Antagonism of the discriminative stimulus properties of cocaine with the combination of a dopamine D1 and D2 antagonist

Abstract

Antagonism of the discriminative stimulus properties of 10 mg/kg cocaine was studied in rats by use of the dopamine D1 antagonist SCH 23390 and the D2 antagonist haloperidol. Whereas SCH 23390 and haloperidol were by themselves unable' to antagonize the cueing properties of cocaine, the combination of both dopamine antagonists resulted in a complete blockade of the cocaine cue. In the presence of a fixed dose of 0.01 and 0.04 mg/kg haloperidol, the ED 50's (it is the effective dose in 50% of the animals) of SCH 23390 for cocaine antagonism were 0.043 and 0.012 mg/kg, respectively. Similarly, the ED 50's of haloperidol in combination with 0.01 and 0.04 mg/kg SCH 23390 were 0.021 and 0.024 mg/kg. The combined treatment of haloperidol and SCH 23390 resulted in strong response-rate reductions. At all combination regimens resulting in a complete blockade of the cocaine cue, response rate was reduced to less than 20% of the control values. These results indicate that the cueing properties of cocaine are both dopamine D1- and D2-mediated and that a combined antagonism of both receptor subtypes can lead to a complete antagonism of the cueing properties of cocaine which is associated with severe attenuation of response rate.