MDMA ('Ecstasy'), oxytocin and vasopressin modulate social preference in rats: A role for handling and oxytocin receptors

In laboratory rats, peripheral administration of the neuropeptides oxytocin (OT) and vasopressin (AVP) induces similar prosocial effects (i.e. increased adjacent lying) to the party drug 3,4-methylenedioxymethamphetamine (MDMA), which are sensitive to vasopressin V1A receptor (V1AR) antagonism. Here, we employed a social preference paradigm to further compare the prosocial effects of OT, AVP and MDMA. We also investigated the possible involvement of the V1AR and oxytocin receptor (OTR) in rodent social preference. The social preference paradigm measures investigation times towards an empty wire cage (presented for 4 min) followed by an identical cage containing a novel rat (also presented for 4 min). Social preference is defined as greater investigation time towards the inhabited cage than the empty cage. Results indicated that well-handled rats exhibited no social preference at baseline, while intraperitoneally injected MDMA (5 mg/kg), OT (0.5 mg/kg) and AVP (0.005 mg/kg) increased social preference. However, this effect was primarily due to reduced investigation of the empty cage. In contrast, rats that received minimal prior handling displayed a social preference at baseline, while MDMA (5 mg/kg), OT (0.5 mg/kg) and AVP (0.005 mg/kg) reduced investigation times towards both the empty and inhabited cages. Lower doses of MDMA, OT and AVP were ineffective. The OTR antagonist Compound 25 (C25, 5 mg/kg), but not the V1AR antagonist SR49059 (1 mg/kg), reduced the baseline social preference seen in minimally-handled rats and prevented the social preference induced by OT and AVP (but not MDMA) in well-handled rats. Overall, these results further confirm prosocial actions of MDMA, OT and AVP, which are dependent on handling history. These findings also indicate that social preference is sensitive to OTR rather than V1AR modulation.