recognised the need for the scientific exploration of consciousness as early as 1902. In an often quoted passage he stated: ........ 'Our normal waking consciousness is but one special type of consciousness. whilst all about it. parted from it by the filmiest of screens. there lie potential forms of consciousness entirely different. we may go through life without suspecting their existence: but apply the requisite stimulus. and at a touch they are all there in all their completeness. definite types of mentality which probably somewhere have their field of application and adaptation. No account of the universe in its totality can be final which leaves these other forms of consciousness quite disregarded. How to regard them is the question. for they are so discontinuous with ordinary consciousness. Yet they may determine attitudes though they cannot furnish formulas. and open a region though they fail to give a map. At any rate. they forbid a premature closing of our accounts with reality.” The class of drugs known as hallucinogens provide an excellent tool to explore and attempt to understand many aspects of altered states of consciousness. as many of the major effects induced by these drugs are characteristic features of other altered states (Ludwig. 1969). The hallucinogenic drug-induced state in humans encompasses pronounced changes in physiological. sensory and psycho- logical functions. Physiological changes involve the sympathetic nervous system and include tachycardia. in- creased blood pressure. mydriasis. hyperreflexia. increased muscle tone and hyperglycauia. Sensory alterations include perceptual distortions in all the sensory modalities usually attributed to a disinhibition of incoming sensory stimuli. The stimulus flooding may lead to hallucinations and synesthesias (colors heard. sounds seen. etc.). Psychological changes include extraoe variations in mood ranging fran deep anxiety and depression to intense euphoria. feelings of unreality. distortions of space and time sense. disintegration of ego function. upsurge of unconscious material. cognitive disturbances and hypersuggestibility. These are not the only effects induced by hallucinogenic drugs. but the listing should suffice to convey some idea of the range of experiences they afford. It should be stressed that the drug itself makes certain types of ex- periences probable but does not in any sense determine a particular experience. The drug experience is in many significant ways very individual. and depends for its structure and content principally upon two non-drug factors: The individual's personal history and the expectancies referred to as the 223 (who he is at that time); and the physical and psychological environment. including other persons present during the trip. referred to as the setting. The significance of these non-drug variables is often not adequately considered in human drug experimentation. either in the laboratory or on the street. A thorough evaluation of one's set as well as a serious effort to provide a physically and psychologically comfortable environment certainly appears to enhance the likelihood of a beneficial drug experience. John Lilly stresses the importance of “programming your trip“ with some dramatic examples in Programming a__r_:__d Metaprogramming i_n_ the Ii_um_ap_ Biocommter (1971). Classification of thg’Hallucinogens Attempts to classify hallucinogenic drugs into mean- ingful categories have resulted in several varied schemes. In the literature one finds different nomenclatures for the general class which reflects the diversity of the experiences afforded as well as the author's bias. Thus. such terminology as hallucinogenic (emphasizing the perceptual alterations). psychotomimetic Oahmicking psychosis) and psychedelic (mind manifesting) are some of the general class names employed. These designations serve to portray the particular attitude and proclivity of the author. so that one can often predict where he stands on the moral. social and ethical ramifications of this controversial class of drugs. I feel that all these appelations appropriately convey some aspect and/or potential of the drug experience. but none of the terms are canprehensive enough to include the vast spectrum of psychological transformations that may eventualize. Contributing to the ambiguity in nomen- clature is the often reported fact that the nature and essence of the drug experience is difficult to comprehend and co-unicate. This sense of the ineffable results from the uniqueness of the subjective experience as well as the limitations of our language systan to describe these states. Recently a new branch of psycholinguistics has developed for the purpose of establishing more descriptive and meaningful tens to express the dimensions of human consciousness (Authur Hastings. personal comunication). For the purpose of this paper. I will use the term hallu- cinogenic drugs. it being the least controversial designation in current usage. A hallucinogenic drug will be generally defined as a chuical which in non-toxic doses produces changes in perception. thought and mood without meuory loss. mental confusion. or profound disorientation for the sense of self. place or time. This distinguishes this class from a group of anticholinergic compounds (deliriants). such as atropine. soopolamine and ditran. thich induce unpleasant hallucinations accompanied by a delirious state including memory loss. mental confusion and dysphoria. Attupts to subdivide agents within the hallucinogenic drug class have generally been based on musical structure and resenblance to biogenic amines purported to be neuro- transmitters in the central nervous system. Thus. two broad categories would include hallucinogens with an indole structure (resubling serotonin) and those with a phenethyl- amine structure (resnbling the catecholamines. norepi- nephrine and dopamine). In addition. the tetrahydrocanna- binols (1110's). the active ingredients of Cannabis. are sometimes regarded as a third subclass of hallucinogens. althougi some difference of opinion still exists as to whether Cannabis is truly an hallucinogen (Jones. 1972). Hallucinogenic agents with a basic indole structure in- clude lysergic acid diethylamide (LSD-25). Psilocybin. N.N-dimethyltryptamine (INT). N,N-diethyltryptamine (BET). and 5-OH nu' (Bafotenin). Examples of catecholamine-like agents include mescaline (3.1+.5-trimethozqr-phenethylamine) and several amphetamine derivatives including 2. 5-dimethoxy- lt-methylluapl'xetamine (mm). The chenical structures of these hallucinogens are illustrated in Figure 1. along with g—amphetamine. a potent central nervous systu stimulant. ligure 1: Chemical 2 “‘8”! ‘- \C‘”' d—c I“ LSD ‘“:JE:;ucAh-¢:lb-lflla c -0" MBSCALINE IN IDLEHIINES 0 e ,0“ ‘OH H a ‘5' ' m‘“t-‘u- ” a €00. # PSI IDCYEIN PHBIE'IHYLAMINES 3* acu‘oefl- ”H; a” . 6”a 0" [IN on. oil Op 6‘ ”u C- ’\ ga‘l’ THC structures of some hallucinogenic drugs C”; I w‘*"”"u’ GM, 1141‘ Qua-9N. MIA. CI” D-AMPHETMEIE Although not typically classed as an hallucinogen. it will be included in these present investigations for cunparison purposes . gistory gn_d_ Importance of Hallucinogenic Drug Research Hallucinogenic plants have been known for milleninums and have been utilized in primitive societies for divination. curing and as a facilitator for coununion with supernatural powers. However. it has only been since the serendipitous discovery of the powerful hallucinogenic effect of LSD-25 by Albert Hoffmann in 1943 that interest was generated among scientific researchers. 140an had been synthesizing various amides of lysergic acid in an attanpt to develop a potent analeptic agent. On the way home from work after having handled the resultant compound. he was seised by a bizarre mental state which be correctly attributed to the accidental ingestion of the material he had synthesised. He subsequently took that he thought to be a modest dose (250 ug) and shortly thereafter was overwhelmed by the ' full impact of the hallucinogenic experience. Later investigations revealed that he had ingested 8 to 10 times the minimal effective dose. The fact that a small amount of a chemical (30 to 50 ug) could trigger such profound paydaological changes led investigators to believe that similar endogenous mechanisms were operating to produce naturally occurring psychosis. Thus. the state induced 10 by hallucinogens was postulated to be a drug model of schizophrenia. and the search was on to elucidate the bio- chuical mechanism occurring in the brain of a schizo- phrenic which resulted in the production of a hallucinogenic- like compound. As the structures of more hallucinogenic drugs were elucidated. it was evident that they all resembled putative central nervous system neurotransmitters. Thus. the hypo- thesis was advanced that faulty metabolism of one of these neurotransmitters yielded endogenous hallucinogenic can- pounds. Figure 2 shows the biosynthetic pathways in neurotransmitter production as well as potential pathways leading to hallucinogenic metabolites. Since that time several enthusiastic reports have periodically appeared claiming to have isolated hallucinogenic-like substances in psychotic patients. In 1952. the adenochrome hypothesis of schizophrenia was suggested by Hoffer. Osmond and Smythies. It was postulated that epinephrine and norspinephrine may not be matabolized properly under stress and instead of following the usual route of metabolism. might be transfomed into a cyclized indole-like quinone (adenochrome) with psychotomimetic effects. This compound was reported to be found in the blood and urine of psychotics. The enthu- siasm generated by this finding was soon dissipated by the failure of other research groups to replicate these findings. 