The Parabrachial Nucleus Modulates Anxiety in Alcohol Withdrawal and Abstinence Following Repeated Stress

Abstract ID 98829 Poster Board 309 Chronic intermittent ethanol vapor exposure (CIE) and two-bottle alcohol choice (2BC) paradigms produce neuronal adaptations in the bed nucleus of the stria terminalis (BNST), a region critical for affective behavior. The parabrachial nucleus (PBN), a sensory alarm, sends calcitonin gene related protein (CGRP) and pituitary adenylate cyclase activating peptide (PACAP) projections to the BNST that remain relatively unexplored in abstinence. Calca-CRE (gene name for CGRP) male mice (n = 5-10/sex/virus group) received bilateral injections of hM4D(Gi) DREADDs or control virus in the PBN. Anxiety was measured in early-withdrawal from CIE (4-6 hr) with the elevated plus maze (EPM) paired with the hM4D(Gi) ligand, CNO (3 mg/kg, IP). PACAP-CRE female mice (n = 4-9/sex/genotype/stress group) received bilateral injections of hM4D(Gi) DREADDs in the PBN and were exposed to 2BC. Anxiety was measured in prolonged-withdrawal (2 wks) from 2BC with the novelty suppressed feeding task (NSFT) followed by repeated restraint stress (RRS) paired with CNO (3 mg/kg, IP). Post-RRS anxiety was measured with NSFT. PBN(CGRP) inhibition increased EPM time immobile in CIE-withdrawal (2-way ANOVA vapor p = 0.05; treatment p = 0.01). PBN(PACAP) inhibition induced a trend for decreased latency to feed in NSFT with no changes on RRS behavior in 2BC prolonged withdrawal. A history of RRS paired with PBN(PACAP) inhibition blunted RSS-induced increase in NSFT latency (2-way ANOVA stress p = 0.004, genotype p = 0.0481). These data demonstrate PBN(CGRP) and PBN(PACAP) neurons modulate anxiety-like behavior in alcohol-abstinence. Given the prominent role of the BNST in abstinence-induced anxiety current studies investigate changes in PBNBNST circuit activity. Given pharmaceutical treatments for migraines targeting CGRP and PACAP inhibition are bioavailable, these studies inform a potential role for treatments in alcohol-abstinence. NIAAA: R00 AA029467, K99 AA029467, R37 AA019455-09S1