The behavioral effects of cocaine (0.03-3.0 mg/kg) and several selective serotonin (5HT) uptake inhibitors, direct agonists and antagonists were determined in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of stimulus termination and a second-order schedule of i.v. drug self-administration. Intermediate doses of cocaine increased fixed-interval response rate markedly, and higher doses decreased response rate below control (nondrug) values. The i.v. self-administration of cocaine (0.025-1.0 mg/injection) maintained schedule-appropriate responding over a range of doses, and response rate under the second-order schedule was a function of drug dose. In contrast, none of the 5HT uptake inhibitors (alaproclate, clomipramine and fluoxetine) or direct agonists ((+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane, (+/-)-8-hydroxy-2-(di-N-propylamino) tetralin and quipazine) increased fixed-interval response rate, nor did the 5HT uptake inhibitors maintain self-administration. In drug interaction studies, the 5HT uptake inhibitors and quipazine produced an insurmountable attenuation of the behavioral-stimulant effects of cocaine, whereas the 5HT antagonists (ketanserin, mianserin and ritanserin) with high affinity for 5HT2 binding sites enhanced the behavioral-stimulant effects of low or intermediate doses of cocaine. Additionally, administration of ritanserin increased response rate for i.v. for self-administration of cocaine over a range of cocaine doses. The pharmacological profile of effects of selective 5HT uptake inhibitors and direct agonists indicates that the behavioral-stimulant and reinforcing effects of cocaine do not depend on inhibition of 5HT uptake, whereas the drug interactions suggest that the serotonergic system can modulate specific behavioral effects of cocaine.