Intranasal Vasopressin Decreases Voluntary Ethanol Drinking in Mice via `Avpr1a` and `Avpr1b` Receptors

Effective pharmacotherapies for Alcohol Use Disorder (AUD) remain limited, necessitating the exploration of novel treatment strategies. Systemic administration of arginine vasopressin (AVP) has shown promise but is often associated with undesirable cardiovascular and stress-related side effects. However, recent research indicates that intranasal (IN) AVP can influence brain function without these systemic complications. This study builds on prior findings that IN AVP reduces sweetened ethanol consumption, aiming to further characterize its potential to regulate unsweetened alcohol drinking and identify the specific vasopressin and oxytocin receptor mechanisms involved.

Researchers investigated the effects of intranasal arginine vasopressin (AVP) on voluntary ethanol intake in C57BL/6J mice. Experiment 1 used single-housed mice, while Experiment 2 involved group-housed mice, both employing a two-bottle choice (2 BC) paradigm for unsweetened ethanol. Mice received IN AVP at doses of 1.0 mg/kg or 3.0 mg/kg. To elucidate receptor involvement, specific antagonists for Avpr1a, Avpr1b, and Oxtr were administered prior to AVP. Experiment 3 utilized c-Fos expression analysis in group-housed mice to identify neural substrates activated by IN AVP (3.0 mg/kg) in brain regions containing AVP and Oxt receptors.

Intranasal arginine vasopressin (AVP) significantly decreased voluntary ethanol (EtOH) intake across various housing conditions. In single-housed mice, IN AVP at 1.0 mg/kg effectively reduced EtOH consumption. This suppressive effect was notably attenuated by pretreatment with antagonists targeting Avpr1a, Avpr1b, or Oxtr receptors, indicating a complex receptor involvement. A higher dose of IN AVP (3.0 mg/kg) also inhibited EtOH intake in single-housed mice, with this effect specifically blocked by the Avpr1a antagonist SR-49059. In group-housed mice, IN AVP at 3.0 mg/kg similarly decreased EtOH intake, an effect that was blocked by either the Avpr1a antagonist or the Avpr1b antagonist, suggesting a dual receptor mechanism in social contexts. Furthermore, IN AVP at 3.0 mg/kg induced robust c-Fos expression in the central nucleus of amygdala (CeA), a brain region critical for anxiety and reward, highlighting a potential neural substrate for its actions.

IN AVP (3.0 mg/kg) decreased ethanol intake in group-housed mice, an effect blocked by either the Avpr1a antagonist or the Avpr1b antagonist.