Synaptic Mechanisms underlying sex-differences in alcohol use disorder

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Alcohol use disorder (AUD) is a major public health problem. The central nucleus of the amygdala (CeA) functions as a hub of stress and anxiety processing and plays a crucial role in the negative affect associated with alcohol dependence and abstinence/withdrawal. Rodent studies attribute negative, reinforcement–driven compulsive behaviors associated with alcohol dependence to an “imbalance” between neurotransmitters in the brain pro-stress and anti-stress systems. Both corticotropin-releasing factor (CRF) and norepinephrine (NE) pro-stress systems are critical in behavioral aspects of addiction, including the anxiogenic effects of drug withdrawal. We have characterized the cellular mechanisms involved in the actions of alcohol and CRF on GABA and glutamate signaling, and the neuroadaptations induced by alcohol dependence in CeA of male rats. In addition, we found that NE, like CRF, strongly modulates CeA GABAergic transmission in naive, alcohol dependent, and withdrawn male rats, and identified specific adrenergic receptors that mediate these effects. However, it is unknown whether similar functional alterations occur in female rats. Notably, our preliminary data identified compelling sex-specific differences showing that CeA GABAergic synapses differ in their sensitivity to the acute effects of alcohol, CRF, NE and nociceptin/orphanin FQ (nociceptin). Concerning the latter, the opioid-like peptide nociceptin exerts anti-stress effects by counteracting the function of endogenous CRF in the brain, and our preliminary data show that nociceptin may also counteract NE functions. Surprisingly, no studies have examined the effects of these neurotransmitter systems on CeA signaling in a sex-dependent manner. Capitalizing on these recent preliminary findings, the main objective of this project is to test the hypothesis that 1) adaptive changes in pro-stress (CRF and NE) and anti-stress (nociceptin) systems in the CeA circuits are differentially and sex-specifically recruited or suppressed through alcohol dependence, and 2) the disrupted balance between these systems leads to significant dysregulation of CeA activity that contributes to the negative affect associated with alcohol dependence and abstinence, as well as the sex differences in alcohol abuse patterns. We propose two specific aims with a multidisciplinary approach using in vitro electrophysiology, molecular biology, and behavioral studies to provide essential mechanistic data that can elucidate the cellular basis of the susceptibility of AUD to stress and relapse. A better understanding of the neuroadaptations shaping the synaptic networks involved in alcohol dependence represents a challenge to alcohol researchers and will be critical toward identifying new promising avenues for therapeutic purposes to alleviate AUD.