The ability of a D1/D2 antagonist combination to antagonize the discriminative stimulus properties of cocaine

Whereas dopamine reuptake inhibitors substitute for the discriminative stimulus properties of cocaine, neither norepinepherine nor serotonin reuptake inhibitors generally do (Kleven, Anthony & Woolverton, 1990), suggesting that the dopamine system mediates cocaine's stimulus properties. Interestingly, selective D1 and D2 agonists do not substitute completely for the cocaine cue (Witkin, Nichols, Terry & Katz, 1991) and selective D1 and D2 antagonists do not block it fully (Baker, Riddle, Saunders & Appel, 1993). These findings suggest that concurrent activity at both D1 and D2 receptor subtypes is necessary to produce the cocaine cue. Accordingly, it would be expected that simultaneous blockade of D1 and D2 receptors would be necessary to block cocaine's stimulus properties fully. The present study tested this hypothesis by examining the ability of various combinations of the D1 antagonist, Schering 23390, and the D2 antagonist, haloperidol, to block the cocaine cue in rats trained to discriminate cocaine (7.5 to 13 mg/kg) from distilled water in a water-reinforced operant procedure. Five of the six subjects tested displayed greater antagonism following a D1/D2 combination than following either antagonist alone which further supports the position that the concurrent activity of dopamine at both D1 and D2 receptors mediates the cocaine cue. The mechanism underlying this activity at the receptor subtypes, however, is unknown. That a D1/D2 agonist combination did not substitute for cocaine to any greater extent than each agonist alone (Spealman, Bergman, Madras & Melia, 1991) and that neither a D1 nor D2 antagonist blocked the cocaine cue consistently (present data) suggests that it is unlikely that this activity between D1 and D2 receptors is additive or synergistic in nature. Therefore, it is possible that other systems affected by cocaine (e.g., norepinepherine and serotonin) may be involved in mediating its stimulus properties. Given that norepinephrine and serotonin reuptake inhibitors have been shown to potentiate the discriminative properties of cocaine (Cunningham & Callahan, 1991), it is possible that these neurotransmitter systems may play some modulatory role in mediating cocaine's stimulus properties.