1.1 Figure 2: Bicsynthetic pathways involved in neurotransmitter production; potential pathways leading to hallu- cinogenic cmpounds. “(a cwvfll- ‘09" . (D'cua‘cua'N”5 (firm-k @ Hug, N -. W ‘2’ a .t (Tryptophan ) (TryptaminO) (INT) “’0‘“. c “u m” hu‘ l (5-011 TmtOPhan) Oman-“’r’ ””a (5-HT) all, out", “with, “w: (Bufotcninf GO“. ' c“- (“If _ I ll. ”"3 L (Tyrosine) “Ocu‘- C." - ‘0.” l. N." 1 (non) mtlg'C‘.‘ “Na. d :go“‘.‘h.~% :wCIh-cu‘.ufl‘ (Dopamine) (mmr‘ - “‘ (Mescalinef' ‘0“. 6 He- NH‘ .“ (NE) * indicates hallucinogenic compound. 12 Another interesting study implicating an endogenous psychotomimetic metabolite of an amine was carried out by Friedhoff and Van Winkle (1962). Engaged in an inves- tigation of the matabolism of catecholamines. these workers discovered the presence in the urine of schizophrenic patients of a metabolite identified as 3.b-dimethoxy-phenylethyl- amine (IMPEA) which is closely related to mescaline and probably derived from abnormal methylation of dopamine (see Figure 2). This finding. along with the observation that methionine ( a methyl donor) caused deterioration in the mental states of schizophrenics (Bruno and Himwich. 1962; Pollin gt 3.. 1961). stimulated extensive investi- gation of abnormal methylation of central amines as the cause of psychosis. Some subsequent reports failed to replicate these early findings and attributed the abnomal metabolite to dietary factors and conflicting methodologies (Perry 93 a__l.. 196+). Nevertheless. intensive interest in this approach has continued to this date and additional methylation hypotheses have appeared. For example. mela- tonin. a pineal gland hormone. is an o-methylated derivitive of serotonin and. although without psychotomimetic activity in man. has been demonstrated by thsaac (196+) to form a metabolite. lO-methoaqr-harmalin. that is structurally related to harmine and harmaline (potent hallucinogens). It is conceivable that psychotomimetic metabolites of this 13 type result as a consequence of a shift in the normal metabolism of serotonin toward these pathways. Another intriguing hypothesis currently attracting much attention states that excessive methylation of endo- genous tryptamines. yielding psychotomimetic products. may be responsible for the onset of schizophrenia. Saavedra and Axelrod (1973) recently dancnstrated that the human brain contains enzymes that will convert endogenous tryp- tamines to INT and bufotenin. This significant finding clearly denonstrates. for the first time. that the human brain is capable of synthesizing hallucinogenic compounds. The tryptamine-methylation hypothesis of schizophrenia is further supported by the following evidence: 1141‘ and bufotenin have been reported to be present in the urine of schizophrenic subjects; and. the adninistration of L- tryptophan. the amino acid precursor of tryptamine and serotonin. along with methionine. to schizophrenic patients resulted in intensification of their symptomatology (Hoffer and Oslaond. 1967).. Further studies. of course. are necessary to validate and extend these findings. Hopefully a rigorous research effort will be made. as the outcome of these studies has tremendous implications for psychiatry. One area of investigation that should be pursued in the evaluation of this hypothesis is the phenomenon of tolerance. An endogenous psychotogen should be one for whim tolerance 11$ does not develop. host of the known psychotomimetic sub- stances have been shown to evoke tolerance quite rapidly. Surprisingly. 1141' has been little investigated in this regard. Another important aspect of research with the hallu- cinogenic drugs is the evaluation of their therapeutic efficacy for certain mental and physical disorders. As mentioned earlier. primitive tribes for centuries have effectively utilized hallucinogenic plants for healing purposes. This is understandable. since they believed that health and disease hinged on their contact and relation- ship with supernatural and spiritual powers. Indeed. the witch doctor often become the most exalted and revered meaber of the tribe as a result of his frequent use of hallucinogenic plants to coo-lune with the spirits and derive his assumed healing powers. In our society. however. the enthusiastic claims for therapeutic usefulness of hallu- cinogens has encountered staunch resistance from the medical "establishment". This opposition arose primarily from fear of the intensity of the responses these drugs evoke. as well as their prestmed potential to induce enotional lability and personality changes. It has been far easier to view this power with alarm and repression than to try to find ways of controlling and utilizing it. Establish- ment attitudes and influence are clearly reflected by the 15 widespread publicity given to studies which purportedly show that hallucinogenic drugs are in some respects harmful. whereas contrary evidence is often ignored. Despite these impediments. encouraging reports have emerged in several therapeutic areas. Psychiatrists throughout the world have enthusiastically reported on the efficacy of hallu- cinogenic drugs in the treatment of several types of mental disorders. In many of these reports. therapists stated that the incidence of recovery or significant improvement was substantially greater than with other therapies used by then in the past. In addition. the trea‘hnent typically required much less time and was accordingly less costly for the patient. The types of conditions stated to respond favorably to treatment with hallucinogens include the psychoneuroses. such as obsessive. canpulsive. anxiety and phobic conditions; depressive states (exclusive of endogenous depression); sexual deviations; criminal psychopathy; psychosomatic disorders; and autism in schizophrenic children. The value of hallucinogens in the therapeutic process may derive from several factors in the drug experience. LSD and related hallucinogens serve as powerful tools to uncover and reveal repressed material and thus provide the patient and therapist with insights into the history of the mal- adaptive behavior. In addition. the patient under the drug 16 may relive some crucial early experience with the re-expression of the’emotions attendant to it. The cathartic effect of releasing pent-up»emotions has been proposed to be effective for resolving neurotic behaviors. Another symptom-complex often expressed by psychiatric patients involves a loss of meaning in life. an absence of purpose and a failure of faith. LSD and similar agents in big: doses often induce religious and mystical experiences accompanied by deep ecstasy which are claimed to inspire a major reorganization of one's beliefs and life outlook. The ability of these agents to induce mystical-religious experiences not only has therapeutic potential for the psychiatric patient. but also may provide those with a spiritual bent the opportunity to probe the wonders of mystical consciousness. Peyote. whose chief active ingredient is mescaline. is currently being uployed by over 50.000 Indians of the North American Native murch as a vital part of their religious cereuonies. It has also been shown experimentally that hallu- cinogenic drugs taken in a religious context can elicit profound mystical experiences. The I'Good Friday“ experiment conducted by Walter Panthke as part of his Ph.D. dissertation uployed a double-blind technique mereby one-half of the participants received 30 mg. psilocybin and one-half received placebo. The subjects were divinity students and the setting was a Good Friday service in a Boston chapel. 17 A nine-category typology of the mystical state of con- sciousness was defined as a basis for measuranent of the phenomena of the drug experience. In all categories the experimental group achieved a statistically significantly higher score. and in most cases the significance was over- whelming. According to the criteria used. follow-up studies six months later showed that the impact and sig- nificance of the drug experience had persisted to enrich their spiritual lives in many dimensions. It is hoped that more experiments of this nature will be undertaken. By judicious manipulation of set and setting. the effects of these agents in combination with various enviromental stimuli on human experience may be evaluated for their propensities to enrich and extend the intellectual and notional impact of the experience. Another area where hallucinogenic drugs have been purported to be efficacious is in the treatment and rehabili- tation of alcoholics. The rationale behind this approach initially derived from the frequent statments of alcoholics that rehabilitation practices were usually undertaken only when they had "hit bottom“ and experienced delirium tremens (dt's). Since dt's are a toxic hallucinatory state, it was reasoned that LSD would perhaps simulate some aspect of this phenomenon. Canadian research groups (Osmond. 1952) uploying big: doses of LSD found that 501.. of their patients 18 were substantially rehabilitated. They reported. however. that the drug was not simulating dt's but rather inducing a “psychedelic" experience (Oslond. 1957) during which patients gained insights into the nature of the factors responsible for their drinking. Subsequent reports. however. have refuted these earlier findings so the area is contro- versial. Nevertheless. since no other medical cure has been developed for alcoholism. this treatment technique. though in doubt. deserves further investigation and trial. Another potential use for hallucinogenic drugs is in the Wheat of painful. teminal stages of serious diseases such as cancer. Hallucinogens serve two useful functions in this regard. They act as potent analgesics (Kast. 1963) as well as attenuating the anxiety associated with antici- pation of iminent death. These effects probably derive from several factors. The rich. expanded sensory experience induced by the drug compels the patient to divert his attention from his immediate pain and thus serves as an escape hatd: through said) his tension can be dissipated. In addition. hallucinogenic agents diminish the cortical control of thoughts. concepts and associations (Silverman. 