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

Abstract

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-NH2,d(CH2)5[D-Tyr2,Thr4]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.

Fig 1. Mean (± SEM) number of a. infusions, b. active and inactive lever presses, as well as c. mean (± SEM) locomotor activity across the 20 days of intravenous METH (0.1mg/kg) self-administration and extinction.

Extinction was conducted for a minimum of 10 days and until less than 25 lever presses were made per session for two consecutive days. Only the data from the first 10 days of extinction is displayed in comparison to the mean of the last three days of self-administration.

Fig 2. Effects of oxytocin or vehicle microinjection in the STh on a. active lever presses, b. inactive lever presses, and c. locomotor activity during METH (1mg/kg, i.p.) primed reinstatement sessions (n = 8).

All animals were exposed to each treatment condition in a counterbalanced manner * p < 0.05, ** p < 0.01 vs prior extinction day. Data are presented as mean ± SEM.

Fig 3. Effects of oxytocin, cocktail, or vehicle microinjection in the STh on a. active lever presses, b. inactive lever presses, and c. locomotor activity during METH (1mg/kg, i.p.) primed reinstatement sessions (n = 8).

All animals were exposed to each treatment condition in a counterbalanced manner # p < 0.05 vs. saline + METH condition; ** p < 0.01 vs prior extinction day. Data are presented as mean ± SEM.

Fig 4. Anatomical coronal diagrams depicting the microinjection sites in the STh.

The coronal diagram on the left shows the injection sites for experiment one, and the diagram on the right shows the injection sites for experiment two. The numbers to the left of the image depict the distance in mm from bregma.