Orexin modulation of brain reward-brain stress system interactions in alcohol withdrawal anxiety

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Alcohol use disorder (AUD) affects ~17 million Americans, contributing to more than 2.5 million deaths each year in the United States alone and costing the United States $249 billion annually. Humans with AUD often experience negative affect during withdrawal (WD), and depressed mood and anxiety are positively correlated with relapse during abstinence. The neurobiological mechanisms underlying an individual’s response to alcohol, and his/her propensity to develop AUD, are not entirely understood. Acute and chronic alcohol alter neurotransmission in mesocorticolimbic circuitry, including the ventral tegmental area (VTA), and chronic alcohol also alters neurotransmission in the central amygdala (CeA), an area involved in increased anxiety during WD. There is a functional connection between the VTA and CeA, and although each of these regions is important for addictive behavior, the role of the connection between them in addictive behaviors is unknown. Our preliminary data indicate that alcohol WD activates the VTA-CeA circuit in alcohol-dependent animals. The goal of this K01 proposal is to determine the mechanism underlying this circuit activation, as well as the contribution of the circuit to increased anxiety-like behavior during WD. The overarching hypothesis of this proposal is that CeA-projecting VTA dopamine (DA) neurons become activated during alcohol WD via an orexin 1 receptor (OX1R)-mediated mechanism, and that activation of this circuit is critical in the development of dependence-associated increased anxiety-like behavior during acute WD. To test this hypothesis, the proposal will utilize a combination of anatomical, cellular, imaging, circuit-based and behavioral techniques. This proposal will provide a promising young scientist with vital research training and professional development opportunities facilitated by experiments that use an integrative approach to test the predictions that: (1) increased VTA-CeADA activity observed in vitro during WD from chronic alcohol is mediated by OX1R/endocannabinoid (eCB) signaling, (2) that increased CeA activity observed in vivo during WD from chronic alcohol is mediated by increased DA input from the VTA, and (3) that VTA OX1R/eCB signaling mediates alcohol WD-induced anxiety-like behavior. The results of these studies will open new avenues of neuroscientific investigation exploring the crosstalk between brain reward and brain stress systems in addiction. This work may also inform development of treatment strategies for reducing negative affective symptoms in individuals with AUD, leading to improvements in quality of life and health of affected individuals, and decreasing morbidity associated with these disorders.