Effects of N-methyl-D-aspartate antagonists in rats discriminating different doses of cocaine: comparison with direct and indirect dopamine agonists.
Dose-response functions for selected N-methyl-D-aspartate (NMDA) antagonists and direct and indirect dopamine agonists were compared in rats trained to discriminate either a low (2 mg/kg) or a high (10 mg/kg) dose of cocaine from vehicle. The NMDA-associated ion channel blockers, dizocilpine, phencyclidine and MgCl2, substituted fully for cocaine (> or = 90% cocaine-appropriate responses) in the majority of subjects under the low-dose training condition, but showed little or no substitution for cocaine under the high-dose training condition. The competitive NMDA antagonist [2R,4R,5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid)] did not substitute for cocaine under either training condition. Cocaine, 1-(2-[bis(4-fluorophenyl)methoxyl)-4-(3-phenylpropyl)piperazine, (+)-amphetamine and the D1 receptor agonist SKF 77434 engendered full substitution for cocaine under both training conditions. Dose-response functions for all four drugs were displaced to the left and average ED50 values were reduced by 3-fold or more under the low-dose compared to the high-dose training condition. The nonselective DA receptor agonist (-)-apomorphine substituted substantially for cocaine only under the low-dose training condition, whereas the D2 receptor agonist (+)-4-propyl-9-hydroxynapthoxazine substituted similarly for cocaine under both training conditions. The results show that change in the training dose of cocaine can affect both the shape and position of the dose-response functions for representative NMDA-associated ion channel blockers and direct and indirect dopamine agonists. The findings further show that under low-dose training conditions, NMDA-associated ion channel blockers can engender cocaine-like stimulus effects comparable to those of direct and indirect dopamine agonists.
Kantak
K M
KM
Department of Psychology, Boston University, Massachusetts, USA.
Edwards
M A
MA
Spealman
R D
RD
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D010078:Oxazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D018491:Dopamine Agonists; D010078:Oxazines; D010879:Piperazines; C042631:naxagolide; D016202:N-Methylaspartate; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C043425:vanoxerine; D003042:Cocaine; C067114:SK&F 77434