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.