1969) so as to reduce the significance of the pain and the associated affect. Finally. hallucinogenic drugs purportedly obliterate ego boundaries so as to promote a geographic separation of the self and the ailing part (Kast. 1961+). 19 Another useful effect of these drugs in this regard is their ability to induce religious-mystical experiences which seem to alter the terminal patient's spiritual and philosophic attitudes about death. A study done by Kast (1961+) in which 80 cancer patients were each given lOOug. LSD showed that 90% responded favorably as evidenced by a brightening of mood. lessening of pain intensity. improved attitude toward death and improvanent of sleep patterns. ‘mese effects persisted in most cases for at least 10 days following the drug. Certainly in our society. which provides little to ease the inevitability of dying. the study of techniques such as these should be extended. Some other fields in which hallucinogenic drugs have been examined for potential applicability include: enhancenent of creativity (Hannah et al.. 1966); training of workers in psychiatry (Hyde. 1968) in order to provide them insights into the nature of psychotic thinking. mood. and perception; and facilitation of the manifestations of psychic phenomena (Roll. 1972). The preceding discussion of the known and potential therapeutic uses of hallucinogenic drugs illustrates the wide spectrum of possible applications for these agents. Althouga medical science has been slow to evaluate their efficacy. it is hoped that in the future this resistance will be mitigated. One means. perhaps. of overcoming this anti-intellectualism is to provide a sound theoretical 20 foundation for the therapeutic utility of hallucinogens based on animal research studies. By integrating data derived from neurophysiological. biochemical and behavioral investigations of hallucinogenic drugs in animals. a better understanding of the fundamental effects of these agents on brain functions will undoubtedly promote greater appli- cation to clinical problems as well as aid in the elucidation of basic neurophysiological and psychological processes. .Extrapolation of data derived from animal studies to humans is often criticized on the basis of evolutionary differences in brain function. social conditioning factors. etc. However. in regard to hallucinogenic drugs. I believe that some extrapolation is justified. Hallucinogenic drugs purportedly interact primarily with phylogenetically primitive brain structures subserving basic perceptual. emotional and vegetative functions. These neural systans are practically identical (neurophysiologically and bio- chanically) throughout the mammalian animal kingdom. up to and including man. Another criticism often expressed in regard to extrapolation is that much higher doses of drugs are necessary in animals to elicit comparable effects seen in humans. I believe this might be understood if one realizes that humans have developed a highly active and sensitive inhibitory system that screens out the majority of internal and external sensory cues. whereas lower animal 21 species passivdly assimilate more of their environment. The active inhibitory system in humans would consequently be more easily disrupted by hallucinogenic drugs requiring a comparitively low dose. A more meaningful evaluation of the extrapolation would be based on comparison of potency ratios for various hallucinogens across species. In this regard. there is a remarkable similarity. For example. LSD for both man and rat is the most potent of the agents. followed by DOM. psilocybin. DMT’and mescaline. This observation strengthens the assumption that similar brain mechanisms are involved across species in generating the hallucinogenic state. There have been many attempts to form a general theory of hallucinogenesis: unfortunately. none can account for more than a small portion of the available data. The following discussion will involve a review of some of the pertinent studies which have evaluated the effects of hallucinogenic drugs in animals. Current theories of the mechanism of action of hallucinogenic drugs will be dis- cussed in relationship to these findings. In order to Judiciously formulate any theories regarding the complex nature of the hallucinogenic drug state. one must inte- grate data from many scientific disciplines. Emphasis in this review will be directed toward biochemical. neuro- physiological and behavioral findings. It should be stated 22 that most of the early studies involved LSD as the proto- type hallucinogenic agent. since it was traditionally assumed that all agents within the hallucinogenic class produced similar subjective and pharmacological effects by sharing common mechanisms of action (Snyder and Richelson. 1968; Kang and Green. 1970). This similarity of action was based on the finding that members of the class showed cross- tolerance in humans (wolbach gt al.. 1962). interpreted by ' most to mean that they all acted on a common receptor site in the central nervous system. It has only been in the last few years that other members of the drug class have been evaluated. Unexpectedly. several studies have revealed significant differences in the action of these agents on several systems. These disparities will have to be con- sidered in any attempt to formulate a unifying hypothesis for the mechanism of action of the hallucinogenic drug class. Research on the biochemical correlates of the hallu- cinogenic drug state has focused on drug interactions with the endogenous central neurotransmitter. serotonin. 5- . hydroxytryptamine (SéHT). This grew out of an early finding that LSD antagonized the action of 543T at certain neuro- muscular effector sites. such as in the gut or uterus (Gaddum. 1957: Woolley and Shaw. 1954). The use of histo- fluorescentwmapping techniques in recent years has revealed that the majority of central nervous system 5-HT neurons 23 are located in the brain stem raphe nuclei (Dehlstrom and run. 1965). The studies of Freedman g 5;. (1961) revealed that LSD had an influence on the metabolism of 5-HT in the brain. causing an elevation in its concentration. It was later seen that this increase was accmnpanied by a fall in the concentration of 5-hydroxyindoleacetic acid (5-HIAA). the principle metabolite of 5-HT (Rosecrans g_t_ al... 1967). Since the converse was seen after stimulation of the raphe. it was suggested that perhaps LSD had specific inhibitory effects on the raphe cell bodies to account for the reduced 5-HT turnover. In an experiment designed to test this hypo- thesis. it he found that LSD in minute parenteral doses (lo-20 ug/kg) caused a caplete inhibition of the spontaneous firing of single neuronal units in the midbrain raphe nuclei of the rat (Aghsjanian gt 5;" 1968). The entire population of raphe units was uniformly inhibited by LSD. The speci- ficity of the effect for raphe neurons was ducnstreted. as surrounding non-raphe neurons were unaffected or increased their firing rates. In addition. many other drugs were tested for this effect and it Is shout that only hellu- cinogenic drugs and agents that elevated 5-HT (monoemine oxidese inhibitors. 5-hydroxytryptcphan) duonstrated this dramatic inhibition. an and psilocybin both completely inhibited all raphe units when the agents were tested in doses approximating their behavioral potencies in rats. 0n the other hand. catecholanine-Jlke hallucinogens. mescaline and 1m. induced a selective depression of raphe units: only those in the ventral portion of the dorsal raphe nucleus were inhibited. whereas other units tested with these latter agents were unchanged or increased their firing rates. It is interesting to note that those units that increased their rates following 1104 and mescaline also duonstrated an increased firing following g—amphetamine (Foote gt a_];.. 1969). This differential action on raphe units by hallucinogens will be further discussed in relation- ship to behavioral findings in the Discussion Section of Section III. Little is know of the functions of the serotonergic raphe syst- and its afferent and efferent connections. Result studies have implicated that it is somehow involved in sleep mechanins (J ouvet. 1968). tuperature regulation (Feldberg ;e_t_ a_l.. 1966). sensory perception (Stevens _e_t_ a_l_.. 1967). stimulus reactivity (Tenen. 196?). habituation (Sheard and awajanian. 196B). aggression (Koella gt a_l_... 1968). neurosecreticn (Bloom gt 5.. 1968) and pain per- caption (Tenen. 1967). Interestingly. most of these functions are also altered by hallucinogenic drugs. Efferents from the raphe have been traced to the hypothalamus and limbic forebrain (Fuxe. 1961+: Anden at. g_1_.. 1966) as well as the basolateral anygdala. ventrolateral geniculate. subiculun and optic tectun (Haigler and Aghajanian. 1971;). 