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) antag onists 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) d ose of cocaine from vehicle. The NMDA-associated ion channel blockers, dizocilpine, phencyclidine and MgCl2, substituted fully for cocaine ( greater than or equal to 90% cocaine-appropriate responses) in the maj ority of subjects under the low-dose training condition, but showed li ttle or no substitution for cocaine under the high-dose training condi tion, The competitive NMDA antagonist (2-amino-4,5-(1,2-cyclohexyl)-7- phosphonoheptanoic acid)] did not substitute for cocaine under either training condition, Cocaine, phenyl)methoxylethyl}-4-(3-phenylpropylpi perazine, (+)-amphetamine and the D-1 receptor agonist SKF 77434 engen dered full substitution for cocaine under both training conditions. Do se-response functions for all four drugs were displaced to the left an d average ED(50) values were reduced by 3-fold or more under the low-d ose 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 D-2 receptor a gonist (+)-4-propyl-9-hydroxynaphthoxazine substituted similarly for c ocaine under both training conditions, The results show that change in the training dose of cocaine can affect both the shape and position o f the dose-response functions for representative NMDA-associated ion c hannel blockers and direct and indirect dopamine agonists. The finding s further show that under low-dose training conditions, NMDA-associate d ion channel blockers can engender cocaine-like stimulus effects comp arable to those of direct and indirect dopamine agonists.