Untangling Mephedrone‐Induced Social Reward in Rats—The Involvement of Oxytocin and Vasopressin V 1A Receptors

The rewarding effects of psychostimulants are strongly influenced by social context, yet the underlying neurochemical and neuropeptidergic mechanisms remain unclear. This study examined the role of oxytocin (OT) and vasopressin (AVP) in context‐dependent reward induced by subchronic mephedrone treatment in rats. Using classic‐ and social‐conditioned place preference (CPP) we assessed reward and later—monoamine levels in the prefrontal cortex (PFC) and hippocampus, plasma OT and AVP levels, and mRNA expression of oxytocin (OTRs) and vasopressin V1A (AVPV 1A Rs) receptors in the nucleus accumbens (NAc) and hippocampus. Pharmacological manipulations of OTRs and AVPV 1A Rs were used to evaluate their role in social‐CPP. We confirmed that mephedrone (5 mg/kg) induced social‐ but not classic‐CPP. In classic‐CPP, mephedrone elevated PFC dopamine, an effect abolished under social conditioning, which instead reduced hippocampal serotonin and noradrenaline. Social context alone lowered baseline monoamines, suggesting dampened neurochemical signaling. Social conditioning increased plasma OT and AVP, whereas mephedrone selectively reversed the OT rise. At the receptor level, mephedrone up‐regulated AVPV 1A R mRNA in the hippocampus and OTR mRNA in the NAc, indicating central adaptations distinct from peripheral peptide changes. Behaviorally, social‐CPP was abolished by OTR agonism (carbetocin) or AVPV 1A R antagonism (SR49059), while OTR antagonism (L‐368,899) or peripheral AVP had no effect. These findings show that mephedrone‐induced social reward is shaped by OT and AVP systems. Social context modulates peripheral neuropeptides and engages central receptor adaptations in the hippocampus and NAc, influencing behavioral outcomes. This study provides insights into the neurobiological mechanisms through which the social environment alters drug reward.