1hese areas are known to influence nood. perception and autonulic functions. Thus. the raphe neurons and their projections may well be intimately involved in the major effects of hallucinogenic drugs. Two hypotheses have evolved attapting to elucidate the interaction of hallucinogens with serotonin and the raphe systa. One theory proposes that hallucinogens antagonize 5-HT mediated functions in the central nervous systu in a manner siailar to their effects in the peripheral nervous systm. Boakes gt 5;. (1970) duonstrated that LSD antagoni zed 5-HT excitation of single brainstu neurons when applied icntophoretically or intravenously. In addition. Roberts and Straughan (1967). in a study of cortical neurons in cats, also found that icntophoretically applied LSD blocked the effects of 5-HT. Furthermore. Couch (1970) has dmonstrated that particular raphe units are excited or inhibited by icntophoretically applied 5-HT and that icntophoretically applied LSD simultaneously blocked raphe excitations caused both by 5-HT and by stimulation of the midbrain reticular fomation. m1: hypothesis was also favored by Brawley and mffield in a recent review article (1972) on the pharaacology of hallucinogens. In contrast. another theory proposes that LSDand other hallucinogenic agents niaic the effect of 5-HT at post-synaptic receptor sites (see references below). his theory postulates a 26 negative feedback circuit at the end of which an excess of 5-HT at a receptor on the raphe cell body may inhibit the firing of these cells. This would account for the decreased turnover of 5-HT in the forebrain seen following hallucinogens. if the drugs acted like excess 5-HT at the raphe cell bodies. Several studies support a 5-HT receptor stimulation action by hallucinogens. Anden st 11;. (1971) in experiments on rat hindlimb reflexes showed that LSD. psilocybin and 1111' caused changes similar to those seen after treatment with 5-hydroxy‘tryptophan (5-HT precursor). Aghajanian (1972; 1973) has daoonstrated that postsynaptic serotonergic raphe receptors respond to very low doses of i.v. LSD (10 ug/kg) and markedly accelerate their firing rate. LSD concomitantly depresses raphe neurons (cell bodies) at this same low dose. Thus. one requirement of a feedback loop is fulfilled. that of a reciprocal effect at a similar dose range. Other supporting evidence for this agonist hypothesis includes studies which demonstrate the similar actions of elevated 5-HT and hallucinogens. Ry stimulating the raphe nuclei electrically. Aghajanian g a_l. (1967) danonstrated that endogenous 5-HT is released in the fore- brain. The most prominent behavioral concomitant was a failure of habituation to repetitive sensory stimuli. A similar loss of habituation was noted by Bradley and Key (1958) following adoinistration of LSD. Tnese two hypotheses 2? attempting to define hallucinogen interaction with the serotonin system both presume that these agents act at 5-HT receptor sites. Other studies have indicated that the interaction may be at a presynaptic locus. In this regard. Chase at 31. (1967) suggested that hallucinogens may inhibit the release of 5-HT. while Freedman (1961) postulated that LSD may enhance 5-HT binding. From the foregoing discussion. it appears evident that hallucinogens interact with 5-HT neural mechanisms but the details of the interaction are not settled by any means. Regarding norepinephrine (NE) and hallucinogens. Anden gt 31. (1968: 1971) have shown that LSD. psilocybin and DMT'increase NE turnover. It was noted. however. that the doses were much higher than those needed for an effect on 5-HT. Some of the hallucinogen-NE interactions proposed include: direct action on the NE receptors (Bradshaw gt_al.. 1971); increased intraneuronal release of NE (Leonard and Tongs. 1969); and increased extraneuronal release of NE (Manon gt a}... 1967; Vrbanac gt al.. 1973). Surprisingly. few investigations have examined the effect of hallucinogens on dopaminergic systaus in the brain. Recent theories regarding the neuroohemical corre- lates of schizophrenia have postulated that excessive dopamine receptor activation may be responsible for the mental aberrations (Snyder. 1973: Matthyssee. 197M). 28 The recent finding that major antipsychotic drugs. 1,2,, chlorpromazine and haloperidol, are potent dopamine receptor blockers lends support to this hypothesis. In this regard. if one assumes that the hallucinogenic agents serve as a dmg model for psychosis (i._e_.. psychotomimetic). it would be reasonable to assume that they interact with dopamine functions. In the only biochemical investigation of this correlation. Daiz (1968) round that dopamine levels decreased in the brain following the administration of LSD. hmplying increased utilization of this amine. Certainly. further study of hallucinogen-dopamine interactions is warranted. In reviewing the literature describing the neuro- physiological correlates of hallucinogenic drug action. one finds much conflicting data due to different metho- dologies. doses employed. species investigated. etc. However. I will attempt to integrate such material so as to present a few general statements which may contribute to a better understanding of hallucinogenic drug action. Studies investigating drug effects on spontaneous cerebral electrical activity have revealed that low doses of hallu- cinogens induce EEG activating effects as manifested by a desynchronized (fast. low'voltage) "beta" activity (Rinaldi and Himwich. 1955). Higher doses generally result in intermittent. hypersychronous bursts superimposed on the “beta" activity. and in some cases continuous hypersynchrony. 29 Differences between various hallucinogenic agents on £30 manifestations have been noted and will be discussed in a later section. In attupting to integrate and interpret the EEG activities. it is useful to observe the ongoing'behavior manifested during a particular EEG state. In cats. Winters (1968) has observed that a "beta" activity reflected an alert. excitable behavioral state. gyAmphetamine will induce this state in animals and humans. The next level of CNS excitation (intermittent hypersynchrony) is accompanied by inappropriate bdxavior characterized by abnomal postures and movaoents. such as swatting at non-enstent objects. and is postulated to represent an hallucinatory state. The next discernable EEG’state constitutes a continuous hypersynchrony and is also indicative of hallucinatory phenomena. The behavioral concomitant of this state is described as a catatonic immobilization. The upper ranges of the continuum include anesthetic agents which induce a very slow. hypersynchronous EEG with a loss of conscious- ness. and finally convulsants with their characteristic epileptoid spiking EEO. It is important to note that this is a progressive excitation continuum so that a behavioral state of seizures would be preceded by alertness and hallucinatory manifestations followed by loss of conscious- ness. This progression of CNS excitatory states is 30 characteristically manifested during an epileptic seizure episode. Typically. excitation followed by an hallucinatory aura and loss of consciousness precedes the seizures. In an attenpt to further characterize neurophysiologically the hallucinatory state. Winters examined modulation of sensory input during various excitatory states. By measuring sensory evoked potentials induced by visual and auditory stimulus cues during the various excitatory states. he derived a theory of hallucinosis based on a breakdown of sensory modulation. He postulated that a subcortical modu- lating system responsive to activity in the reticular acti- vating systao undergoes a progressive functional disor- ganization during progressive excitatory states so that it exerts reduced control over incoming sensory information. Thus. in the alert. activated state ("beta activity") the auditory evoked response (AER) is decreased as compared to the awake but resting control. due to an increased modulation of its input. airing the intermediate stages of excitation (hallucinatory) the breakdown of modulation results in an enhanceuent of the AER which progresses to a manmum in seizure states. The visual system. he found. takes a high priority during arousal states and appears to resist modulatory control as evidenced by a progressive increase in the visual evoked response during arousal states (this would confer an adaptive advantage). The excessive activation 31 of the visual systmn as one progresses along the excitation continuum induces disruption of the modulating systu at a time prior to the breakdown of auditory modulation. In this way. visual hallucinations occur prior to ($.93. at a lower state of excitation) the onset of multismscry aberrations (auditory. tactile. proprioceptive. etc.). Although Winters does not speculate on the neural sub- strate responsible for this sensory modulation. it some possible that the raphe nuclei may be mediating this function. As previously noted. g-amphetamine increases the firing of raphe units (93.. increased modulation). thereas hallu- cinogens inhibit their activity (breakdown of modulation). The biochmical data also support this idea: g-amphetamine induces an increased utilization (turnover) of 5-HT (Diaz and Huttenen. 1972) mile hallucinogens decrease turnover. In an attempt to locate the central site of action responsible for EEG effects of hallucinogenic drugs. Fugimori and Himwich (1969) perfomed brain transaction experiments in the cat and detemined that g-amphetamine induced typical EEG desynchronization at a midbrain site. whereas hallucinogenic amphetamines (mm. on. MDA. etc.) induced their RIG effects (arousal progressing to hyper- synchrony) in the medulla. A later study revealed that the hallucinogenic agents LSD. psilocybin and mescaline also exerted their EEG effect in the medulla. These authors 32 thus postulated that hallucinogenic agents act by inhibiting a medullary center. releasing from its restraint the midbrain activating system. These data thus imply a lower brainstau serotonergic feedback systan which is activated during states of arousal and is sensitive to disruption by hallucinogenic drugs. Data from other studies support this hypothesis. Couch (1970) reported that LSD blocked the facilitation of raphe units induced by icntophoretically applied 5-HT or stimulation of the midbrain reticular formation. Koella and Czienan (1966) showed that admini- stration of 5-HT via the vertebral artery in cats resulted in EEG syndlrony. as does topical application of 5-HT to the area postrena. where some raphe units appear to terminate (Fuxe. 1965). Topical application of LSD to the area postrana blocked both of these effects. A study by Branzano (1971) denoustrated that evoked responses elicited in medullary sites (anterior portions of the nucleus of the solitary tract-HTS) by stimulation of the midbrain reticular formation were potentiated by topical application of 5-HT to this area. 5-HT cell bodies have been identified in NTS and the area postrena (Fume. 1965). That there may be a hallucinogen-sensitive feedback circuit involving the area postrena. NTS and the raphe nuclei. is further supported by the report of Morest (1960). who has dauonstrated anatomical connections between these areas. Additional 33 eVidence for the interaction of hallucinogens with this feedback system is indicated by reports demonstrating that the subjective effects and amount of EEGvactivation induced by hallucinogenic drugs depend on the level of environ- mental stimulation (Cohen gt al.. 1963: Pollard gt_§l,. 