The Involvement of Oxytocin in the Subthalamic Nucleus on Relapse to Methamphetamine-Seeking Behaviour

The psychostimulant methamphetamine (METH) is an addictive drug of abuse. The neuropeptide oxytocin has been shown to modulate METH-related reward and METH-seeking behaviour. Recent findings implicated the subthalamic nucleus (STh) as a key brain region in oxytocin modulation of METH-induced reward. However, it is unclear if oxytocin acts in this region to attenuate relapse to METH-seeking behaviour, and if this action is through the oxytocin receptor. We aimed to determine whether oxytocin pretreatment administered into the STh would reduce reinstatement to METH use in rats experienced at METH self-administration, and if this could be reversed by the co-administration of the oxytocin receptor antagonist desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT. Male Sprague Dawley rats underwent surgery to implant an intravenous jugular vein catheter and bilateral microinjection cannulae into the STh under isoflourane anaesthesia. Rats were then trained to self-administer intravenous METH (0.1 mg/kg/infusion) by lever press during 2-hour sessions under a fixed ratio 1 schedule for 20 days. Following extinction of lever press activity, the effect of microinjecting saline, oxytocin (0.2 pmol, 0.6 pmol, 1.8 pmol, 3.6 pmol) or co-administration of oxytocin (3.6 pmol) and desGly-NH(2),d(CH(2))(5)[D-Tyr(2),Thr(4)]OVT (3 nmol) into the STh (200 nl/side) was examined on METH-primed reinstatement (1 mg/kg; i.p.). We found that local administration of the highest oxytocin dose (3.6 pmol) into the STh decreased METH-induced reinstatement and desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT had a non-specific effect on lever press activity. These findings highlight that oxytocin modulation of the STh is an important modulator of relapse to METH abuse.