The NMDA/glycine receptor antagonist, L-701,324, produces discriminative stimuli similar to those of ethanol.
The ethanol-like discriminative stimulus properties of a novel NMDA glycine receptor antagonist, L-701,324 ((7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2-(1H)-quinolone), a polyamine receptor antagonist, eliprodil, and a non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), were examined in rats trained to discriminate ethanol from vehicle in a two-lever discrimination procedure. In rats trained to discriminate ethanol from vehicle, L-701,324 and MK-801 substituted for ethanol in a dose-dependent fashion with a complete substitution noted following administration of 7.5 mg/kg L-701,324 and 0.2 mg/kg MK-801, respectively. Full substitution for ethanol was achieved with no alteration in the rate of responding. In contrast, administration of eliprodil (in doses up to 5 mg/kg) showed only a partial, but not dose-dependent, substitution for ethanol. These findings indicate that a reduction of NMDA receptor activity, produced either via a blockade of non-competitive NMDA recognition sites or of NMDA/glycine-sensitive regulatory sites, had discriminative stimulus properties that are similar to those produced by ethanol. Furthermore, the observation that the NMDA/glycine receptor antagonist, L-701,324, was a more effective substitute for ethanol than was the polyamine antagonist, eliprodil, suggests that several NMDA receptor subunits, and thus not only NMDAR2B receptor subunits, are of importance for the discriminative stimulus effects of ethanol.
Kotlinska
J
J
Department of Clinical Neuroscience, Karolinska Hospital, Stockholm, Sweden.
Liljequist
S
S
D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004193:Discrimination Learning / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D015363:Quinolones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D016291:Dizocilpine Maleate; C094635:L 701324; C058083:eliprodil