1965). Subjective effects of LSD are attenuated under con- ditions of sensory restirction and accentuated by increasing stimulation. Perhaps this can be interpreted neurophysio- logically as follows: Increased sensory stimulation on- hances the "tone" in the serotonergic feedback circuit. providing an active neural substrate for disruption by antagonists. When the environment supplies little input. this pathway would be relatively inactive and therefore not critically disrupted by hallucinogens. It should be noted that this hypothesis assumes that hallucinogens antagonize 5-HT mediated functions. which. as mentioned previously. is controversial. Another neural circuit that would be expected to be influenced by hallucinogenic drugs is the visual pathway. Several findings have demonstrated a depressant action of LSD as well as 5-HT on lateral geniculate neurons (Curtis and Davis. 1961: Phillis 93g 51.. 1967; Everts. 1957). These nuclei serve as relay stations for visual sensory pathways to the striate cortex. These findings and the observation that visual evoked potentials are potentiated 34 following hallucinogens (unters. 1970; Purpura. 1956) imply that visual stimuli are less subject to modulation and consequently may flood into consciousness. resulting in hallucinations. Studies investigating the action of hallucinogens on retinal ganglion cells have yielded con- flicting results. Schwartt and Cheney (1965) reported that both spontaneous and light-induced discharge rates of these units were stimulated by LSD. Heiss gt a_l_. (1973) found that 1141' depressed the spontaneous activity of retinal ganglion cells. It has also been shown that 5-HT similarly has a depressing effect on these units (Straschill. 1968). Heiss postulated that the MT-induced alteration of spon- taneous activity might be of some relevance for the origin of visual hallucinations: maintained illumination was found to decrease the discharge rate of retinal ganglion cells: thus. the depression of the spontaneous activity caused by TNT might be interpreted by the brain as “light" and this might contribute to the orign of abnormal reactions in the visual pathways of the brain. In this regard. it has recently been demonstrated that environmental limiting in- formation is conveyed to many brain structures via the inferior accessory optic tracts. These nerve bundles separate from the primary optic tracts just behind the optic chaima. enter the hypothalamus. traversing the medial forebrain bundle to synapse in the midbrain. hon this 35 site they pass through the medulla to synapse in the thoracic cord. Praganglionic fibers go to the superior cervical ganglion from which postganglionic fibers project to the pineal gland. The pineal gland thus serves as a neuro- endocrine transducer sensitive to light influences. The synthesis and release of melatonin. the principle hormone of the gland. is regulated by environmental lighting and is very sensitive to small changes in light spectra and intensity (Wurtmann. 1969). Melatonin exerts profound effects on brain function. probably acting as a modulator of other CNS neurotransmitters. Prominent elevations of 5-HT occur in midbrain sites following i.p. injections of melatonin (Anton-Tay. 1970). Thus. the alterations of the spontaneous activity of retinal ganglion cells induced by hallucinogens are likely to be sensed by neural circuits involving the pineal and may play a prominent effect in inducing the visual distortions of hallucinations. The perception of a brilliant "white light“ often reported at the peak of drug and mystical experiences (Tart. 1972) may result as a conse- quence of these mechanisms. Another indication that hallucinogens may be inter- acting with pineal gland function was demonstrated by Snyder and Reivich (1966). Studying the distribution of LSD. they found the highest concentration of the drug in the pineal. which contained eight times the amount found in cerebral 36 cortex:and four times that found in any other subcortical structure. The authors argued that this cannot be explained by regional differences in blood flow or lipid solubility and suggested that the selective concentration of LSD‘might be related to the perceptual and emotional effects of this drug. The high concentrations of 5-HT in the pineal also suggest a likely site for hallucinogenic interactions. Visual discrimination and gereralization studies have revealed additional perceptual alterations induced by hallucinogens. In humans (Hollister. 1962) and animals (Bradley and Kay. 1958) it has been shown that hallucinogenic drugs facilitate the subject's responding to irrevelant stimulus cues (stimulus generalization). Discrimination studies investigating accuracy of perception. however. have revealed that hallucinogens have an enhancing effect (Slough. 1957: Becker. 1967). Thus. ever though more visual sensory data is impinging on cortical interpretative areas. the discrimination capabilities are not.impaired. Perhaps selective attention mechanisms are facilitated by hallu- cinogens to allow enhanced perception of task-relevant inputs. Another phenomenon associated with hallucinogen interaction with visual systems is the occurrence of persisting after-images. This nas been demonstrated in humans with psilocybin (Keeler. 1965) and in monkeys under LSD (Peterson. 1966). This may be related to effects on 37 habituation mechanisms. As previously noted. hallucinogenic drugs impair the normally limiting and inhibiting effect of the process of habituation. An important aspect of habituation is that it occurs only if the stimulus is without signifi- cance to the subject. In this manner. irrevelant cues are screened from awareness. In the hallucinogenic state. however. visual stimuli acquire a uniqueness so as to compel central interpretive mechanisms to retain the novel image for'maximal evaluation. This loss of habituation coupled with the enhanced sensitivity to discrimination of stimuli may account for the often stated reports of the increased significance and meaning attributed to objects and events during the drug state. While it is generally acknowledged that hallucinogens interact with lower brainstem mechanisms. little is known regarding their involvement with forebrain limbic structures. Since hallucinogenic drugs induce affective. attentional and perceptual changes and since the temporal lobe. hippo- campus. amygdala. hypothalamus. septal area and their connec- ting pathways are implicated in such functions. it would be logical to assume that these drugs might exert some effects on these structures. The fact that 5-HT terminals have been traced to these structures (Fuxe. 1965) and that raphe stimulation facilitates 5-HT turnover in these areas further implicates their interaction with hallucinogens. 38 Indeed. it has been reported that the behavioral effects of LSD are not seen after temporal lobectomy in monkeys (Baldwin 25.2irv 1957). The advance of stereotaxic tech- niques have made it possible to record the electrical activity of deep structures in the human brain. LSD in doses of 50 to 200 ug. administered to schizophrenics induced paroxysmal. hypersynchronous bursts in many subb cortical structures (Adey. 1962; Eidelberg, 1965). These abnormal brain wave activities were correlated with overt psychotic behavior in these patients. Animal studies have also revealed widespread hypersynchrony in many subcortical structures following hallucinogenic agents (Schwartz. 1956; Fairchild. 1967; Adey. 1962). It was suggested by Killam and Killam (1956) that paroxysmal electrophysiological abnormalities induced by hallucinogens might be specific for limbic structures. They reported that LSD exerted little effect on the diffuse thalamocortical or reticular activation system. The widespread hypersynchrony noted in many limbic structures may represent a reverberating circuit that has functional significance in the control of behavior. In 1937. Papez proposed the existence of a limbic circuit interconnecting several of the above mentioned structures that was operational in controlling emotional behavior. Since that time many studies have appeared regarding Papez's circuit and its significance for a variety of 39 brain functions (Leaton. 1971). Iontophoretic studies in which S-HT has been applied to limbic structures have revealed a depression of the spontaneous activity in amygdala (Legge, 1966). septum (Hers and Gogalak. 1965). hippocampus (Salmoiraghi and Stefans. 