Discriminative stimulus properties of cocaine in relation to dopamine D₂ receptor function in rats

Previous studies indicate that the discriminative stimulus effects of cocaine are mediated predominantly by indirect activation of dopamine (DA) D₂ postsynaptic receptors, although DA D₁ receptors may also be involved. In the present study, full or partial D₂ agonists and D₂ antagonists were tested for their ability to substitute for, potentiate or antagonize the stimulus effects of cocaine in rats (n = 15) trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced task. The full D₂ agonists bromocriptine (1.25-20 mg/kg) and quinpirole (0.013-0.2 mg/kg) engendered substantial cocaine-lever responding (>80% drug-lever responding), whereas the partial D₂ agonists preclamol (2.5-10 mg/kg) and terguride (0.313-1.25 mg/kg) produced less than 50% cocaine-lever responding. Co- administration of a threshold dose of cocaine (1.25 mg/kg) with low doses of bromocriptine (1.25-5 mg/kg) or quinpirole (0.025-0.1 mg/kg) induced higher percentages of cocaine-lever responding as compared with occasions when these D₂ agonists were given alone. However, co-administration of this dose of cocaine with preclamol (2.5-10 mg/kg) or terguride (0.313-1.25 mg/kg) did not alter the percentage of cocaine-lever responding observed when these partial D₂ agonists were administered alone. Pretreatment with the D₂ antagonists bromuride (0.25-1 mg/kg) and haloperidol (0.125-0.5 mg/kg) significantly reduced the percentage of cocaine-lever responding. Preclamol (0.625-10 mg/kg) and terguride (0.019-5 mg/kg), but not bromocriptine (2.5-20 mg/kg) or quinpirole (0.01-0.08 mg/kg), significantly reduced the percentage of cocaine-lever responding. These results suggest that full D₂ agonists substitute completely for cocaine, whereas partial D₂ agonists do not produce cocaine-like responding. Furthermore, additive effects amounting to full substitutions (>80% cocaine-lever responding) are observed only when full, not partial, D₂ agonists are combined with a low dose of cocaine. Additionally, partial D₂ agonists antagonize the discriminative stimulus effects of cocaine to an extent similar to that of classical D₂ antagonists.