Blockade of the acquisition of cocaine self-administration by the NMDA antagonist MK-801 (dizocilpine)

In an attempt to assess the contribution of the NMDA receptor system to the development of cocaine self-administration, acquisition of intravenous self-administration (0.25 mg/kg/infusion) was assessed in rats that received pretreatment with MK-801 (0.0, 0.1 or 0.25 mg/kg). For control rats, reliable self-administration was obtained in 3–8 days of testing. These rats rapidly discriminated between depression of a lever that resulted in the delivery of cocaine and an inactive lever. Within the initial 10 day test period, most of the rats pretreated with MK-801 failed to acquire a preference for an active lever which, when depressed, resulted in a cocaine infusionresponding was generally high on both the cocaine reinforced and inactive lever. For six rats, MK-801 treatment was discontinued after 10 days. Although some of these rats had received substantial exposure to cocaine during the initial 10 days, self-administration subsequent to the termination of treatment progressed either with a time course comparable to cocaine-naive rats, or not at all. For rats that continued to receive MK-801 treatment, most failed to acquire reliable self-administration within the 18 day test period. These data suggest that the glutamatergic NMDA receptor system plays an important role in the establishment of cocaine as an effective reinforcer.