Continuous exposure to the competitive N-methyl-D-aspartate receptor antagonist, LY235959, facilitates escalation of cocaine consumption in Sprague-Dawley rats

Rationale Chronic high dose consumption of cocaine is associated with significant negative effects to individual users and society. Nevertheless, the precise mechanisms that mediate increases in cocaine consumption in a drug-using individual are not fully understood. Objectives This study used a long access version of the drug self-administration procedure to determine whether escalation of cocaine consumption is mediated by increased activity through N-methyl-D-aspartate (NMDA) receptors. Materials and methods Male Sprague-Dawley rats (n=63) were first trained to self-administer cocaine (0.33 mg/infusion, i.v.) under a fixed-ratio 1 schedule of reinforcement. After training, some rats were implanted with subcutaneous osmotic minipumps filled with vehicle or the competitive NMDA receptor antagonist, LY235959, and subsequently allowed to self-administer cocaine in short (2 h) or long (6 h) access self-administration sessions. Results Vehicle-treated rats escalated cocaine self-administration across 14 long-access self-administration sessions. Rats treated with LY235959 via osmotic minipump, but not twice daily injections, escalated cocaine self-administration at a greater rate and to a greater degree than vehicle-treated rats. In post-escalation cocaine dose-infusion tests, rats treated continuously with LY235959 self-administered more cocaine (0.08-1.32 mg/infusion) than vehicle-treated rats, regardless of access condition, shifting the dose-infusion curves upward. During extinction sessions, which were conducted after the escalation phase of the study, rats that had long (6 h) access to cocaine stopped responding sooner than rats that had short (2 h) access to cocaine, independent of LY235959 treatment. Conclusions These data are consistent with hypo-glutamatergic consequences of repeated cocaine exposure.