Drug discrimination analysis of NMDA receptor channel blockers as nicotinic receptor antagonists in rats

Rationale: Antagonists acting at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors inhibit various phenomena associated with exposures to nicotine (e.g., tolerance, sensitization, dependence, and intravenous self-administration). These effects are often discussed in terms of nicotine-induced glutamate release with subsequent glutamate-dependent stimulation of dopamine metabolism and neuronal plasticity in brain areas critically involved in drug-addiction mechanisms. However, it is also well established that certain types of NMDA receptor antagonists (channel blockers) potently bind to nicotinic receptors and may act as nicotinic receptor antagonists. Objectives: The present study aimed to evaluate the discriminative-stimulus effects of the NMDA receptor channel blockers (+)MK-801, dextromethorphan, and memantine in rats trained to discriminate nicotine from its vehicle. Methods: Adult male Wistar rats were trained to discriminate 0.6 mg/kg nicotine from saline under a two-lever, fixed-ratio 10 schedule of food reinforcement. During test sessions, injections of (+)MK-801 (0.03-0.3 mg/kg, i.p.), dextromethorphan (30 mg/kg, s.c.), or memantine (1-10 mg/kg, i.p.) were co-administered with s.c. nicotine (0.075-0.6 mg/kg; interaction tests) or saline (generalization tests). Additional interaction and generalization tests were conducted with the selective nicotinic receptor antagonists mecamylamine (0.1-3 mg/kg, s.c.) and MRZ 2/621 (0.3-10 mg/kg, i.p.), and the mGlu5 receptor antagonist MPEP (3-10 mg/kg, i.p.). In generalization tests, none of the compounds produced any appreciable levels of substitution for nicotine. The nicotine discriminative-stimulus control was dose dependently attenuated by mecamylamine (ED50=0.67 mg/kg) and MRZ 2/621 (ED50=9.7 mg/kg). Both agents produced a marked downward shift in the nicotine dose-response curve. Memantine and MPEP slightly attenuated nicotine discriminative-stimulus effects, while (+)MK-801 and dextromethorphan did not affect the nicotine-appropriate responding. NMDA receptor channel blockers, such as (+)MK-801, dextromethorphan, and memantine, have minimal interactions with the discriminative-stimulus effects of nicotine.