Activation of the Oxytocin System by Neuropeptide S to Generate Anxiolysis and Curb Alcohol Drinking

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Project Summary Alcohol dependence (AD) is characterized by exacerbated brain stress signaling that drives an anxious state in alcohol withdrawal and contributes to the intensity of alcohol drinking, which can contribute to alcohol use disorder (AUD). AUD is a global public health issue for which more effective treatments are urgently needed. Preclinical data suggest that Neuropeptide S (NPS) treatment induces an anxiolytic effect that can counter the enhanced anxiety observed in rodent models of AUD. Interestingly, it has been recently demonstrated that NPS treatment activates hypothalamic oxytocin neurons (oxytocin system activation in alcohol dependence is the focus of the parent R00 award). We hypothesize that 1. Neuropeptide S treatment will produce a therapeutic action of anxiolysis in AD, thereby lessening the motivation to consume alcohol and that 2. NPS can produce anxiolytic and anti-drinking effects through activation of oxytocin neurons within the hypothalamus. While the NPS system is listed as an important target in AUD by the National Institutes of Alcohol Abuse and Alcoholism, we are not aware of any study that has reported the effect of NPS on alcohol drinking in alcohol dependence. Tests of NPS’s effects on anxiety and alcohol drinking in genetic lines selected for high drinking support our hypothesis that NPS produces an anxiolytic and anti-drinking effect, however, we are eager to conduct the experiments which can systematically demonstrate a role for NPS in alcohol dependence contrasted with non-dependence. Further, we seek to test our hypothesis that NPS can produce these putative therapeutic actions via activation of the brain oxytocin system. To test our hypotheses, we propose to first test the effect of NPS in an acute model of alcohol-withdrawal-induced anxiety, while monitoring oxytocin release in the central amygdala (a terminal region for hypothalamic oxytocin projection neurons, and a major focus of the parent grant). Next, we will test the effect of NPS on the motivation to self-administer alcohol in the chronic- intermittent exposure to vapor model of alcohol dependence, while also determining whether optogenetic inhibition of hypothalamic oxytocin neurons (see parent R00 award) can prevent this NPS action. The proposed project will serve as a training opportunity for John Marendes Jr. Our Research Plan is designed to allow John to work within the scope of the parent grant, undertaking his graduate training with close mentorship, but at the same time, to begin developing an independent research niche. This critical aspect of the proposal will greatly benefit John in preparing for an independent research career in the future. With this behavioral neuropharmacology approach, John’s completion of the proposed project is expected to reveal new information about the role of NPS and oxytocin signaling in alcohol dependence. It is anticipated that this data will open a new avenue for research into the neurobiology of alcohol dependence, and thereby have a sustained impact on alcohol research in terms of both basic neuroscience and translational medicine.