1968). and hypothalamus (Bloom 9_t_ al.. 1972). These findings. based on microelectrode recording and ion- tophoretic drug application. would imply that the raphe based serotonergic system normally functions to inhibit the activity of limbic structures. Bloom (1973) investigated the suprachiasmatie nucleus in the hypothalamus in an attanpt to develop a model system for the study of drugs which specifically interact with S-HT mediated synapses. Histo- chunical fluorescence had revealed a high concentration of 5-HT containing nerve terminals at this site (Dahlstrom and Fuxe. 1965). In addition. raphe lesions are known to result in terminal degeneration in this nucleus. Microionto- phoretic S-HT depressed the spontaneous or glutamate- induced activity of these neurons. Furthermore. electrical stimulation of the median raphe mimicked this effect of depression. It was then found that LSD in large parenteral doses (200 ug/kg) would not block the effect of raphe stimu- lation: that is. the neurons continued to respond to the inhibitory effects of raphe stimulation. Utilizing a similar model. Haigler and Aghajanian (1974) likewise daonstrated that the inhibition of postsynaptic terminals of raphe neurons induced by S-HT was not blocked by 1.81]. This was dancnstrated in the amygdala as well as non-limbic structures receiving raphe S-HT terminals. including the lateral geniculate, tectum and subiculum. These studies would thus refute the 5-HT antagonist theory of hallucino- genic drug action held by many researchers in the field. Since the normal physiological functions of limbic structures are obscure. it is difficult to ascertain the significance of their interaction with hallucinogenic drugs. In general. however. it is presumed that portions of the limbic systaa are associated with inhibitory functions (McCleary. 1966: Leaton. 1971). both in a physiological and a behavioral sense. The hippocampus and septum may serve to selectively filter from consciousness those stimuli which have no biological significance and rewarding consequences (Carlton. 1963). Animals with hippocampal lesions perform poorly on behavioral tasks that require the inhibition of responses (Douglas. 1967). It appears as if hippocampectaay renders an animal ineffective in withholding inappropriate responses. In addition. habituation mechanisms are disrupted following hippocampal ablation. Carlton (1963; 1969) has compiled considerable evidence which suggests that a 'com- ponent of this systm involved in response inhibition is cholinergic. Anticholinergic drugs (atropine and scopol- amine) produce similar behavioral deficits as those seen ‘41 following hippooapal lesions. An interaction of 5—HT‘ with this cholinergic inhibitory systen was suggested by Swonger and Roch (1972). They postulated that S-HT‘ neurons origi- nating in the raphe nuclei and. projecting to limbic regions modulate sane cholinergic inhibitory mechanisms. 'me 5-H‘1' neurons act to monitor the amplitude setting of the reticular activating systu and then exert a gain-controlling function on certain limbic pathways representing a discriminatory process. According to the level of signals passing through the reticular formation and to past experience. the 5-HT' pathways increase the gain of particular cholinergic tracts to enhance the inhibitory control on certain sensory and motor systems. i.9_.. those representing non-adaptive response pattems. The total effect would be a filtering mechanism. with only the relevant signals being transmitted to higher centers and exerting a large control over behavior. Other inappropriate signals would be processed only to the extent of recognizing their unimportance. and further projection throughout the brain would be curtailed by an increased inhibitory tone in related limbic tracts. This theory assumes that in moderate or low arousal states. the cholinergic inhibitory systen would function adequately and independently in discriminatory functions. thereas high arousal levels necessitate mediation by the 5-HT‘ systen to enhance selective inhibition. Hallucinatory phenomena. #2 they propose. would result from the dual change of increased arousal and reduced 5-HT'modulation. This theory nicely accounts for the previously mentioned finding that the subjective and behavioral effects of hallucinogenic drugs are attenuated in a sensory-poor environment. In this situation, according to their theory. 54HT mechanisms (which are disrupted by hallucinogens) would not be essential for the maintenance of homeostasis. Turning now to a discussion of hallucinogenic drug effect on neocortical structures. it is difficult to assess and differentiate direct from indirect drug effects. Thus. a facilitation or inhibition of cortical neurons might reflect indirect mechanisms deriving from the drug interaction with subcortical mechanisms. In an attempt to circumvent this. Marrazzi (1957) utilized the trans- callosal response (intercortical transmission) and reported that LSD directly inhibits cortical cells at axodendritic synapses. However. latencies between stimulus and re- sponse were quite long and variable to have been true transcallosal responses: the potentials may in fact have been related to impulses traversing subcortical or even spinal tracts. In addition. Krnjevie and Phillis (1963). employing single unit studies. demonstrated that several hallucinogenic drugs injected microiontophoretically had short latency. depressant actions on cortical cells. “3 Roberts and Straughan (1967) found that icntophoretically applied LSD tended to depress firing rates and amplitudes of cortical cells and in addition antagonized S-HT‘mediated excitations of these units. 5-HT induced inhibition of these cells was unaffected by LSD. Purpura (1956). working with cats. observed decreased electrical activity from the primary sensory cortex to cortical association areas follow- ing LSD. concomitant with an increased activity in the discrete sensory pathways to the cortex. Silverman (1971) interpreted these findings to represent a homeostatic. compensatory adjustment by the organism: The inhibition is an automatic attempt by the sensory control apparatus to reduce the intensity of overloading stimulation. This inhibition in association pathways following LSD should result in disturbances of integration of sensory and perceptual information into organized and meaningful configurations. with the end result that previously learned response patterns may no longer be accessible to conscious- ness; or. alternatively. that previous experiences that are inappropriate to the present stimulus input are recalled from memory in an uncontrollable manner. Since the asso- ciational mechanisms are disrupted in the drug state. the organism would be compelled (stimulus-bound) to attend to the multitude of stimulus cues in attempting to make sense out of his environment: irrevelant and innocuous events on now would demand as much attention as biologically or psychologically relevant cues. Stimulus flooding thus would ensue without a corresponding increase in rate of data processing. leading eventually to hallucinations. This hypothesis is similar to other ”arousal" theories for hallu- cinogenic drug action. but differs in terms of the impor- tance attributed to cortical association areas in the genesis of hallucinations. Although it has traditionally been assumed that hallu- cinogenic drugs induce a rather unique physiological state. it is interesting to note the similarities between this state and the condition that prevails during RBMZ(dreaming) sleep. The subjective effects (where am states are recalled) are quite similar and include the production of endogenously- generated imagery. loosening of associations. distortions of time and space. emergence of repressed memories and unconscious elements. etc. The hallucinatory state occurring spontaneously and precipitantly in subjects drprived of REM sleep for a number of days may show even more elements in common. The likelihood that hallucinogenic drugs Shift the activity pattern of brain structures in the direction of that manifested during REM sleep is supported by the following findings. In both states. cortical EEG recordings have revealed a lowavoltage. fast activity ("beta' pattern) indicative of an activated cortex. Depth recordings of 45 electrical activity in subcortical structures have also disclosed a remarkably similar pattern of activity. As mentioned previously. hallucinogens induce hypersynchronous splicing in these areas. The parallelism to the R34 state is the occurrence of "PCD" spikes obtained from the poms. lateral geniculate and occipatal cortex (J ouvet. 1967). These hypersynchronous bursts are observed only during am episodes under normal physiological conditions. Rm dep- rivation. however. will result in the emergence of P00 spikes into the waking state. at which time hallucinatory experiences are often reported (Dement. 1967). Furthemore. LSD will shift Pm spiking from man into the waking state (Stern gt _a_]_... 1972). A possible mechanism to account for this effect may be related to the activity of the raphe neurons. It has recently been demonstrated by McGinity (1973) that anterior raphe units projecting to the forebrain cease to fire during REM sleep. Hallucinogens. as mentioned earlier. also induce a dramatic cessation of firing of these units. ‘McGinity recorded the electrical activity of several subcortical structures and noted that. during the waking state. raphe units displayed a very stabile rhythm (0.5 to 2.0 cps) which was not disrupted by environmental stimuli introduced during the recording session. It was only immediately preceding and during am that these units deviated from their normal rhythm. at which time they 1+6 periodically stopped firing. He determined that PCD spiking was reciprocally related to raphe firing and only occurred when raphe neurons were quiescent. then raphe cells did fire. Pm activity was completely suppressed. Thus. it appears that in both REM sleep and during the state induced by hallucinogens. raphe activity periodically ceases and allows the energence of PCB spiking. thich may be the elec- trical sign marking the brain trigger site of hallucinatory phenomena. Other parallelisms include: LSD produces in the dorsal hippocampus (Adey. 1962) hypersynchronous h-s cps waves (theta rhythm). a pattern whcih according to Jouvet (1963) is also observed during REM states in the cat; ablation of the raphe abolishes the effect of hallucinogenic drugs (Rosecrans. personal ccmunication) as well as Rm sleep (Jouvet. 