Vagal-hypothalamic modulation of alcohol intake

Abstract Alcohol use disorder (AUD) is the third leading cause of preventable death in the U.S. and 32.6 million adults have AUD. AUD etiology is highly diverse and current treatment strategies for AUD have high rates of relapse (40 to 60%). Therefore, identifying novel factors facilitating development of AUD is critical, and expansion of the `tool-box' beyond current behavioral and pharmacological targets is required for development of novel effective treatments. A critical gap that hampers discovery of novel AUD treatment is the lack of studies examining the interaction of the brain and body during various stages of the disease. The vagus nerve is the main conductor of brain-body signals and previous clinical and preclinical evidence, as well as our preliminary data, suggest dysfunction of vagus nerve activity is a driver of AUD development and relapse risk. Furthermore, our preliminary data shows that a selective gastric vagotomy (VX) results in increased alcohol intake and preference in rodent models and is associated with alterations in paraventricular (PVN) hypothalamic neurocircuits. Therefore, we propose to use a combination of behavioral, electrophysiological, molecular, histological and viral transgenic techniques to test the novel hypothesis that disruptions of the gastric vagus nerve activity may increase alcohol preference via selective down-regulation of PVN oxytocin function. As a corollary to this, we will investigate whether targeting PVN oxytocin neurons may rescue VX- induced increases in alcohol preference. Specific Aim 1 will test the hypothesis that VX will increase alcohol reward (preference and seeking) and alters PVN gene expression. Specific Aim 2 then will test the hypothesis that activation of PVN oxytocin neurons will rescue increased alcohol preference following VX. Identifying specific brain targets and mechanisms underlying the beneficial effects of healthy vagal activity to reduce alcohol preference, thus reducing motivation for alcohol consumption, could further aid development of both novel pharmacological and non-pharmacologic AUD interventions.