Continuous exposure to dizocilpine facilitates escalation of cocaine consumption in male Sprague-Dawley rats.

Abstract

Although the escalation of cocaine consumption is a hallmark of cocaine dependence, the neurobiological mechanisms that underlie this change in behavior are not well understood. This study used an extended access version of the drug self-administration procedure to explore how N-methyl-d-aspartate (NMDA) receptors are involved in escalation of cocaine consumption. Male Sprague-Dawley rats (n=59) were first trained to self-administer cocaine (0.33 mg/infusion, i.v.) under a fixed-ratio 1 (FR1) schedule of reinforcement. After training, rats were implanted with subcutaneous osmotic minipumps filled with vehicle or the non-competitive NMDAR antagonist, dizocilpine (0.2 or 0.4 mg/kg/d), and subsequently allowed to self-administer cocaine in 2h or 6h self-administration sessions. In the 6h groups, vehicle-treated rats escalated cocaine self-administration across 15 self-administration sessions; rats treated with dizocilpine escalated cocaine self-administration at a greater rate and to a greater degree. Rats that self-administered cocaine during 2h sessions did not escalate consumption of cocaine under any treatment condition. Discontinuation of dizocilpine treatment in the 6h access condition led to a substantial decrease in cocaine consumption, down to pre-escalation levels, and then control rates of escalation thereafter. Despite large differences in intake under the FR1 schedule, post-escalation break point under a progressive ratio schedule of reinforcement did not differ between groups. These data suggest that glutamate tone through NMDA receptors can play a dynamic role in regulating cocaine intake and escalation of consumption.