1967). The similarity of these states might suggest that an endogenous hallucinogen-like dream trans- mitter may be responsible for the onset and maintenance of Rm sleep. In this regard. the recent in giy_o danonstration of TNT synthesis in human brain (Saavedra and Axelrod. 1973) has implications for elucidating dream mechanisms. It was found that the methylation enzyme in the INT synthetic pathway was inhibited by normally occurring compounds in the brain. It is conceivable that the restraints on this enzyme are removed during REM episodes to facilitate the production and utilization of TNT. 47 Having reviewed some of the biochanical and neuro- physiological correlates of hallucinogenic drug action. I would now like to focus on the behavioral concomitants of the hallucinogenic state. The earliest behavioral studies of hallucinogenic drugs involved crude measurements of such ambiguously labeled. naturally occurring behaviors as general excitation. aggression and emotionality during stressful situations. It is not surprising to find dis- crepancies in reported findings. as the definitions of the measured behavior. species investigated. doses uployed. etc.. have varied considerably in different laboratories. Thus. for example. Brown (1957) reported that LSD increased spontaneous motor activity. whereas Szara and Hearst (1963) found that most hallucinogens suppressed motor activity and exploratory behavior. Furthermore. Elder and Dille (1962) found that LSD increased aggression in the cat. but Chen and Watson (1960) reported increased decility in monkeys following LSD. The next level of cmplexity in behavioral design to assess drug effects consisted of simple conditioning tech- niques such as the conditioned-avoidance response. These techniques can provide useful data. but their unstabile baselines and lack of specificity severely curtail their predictive or interpretive power (mythies. 1969). In general. results from these types of investigations show 48 that an animal under the influence of hallucinogenic drugs will react to the conditioned stimulus (bell. light. etc.) as if it were the unconditioned stimulus (shock; Bridger and Handel. 1967: Bridger and Gnatt. 1956). Thus. the conditioning stimulus comes to act as if it were the shock itself. eliciting emotional and autonomic disturbances so as to disrupt avoidance responding. A further sophistication and increased specificity of behavioral paradigms followed the introduction of operant conditioning techniques as tools to measure drug-induced behavioral effects. The methods are based upon a sample principle: The characteristics of behavior are. to a large extent. determined by the environmental events that have been consequent upon past occurrences of the behavior. The behavior operates on the environment (operant behavior) and the process of manipulating such behavior by means of its environmental consequences is termed "operant condition- ing” (Skinner. 1938). Utilizing operant paradigms. one is able to investigate a sample of behavior under rigid ex- perimental controls and ascertain the influence of drugs on this particular well-established behavior. In this manner. drug-induced changes in behavior can often be related to programmed events in the animal's environment as well as to pharmacological variables. Thus. operant conditioning offers the most precise. sensitive and reproducible 14,9 technique for controlling the behavior of a subject. Operant conditioning schedules were employed in these studies pri- marily as a means of comparing and contrasting various agents within the hallucinogenic drug class and elucidating their possible mechanisms of action. Less emphasis will be directed toward interpreting the particular behavioral manifestations during the drug states. as the author feels that behavior generated in an artificial. well controlled. sterile environ- ment (93.. operant chamber) may not reflect natural be- havioral functions that would be displayed in the animals' "home ground". Since operant behavioral patterns are controlled by a delicate balance between facilitatory and inhibitory systens. they are susceptible to differential disruption by a variety of drugs. Although much research utilizing operant tech- niques has been carried out on tranquilizers. barbiturates. and stimulants. few investigations have explored the effects of hallucinogens on these paradigms. Consequently. Section I of my research project will involve the investigation of dose-response relationships of several hallucinogenic drugs on a wide variety of operant behavioral paradigns. This effort was directed at ascertaining similarities and dif- ferences within the hallucinogenic drug class. as well as establishing behavioral profiles for these agents which may be utilizable in drug-screening programs. Section II will include an evaluation of the effects of long term. repeated hallucinogenic drug administration on the performance of rats in operant paradigms. Those agents that induce tolerance will be utilized for cross-tolerance studies in an attempt to determine similar mechanisms of action within the drug class. In addition. the mechanisms involved in tolerance development will be explored. Section III will involve drug-interaction studies to determine whether alterations of neurotransmitters and their receptors will influence the behavioral effects of hallucinogenic drugs. Using these data. possible mechanisms of action of hallucinogens will be presented. 51 SECTION I INTMWC'HON The hallucinogenic drug class includes a large number of compounds with varied chemical structures. Attupts to categorize these agents on the basis of biochemical. psychological. and pharmacological activity have generally resulted in three classes (Brawley and Duffield. 1972). The anticholinergics such as atropine or ditran and the tetrahydrocannabinols appear to differ free a third class which include indoleamine and catecholamine-containing hallucinogens. Drugs in this latter category comprise the better-known) hallucinogens such as lysergic acid diethyl- amine-25 (LSD). mescaline. psilocybin. and 2.5-dimethoxy- h-methylamphetamine (m1). These drugs produce similar subjective and pharmacological effects in man (Wolbach .e_t_ 11.. 1962: Rosenberg e_t_ a_1_.. 1963; Hollister _e_t_ a_]_._.. 1969) and it has been frequently proposed that they share some common mechanism or act on the same common receptor or site (Wolbach _e_t_ a_l... 1962: Snyder and Richelson. 1968; Kang and Green. 1970: Barker gt al.. 1973). However. Brawley and Duffield (1972) recently concluded that there may be no single underlying mechanism for the agents of this class of hallucinogens. This conclusion is supported by recent electrophysiological (Aghajanian _e_t al.. 1970; Haigler and 52 Aghajanian. 1973) and neurochemical (Freedman gt_g;.. 1970: Tilson and Sparber. 1972: Stolk 93 31,. 197#) data indicating major differences among representative hallucinogenic substances. The behavioral effects of the hallucinogens in rodents have been described extensively by Smythies and his colleagues (Smythies et al.. 1969). particularly in regard to the effects of these drugs on signalled continuous avoidance responding. However. few if any dose-response comparisons of representative hallucinogens have been reported for other types of behavioral contingencies. although individual compounds such as LSD have been studied (Jarrard. 1963: Freednxan at al.. 1969: Appel. 1971; Tilson and Sparber. 1973). The purpose of the present investigation was to compare indolealkylamine-type hallucinogens such as LSD-25 and psilocybin with an hallucinogenic amphetamine derivative. D04. using three different schedules of operantly reinforced responding. Behavioral comparisons with gramphetamine were also included. since this drug is a potent central nervous stimulant not usually considered to be hallucinogenic. 53 MEmHODS Subjects: Albino rats of the Sprague-Dawley and Fisher strains were used as subjects in these investigations. Animals were housed in groups of 2.u in controlled quarters under a 12-hour light-dark cycle. Food and water were freely available in the home cages of animals trained on an avoidance schedule. whereas only water was freely available to animals trained to respond for food reinforcement. Apparatus: Daily behavioral sessions were conducted in operant chambers enclosed within a ventilated. sound- and light-attenuated outer chamber. Control of schedule events in the chamber and recording of response data were accomplished by means of appropriate electromechanical components. Drug injections and data analysis: The behavioral effects of various doses of gyamphetamine sulfate (K and X Labs. Plainview. N.Y.). lysergic acid diethylamide-ZS (LSD) tartrate. psilocybin. and 2. 