"Depression and opiate addiction are two prevalent neuropsychiatric diseases that produce a significant societal burden in terms of health and economic costs. Despite the substantial prevalence of depression and addiction both in the United States and worldwide, our understanding of the underlying neurobiological mechanisms remains incomplete, and elucidation of these neuroadaptations is necessary to develop more effective pharmacological therapies. Depression and addiction are often co-morbid, suggesting that similar neuroadaptations may underlie both diseases. The ventral tegmental area (VTA) is an important brain region in the reward circuit with a well-established role in the effects of drugs of abuse and development of addiction. Interestingly, increasing evidence suggests that dysfunction of the reward pathway may also contribute to depression. Similar biochemical changes, specifically the phosphorylation of AKT, a serine/threonine kinase, at S473, occurs in the VTA in response to chronic social defeat stress (CSDS), a pre-clinical model of depression, and chronic morphine treatment. Importantly, manipulation of AKT S473 phosphorylation alters both depressive- and addictive-like behaviors. Thus, regulation of AKT S473 phosphorylation may be a critical determinant in the development of depression and addiction. The protein complex responsible for phosphorylation of AKT S473 is mammalian (or mechanistic) Target of Rapamycin Complex 2 (TORC2). Previous work has demonstrated a critical role for VTA TORC2 in mediating morphine reward, but its role in stress had not been examined. Thus, this dissertation investigated whether VTA TORC2 signaling mediated susceptibility to CSDS. Furthermore, it has been established that CSDS alters the rewarding effects of drugs of abuse, including morphine. Given that both CSDS and chronic morphine similarly decrease AKT S473 phosphorylation, these studies also determined whether TORC2 signaling was necessary for stress-induced changes in morphine reward. Finally, one mechanism by which TORC2 signaling is thought to mediate long-term adaptations underlying behavioral changes is the alteration of VTA DA neuronal morphology. Therefore, these studies also sought to determine whether TORC2 promotes cytoskeletal remodeling in the VTA via regulation of Rac1 signaling. Through viral and genetic manipulation of Rictor, an essential protein for TORC2 activity, this dissertation investigated the central hypothesis that alteration of TORC2 signaling in the VTA contributes to changes in stress-induced morphine reward and CSDS susceptibility through modulation of specific downstream signaling molecules such as Rac1. Overall, the results of these studies reveal novel information and significance regarding the physiological role of VTA TORC2. While decreased TORC2 signaling in the VTA, or dopamine neurons, is not sufficient to increase susceptibility to CSDS or stress-induced drug reward, we identified a novel role for VTA TORC2 signaling in general consummatory behavior. Moreover, the data from our studies suggest that catecholaminergic TORC2 signaling might regulate behavior in a sex-specific matter, presenting novel opportunities for future studies. Finally, these data indicate that VTA TORC2 does not alter Rac1-PAK-Cofilin signaling and thus, further studies are needed to elucidate the mechanism by which TORC2 facilitates morphine-induced changes in VTA DA morphology."--Pages ii-iii.
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