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


OBJECTIVE
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.).


RESULTS
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 (ED(50)=0.67 mg/kg) and MRZ 2/621 (ED(50)=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.


CONCLUSIONS
NMDA receptor channel blockers, such as (+)MK-801, dextromethorphan, and memantine, have minimal interactions with the discriminative-stimulus effects of nicotine.
Zakharova
E S
ES
Laboratory of Behavioral Pharmacology, Institute of Pharmacology, Pavlov Medical University, St. Petersburg 197089, Russia.
Danysz
W
W
Bespalov
A Y
AY
D000818:Animals; D004193:Discrimination Learning / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008464:Mecamylamine / Q000494:pharmacology; D008559:Memantine / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D008464:Mecamylamine; D016291:Dizocilpine Maleate; D009538:Nicotine; C121465:6-methyl-2-(phenylethynyl)pyridine; D008559:Memantine