5-dimethoaq-h-methylammetemine (1'04) hydrochloride on three schedules of reinforced behavior were studied. The hallucinogens were obtained from.the FDA/mm Psychotomimetic Agents Advisory Comittee. All drugs except psilocybin were dissolved in isotonic saline solutions and were injected i.p. immediately before placing the animal into the operant chamber. Psilocybin was dissolved in 0.01 N H01 solution. Each rat served as his own control and received each drug at “-5 dose levels twice in an ascending-descending order. Drug sessions were separated by at least two daily control sessions in which the vehicle was injected. (roup means were established for the baseline behavioral measures obtained from each schedule of reinforcement investigated. In most cases. drug-induced alteration in these measures were compared to upper and lower limits of control responding (NaCl injection). A significant drug effect is defined as an average behavioral measurement that is equal to or greater than 3,2 standard deviations from grouplNaCI control means (Tilson and Sparber. 1973). The drugs were studied randomly one at a time until canpletion of a dose-response evaluation. Two weeks separated the end of one series of dose-response studies for one drug and the beginning of the next series. Schedule 1: gglrl§.respgnding: A rat on a drl schedule receives reinforcement only if it does not make the den signated response (bar-press) for a predetermined length of time since the last response. Responses occurring before the end of the interval reinstate the entire interval and postpone reinforcement. This schedule promotes low response rates and is a good measure of timing behavior. Several reports in the literature indicate that hallucinogenic drugs alter "time sense" in humans (Hollister. 1968: Aronson.g§,§l.. 1959) and thus one might expect these agents to affect drl performance. 55 Four fuale Sprague-Dawley rats weighing appronmately 250 grus at the beanning of the experiment were food- deprived to 80% of their free-feeding body weight. The rats were trained to lever press for food reinforcement (Noyes food pellets. 1+5 mg.) initially and the requireuent for reinforcement was increased gradually to a drl-18 second schedule of reinforcement (Ferster and Skinner. 1957). 11in training for 10 weeks was required to produce stabile control rates of responding (3.2-3J4 responses/min.). Dose- response effects of the drugs were studied as described previously. The response measures analyzed were mean number of responses omitted and number of reinforcers received during 60-min. sessions. In addition. the average time between unreinforced responses (IRT' s) was obtained by dividing the time lapsed between unreinforced responses into Z-sec. categories. Schedule gm (Continuous) Avoidance: Eight male Sprague-Dawley rats (300-400 9:.) were trained over a period of two months to avoid electric foot shock on an unsignalled continuous avoidance schedule. In this paradigm behavior is controlled by negative reinforcuent. The subject must bar-press to avoid an electric shock (2 ma.- 0.5 sec. duration) delivered every 5 sec. (shoals-shock interval). A bar-press will delay the shock for 30 sec. (response-shock interval). The mean number of responses 56 uitted. number of shocks received and IRT's (based on 2 sec. class intervals) were measured during 60 min. sessions. Four of the animals were used to study the effects of g- amphetamine and LSD. while the retaining four were used to study psilocybin and TIM. Schedule 3-MQ-Intewa : Four male Fisher strain rats weighing approximately 150-175 grams at the beginning of the experiment were food-deprived to 80% of their free- feeding body weight. The subjects were trained gradually to lever press for food reinforcement on a fixed interval 60 sec. (FT-60 sec.) schedule of reinforcenent. On this paradigm. a food-deprived rat receives food reinforcement (#5 mg. Noyes pellet) for the first response following a fixed time interval (60 see.) from the last reinforcer. Sessions were terMnated following 50 reinforcers. Re- sponses occurring during consecutive 15 sec. segments of each 60 sec. interval were measured. Average response rates during each 15 sec. sement and the overall response rate were determined (Tilson and Sparber. 1973). The rate- dependent effects of the drugs were analyzed by comparing average vehicle control response rates during each of the four 15 sec. segments and drug-induced changes in rate (McMillan. 1973). In the present study. each group's average control rate during each 15 sec. sement is plotted on the abscissa and the drug rates as a percentage of the average 57 control rate on the ordinete. The values were plotted on a log-log scale and the slopes of the resulting regression lines were determined by the method of least squares. In addition. the percent change in rate following drug (Yb variable) was extrapolated from the regression line for a control rate of 0.1 responses/sec. (vaariable; see Table 5). 58 RESULTS s as dr e n in : Under vehicle-control conditions. the drl-18 sec. schedule of reinforcenent generated stabile responding with an average rate of 3.28 responses/min. An analysis of the average rates of responding. number of reinforcers received and mean unreinforced IRT's for controls during each of the four experiments indicates little shift in responding occurred during the 5 month course of the experiment (Table 1). As reported by numerous investigators (Zimerman and Schuster. 1962; Schuster gt_ g" 1966). _q-amphetamine increased markedly the rate of drl responding. This behavioral stimulation was associated with a decrease in the number of reinforcers received and a decrease in the average time between unreinforced responses (shorter IRT's; Fig 1). Significant alterations in responding (above or below 2 5.0. from the mean) were observed for each of the 3 behavioral measures at 0.5 to 1.5 mg/kg of _e_- amphetamine. Higher doses up to 3.0 mg/kg (not shovm in Fig.1) also increased the rate of drl responding. but the change in behavior was not as prominent as observed with 1. 5 mg/kg of g-ammetamine. 'lhe hallucinogenic amphetamine deriVitive. mM. significantly decreased the number of reinforcers received at 0.10 mg/kg in a manner similar to 0.25 mg/kg of g—amphetamine. In addition. 0.25 mg/kg and 0.50 mg/kg of EM significantly increased response rates 59 Table 1. Control drl responding during various phases of the experiment. Average behavioral measure during congol drl responding m gasponses (min. Reggorcers non-reinforced 132' s 9.. g-Amphetamine 3. 2810.144 ilk-:19 16. 3:1. 6 In! 3. 2530.00 118-310 16.312. 0 L81) 3. 201-0. 30 117113 16. 631. 8 Psilocybin 3. 371-0. 50 112315 16. 0:2. 0 51 Each value is the mean of four animals. each receiving 12-11; NaCl control sessions. Variability is expressed as 2 standard deviations since upper and lower limits of control responding correspond to 12 8.1). of control responding. 60 Figure 1: The dose-response effects of gramphetamine and DOM on drl-id response patterns. Drug dosages are represented on the abscissas. The behavioral measures are represented on the ordinates. Drug effects are expressed as a mean percent of control. Each point represents the mean of eight observations (a rats; 2 observations/rat at each dose of each drug). The dotted lines represent the upper and lower limits (2 standard deviations) of the mean group control measures. Significant drug effects there- fore are represented as points outside of the 2 standard deviation boundry. IRIs= mean interresponse tunes. DOM _“ m. _ 31.“ mumzmemmm .6528 H w 38:82.! “—0 .szomwa 62 and decreased reinforcers reedved and 1121" 3. me next higher dose of I!!! (0.75 mg/kg) simificantly increased responding and decreased the number of reinforcers received. but the average 131‘ was within the 2 S. D. lower limit of control responding. 'lhe behavioral effects of mle up to this point resanbled those produced by d-amphetamine. but the next dose of non studied (1.0 mg/kg) produced pausing in drl responding and was associated with a significant loss of reinforcers along with an increase in' the mean IRT. Figures 2 and 3 show the cumulative records for one mind depicting response patterns to varying doses of d-amphetamine (Fig. 2) and psilocybin (Figure 3). 'me two indolealkylamine-containing hallucinogens. LSD and psilocybin. had different effects on drl responding as culpared to DOM and d-ammetamine. LSD tended to increase the response rate at 0.08 to 0.20 mg/kg. but the effect was not significant (Figure 4). A significant decline in responding was noted at 0.21; mg/kg. ’Ihese results are similar to those of Appel (1971) who reported that low doses of LSD (0.01 to 0.08 mg/kg) increased drl responding. while higher doses (0.16 mg/kg) decreased it. However. we found that LSD markedly decreased reinforcers and that this effect was associated with a tendency toward shorted IRT's. Analysis of the IRT distributions indicated that LSD in doses of 0.08 to 0.20 mg/kg appeared to decrease the time between responses enough to result in a loss of reinforcement. but 63 Figure 2: Sample cumulative records depicting response patterns of Rat B-2 on drl-18 induced by various doses of g-amphetamine. Panel A shows the control response record for a 60 minute session. Panels B-F depict the responding characteristics tonmng Gel. 0e25. 0e”. 1.0 and le5 ‘g/k‘ g. amphetamine. respectively. Each downward de- flection of the event pen represents a food rein- forcement. The slope of the responding record fives an indication of the responding rates (ug.. steeper slope=faster rate and loss of reinforcaent). 65 Figure 3: Sample oumlative records depicting response patterns of Rat 3-2 on drl-18 induced by various doses of psilocybin. Panel A shows the control response record for a 60 minute session. Panels B-F depict the responding characteristics following 0.1. 0.25. 0. 50. 0.75 and 1.0 mg/kg psilocybin. See Figure 2 for further detail. The typical hallucinogenic “pause" is evident in Panel P. 66 .-'-‘"/. -// c / w," _ ,-.. D / E'. L 67 Figure h: The dose-response effects of LSD and psilocybin on drl-18 reaponse patterns. Each point represents the mean of eight observations. See Figure 1 for details. PSILOCY BIN LSD II Ill-ll m w m e m m m » om m m. cl 1 mug—2mm: mmmOmOm-émc 4015.200 “.0 hszmmm z