Intranasal Vasopressin Decreases Voluntary Ethanol Drinking in Single‐ and Group‐Housed Mice Through Mechanisms Involving Vasopressin 1a and 1b Receptors

BACKGROUND: Alcohol use disorder (AUD) remains a significant global health challenge, necessitating the exploration of novel pharmacotherapeutics. Our recent study observed that intranasal (IN) administration of arginine vasopressin (AVP) decreases voluntary consumption of sweetened ethanol (EtOH) in mice, a promising development, given that IN AVP does not affect the blood pressure or stress responses associated with systemic AVP administration. To characterize AVP's potential to regulate alcohol drinking, here we investigated the effects of IN AVP on voluntary intake of unsweetened ethanol (EtOH) in single- and group-housed mice, the involvement of AVP and Oxytocin (Oxt) receptors, and the potential neural substrates of these effects. METHODS: Experiment 1 examined the effects of treatments on two-bottle choice (2 BC) drinking in single-housed C57BL/6J mice. Experiment 2 examined the effects of treatments on 2 BC drinking in group-housed C57BL/6J mice. Experiment 3 examined the effects of IN AVP on c-Fos expression in brain regions containing AVP and Oxt receptors in group-housed C57BL/6J mice. RESULTS: IN AVP (1.0 mg/kg) decreased EtOH intake in single-housed mice, an effect attenuated by pretreatment with Avpr1a, Avpr1b, or Oxtr antagonists. A higher dose of AVP (3.0 mg/kg) also inhibited EtOH intake in single-housed mice, and this effect was blocked by the Avpr1a antagonist SR-49059. In group-housed mice, IN AVP (3.0 mg/kg) decreased EtOH intake, an effect blocked by the Avpr1a antagonist or Avpr1b antagonist. IN AVP (3.0 mg/kg) induced c-Fos expression in the central nucleus of amygdala (CeA). CONCLUSIONS: IN AVP decreases voluntary EtOH intake in both single- and group-housed mice. The suppressive effects of IN AVP involve Avpr1a in single-housed mice. In group-housed mice, this effect involves Avpr1a and Avpr1b and engages the CeA. These findings suggest IN AVP may be a potential therapeutic target for AUD, warranting its further investigation.