Mephedrone-induced social reward in rats depends on oxytocin and vasopressin V1A receptor modulation, not classic reward pathways.

The rewarding effects of psychostimulants are profoundly influenced by social context, yet the precise neurochemical and neuropeptidergic mechanisms remain poorly understood. Current addiction treatments often overlook the critical role of social cues in drug seeking and relapse. This study addresses this gap by investigating the involvement of oxytocin (OT) and vasopressin (AVP) systems, known modulators of social behavior, in context-dependent reward induced by subchronic mephedrone treatment. Understanding these pathways could reveal novel therapeutic targets for psychostimulant addiction.

Researchers administered subchronic mephedrone (5 mg/kg) to rats, assessing reward using both classic- and social-conditioned place preference (CPP) paradigms. They measured monoamine levels (dopamine, serotonin, noradrenaline) in the prefrontal cortex (PFC) and hippocampus, and plasma OT and AVP levels via ELISA. mRNA expression of oxytocin receptors (OTRs) and vasopressin V1A receptors (AVPV1ARs) was quantified in the nucleus accumbens (NAc) and hippocampus using qPCR. Pharmacological manipulations included OTR agonism (carbetocin), OTR antagonism (L-368,899), AVPV1AR antagonism (SR49059), and peripheral AVP administration to evaluate their role in social-CPP.

Mephedrone (5 mg/kg) selectively induced social-CPP, demonstrating no effect in the classic-CPP paradigm. In classic-CPP, mephedrone elevated PFC dopamine, an effect completely abolished under social conditioning. Instead, social conditioning with mephedrone reduced hippocampal serotonin and noradrenaline levels. Social context alone lowered baseline monoamines, suggesting dampened neurochemical signaling. Social conditioning significantly increased plasma OT and AVP levels, but mephedrone selectively reversed the OT rise. At the receptor level, mephedrone up-regulated AVPV1AR mRNA in the hippocampus and OTR mRNA in the NAc, indicating distinct central adaptations. Behaviorally, social-CPP was abolished by OTR agonism with carbetocin or AVPV1AR antagonism with SR49059. Conversely, OTR antagonism with L-368,899 or peripheral AVP administration had no effect on social-CPP.

These findings highlight that mephedrone-induced social reward is critically shaped by the interplay of OT and AVP systems, with distinct central receptor adaptations.