Regionally Specific Effects of Oxytocin on Reinstatement of Cocaine Seeking in Male and Female Rats

Background: Oxytocin reduces cued reinstatement of cocaine seeking in male and female rats, but the underlying neurobiology has not been uncovered. The majority of effort on this task has focused on oxytocin and dopamine interactions in the nucleus accumbens core. The nucleus accumbens core is a key neural substrate in relapse, and oxytocin administration in the nucleus accumbens core reduces reinstatement to methamphetamine cues. Further, the nucleus accumbens core has strong glutamatergic innervation from numerous regions including the prefrontal cortex. Thus, we hypothesize that oxytocin regulates presynaptic glutamate terminals in the nucleus accumbens core, thereby affecting reinstatement. Methods: To begin to evaluate this hypothesis, we examined the effects of intra-nucleus accumbens core oxytocin on extracellular glutamate levels in this region. We next determined if direct infusion of oxytocin into the nucleus accumbens core could attenuate cued reinstatement of cocaine seeking in a manner dependent on metabotropic glutamate 2/3 receptors. Finally, we tested if site-specific application of oxytocin in the prefrontal cortex reduced cued reinstatement of cocaine seeking. Results: We found an increase in nucleus accumbens core extracellular glutamate for several minutes following reverse dialysis of oxytocin. In male and female rats with a history of cocaine self-administration, site-specific application of oxytocin in the nucleus accumbens core and prefrontal cortex had opposing effects, decreasing and increasing cued reinstatement, respectively. The mGlu2/3 antagonist LY-341495 reversed oxytocin's ability to attenuate cued reinstatement. Conclusions: While the precise mechanism by which oxytocin increases nucleus accumbens core glutamate is yet to be determined, the present results clearly support oxytocin mediation of glutamate neurotransmission in the nucleus accumbens core that impacts cued cocaine seeking.