Inhibiting pituitary adenylate cyclase-activating peptide to alleviate anxiety during alcohol abstinence

(b) Abstract Abstinence from alcohol use induces a negative affective state that can lead to maladaptive responses to stress and relapse. As the field develops a deeper understanding of the circuitries participating in addiction and negative affect, the next step is to identify peptide targets within these circuits and investigate if they are differentially regulated in females and males. The sexually dimorphic bed nucleus of the stria terminalis (BNST) is a fundamental component of abstinence-relevant neurocircuitry that modulates stress and alcohol-related behavior in a neuropeptide-dependent manner. This study will investigate the sex-specific role of pituitary adenylate cyclase-activating peptide (PACAP) in decreasing anxiety-related disturbances during alcohol abstinence in the BNST. PACAP, a sexually dimorphic neuropeptide involved in anxiety, fear, and stress responses, will be targeted as a potential treatment for negative affective disorders. PACAP inhibitors are in clinical trials for treating migraines and PTSD. The aims of this application are to identify how PACAP+ projections in the BNST influence neurotransmission during abstinence and whether inhibiting PACAP can reduce anxiety after stress exposure. The parabrachial nucleus sends PACAP+ projections to the BNST. Our published and preliminary data demonstrate that the parabrachial nucleus (PBN) modulates anxiety in alcohol abstinence in females. We hypothesize that projections from the PBN underlie the anxiogenic effect of PACAP in the BNST in part by driving dysregulated neurotransmission in females. To investigate how PACAP+ projections from the PBN to the BNST contribute to anxiety and stress response during abstinence, Aim 1 will focus on determining how these projections modulate neurotransmission during abstinence and after stress, with experiments examining the effect of inhibiting PACAP via ex vivo recordings of neuronal activity. Aim 2 will investigate how these projections modulate in vivo neurotransmission, stress, and anxiety-like behavior during abstinence. By exploring the role of PBN PACAP+ projections on stress, anxiety, and neurotransmission in the BNST, the study aims to assess if PACAP inhibitors can sex-specifically treat dysregulated neurotransmission and anxiety in alcohol-use disorder.