The role of dopamine receptor subtypes in the discriminative stimulus effects of amphetamine and cocaine in rats.

The role of dopamine (DA) receptor subtypes in the discriminative stimuli of the psychostimulant drugs of abuse amphetamine and cocaine was evaluated by the ability of DA D1, D2 and D3 receptor subtype ligands to either substitute for or antagonize these effects. Separate groups of rats were trained to discriminate between amphetamine (0.5 mg/kg) and saline, and between cocaine (5 mg/kg) and saline. Both the training drugs evoked cross-substitution. In further substitution experiments, (+)-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H -3-benzazepine (SKF 38393; 5-20 mg/kg), a selective D1 agonist, moderately substituted for cocaine, but not for amphetamine. The D2 agonist bromocriptine (2.5-20 mg/kg) mimicked both training drugs' cues. Pramipexole, a D3-preferring agonist, in a dose of 0.5 mg/kg induced over 80% substitution for cocaine, and a weaker one (ca. 62%) for amphetamine. Combination tests with DA antagonists showed that the D1 antagonist (+)-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H -3-benzazepine (SCH 23390; 0.01-2 mg/kg), and the D2 blocker raclopride (0.13-1 mg/kg) significantly (78-100%) attenuated the effects of psychostimulants, while the D3-preferring antagonist cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232; 5-20 mg/kg) did not affect them. The present results indicate a critical role of D2 receptor subtypes in the discriminative stimuli of amphetamine and cocaine in rats, as well as a less pronounced involvement of D1 and D3 subtypes in the effects under study.