Fluoxetine does not alter the ability of dopamine D1- and D2-like agonists to substitute for cocaine in squirrel monkeys

Fluoxetine has been shown to enhance several behavioral effects of cocaine, including its discriminative-stimulus effects. An interaction between increased serotonergic and dopaminergic actions produced by blockade of serotonin and dopamine reuptake, is one possible mechanism for the enhancement. The present study investigated the effects of fluoxetine on the cocaine-like discriminative-stimulus effects of the D₂-like agonists quinpirole and (−)-NPA, and the D₁-like agonist SKF 82958 in squirrel monkeys trained to discriminate cocaine. The direct dopaminergic agonists, injected 5 min before testing, produced maximal levels of cocaine-appropriate responding of 50% (0.3 mg/kg, SKF 82958), 67% (0.003 mg/kg, (−)-NPA), and 77% (0.1 mg/kg, quinpirole) with ED₅₀ values of 0.43, 0.003, and 0.06 mg/kg, respectively. Fluoxetine at doses up to 10 mg/kg (also 5 min before testing) did not alter the effectiveness or the potency of any of the dopamine agonists in substituting for cocaine. The present failure of fluoxetine to alter the cocaine-like discriminative effects of the dopamine agonists is consistent with the notion that the mechanism underlying the enhancement of the effects of cocaine by fluoxetine is not simply an interaction between enhanced serotonergic and dopaminergic activation as it is not obtained with direct-acting dopamine receptor agonists.