Olfactory targets of alcohol use disorder medications

Project Summary Alcohol use disorder (AUD) is a severe public health problem. Limited FDA-approved pharmacotherapies exist for AUD, and their efficacy is often insufficient. Therefore, development of new approaches for AUD treatment is necessary. A large number of preclinical studies showed that administration of oxytocin (OXT) decreases alcohol consumption in rodents. In clinical studies, intranasally administered (IN) OXT can also decrease alcohol craving, alcohol cue reactivity and measures of heavy alcohol drinking. However, some recent studies have reported lack of OXT's effects on measures of excessive alcohol drinking indicating the need for developing more nuanced treatment approaches. Understanding mechanisms underlying OXT's effect on alcohol intake may help the development of such approaches. IN-administered labelled OXT in non-human primates was distributed along the olfactory and trigeminal nerves. Therefore, exogenously administered OXT is likely to act along this route, with its potential first stage of actions in the anterior olfactory areas. Indeed, the anterior olfactory nucleus (AON) and the main olfactory bulb (MOB) express high levels of OXT receptor (OXTR) and the vasopressin receptor 1a (AVPR1a), respectively. We hypothesize, therefore, that activation of these receptors in the anterior olfactory regions results in decreased alcohol consumption. The goal of this exploratory project is to address this innovative hypothesis. This goal will be achieved in three specific aims. In Aim 1, we will examine whether chemogenetic activation of OXTR-containing AON neurons can regulate alcohol consumption in male and female mice. In Aim 2 we will examine whether chemogenetic activation of AVPR1a-containing MOB neurons can regulate alcohol consumption in male and female mice. In Aim 3 we will examine whether the anterior olfactory OXTR and AVPR1a contribute to OXT's inhibitory effects on alcohol consumption in male and female mice through a region-selective conditional deletion of OXTR. Taken together, these experiments will thoroughly test the role of anterior olfactory OXTR and AVPR1a in voluntary alcohol drinking. On one hand, they will provide a background for a thorough investigation of mechanisms involved in this role. On the other hand, they may provide a translational background for the potential of targeting the olfactory systems in the treatment of AUD.