Dopamine D1/D2 antagonist combinations as antagonists of the discriminative stimulus effects of cocaine.

Although data suggest that the dopaminergic system mediates the discriminative stimulus effects of cocaine, neither selective D1 or D2 dopamine agonists nor selective D1 or D2 antagonists substitute reliably for or consistently block these effects. These findings suggest that concurrent activity at these receptor subtypes may underlie this discrimination. Accordingly, it would be expected that simultaneous blockade of these receptors may be necessary to block it fully. The ability of various combinations of the D1 antagonist, SCH 23,390, and the D2 antagonist, haloperidol, were tested for their ability to block the cocaine stimulus in rats trained to discriminate cocaine (7.5, 10, or 13 mg/kg) from vehicle. Antagonist combinations decreased the percentage of cocaine-appropriate responses 10-95% below the cocaine baseline at doses of the antagonist that were inactive when given separately. These findings support the position that activity at D1-like and D2-like receptor subtypes may account for more of the pharmacological action of cocaine than activation of a single dopamine receptor subtype.