The present study investigated the actions of cocaine and some of its metabolites and analogs upon the synaptosomal (P2) synthesis and release of dopamine appearing from [14C]phenylalanine. Also examined was the influence of reserpine upon these actions of cocaine. The P2 preparations from the rat caudate nucleus were incubated with the drugs for [14C]phenylalanine and, after filtration, the particulates and medium fractions were analyzed for [14C]dopamine and [14C]phenylalanine. Labelled dopamine in the medium was taken as a measure of its release by any addition of drug. Cocaine, norcocaine and the synthetic cocaine analogs WIN 35428 and WIN 35-065(2) each stimulated both the total (medium plus particulates) formation and the release of dopamine, while benzoylecgonine and ecgonine were without effect. Reserpine inhibited the synthesis and enhanced the release of dopamine. An addition of reserpine blocked the stimulating effect of cocaine, norcocaine, WIN 35428 and WIN 35-065(2) on synthesis and furthermore, these drugs had, in the same experiments, inhibitory effects on the synthesis, additive to the reserpine-induced inhibition. Benzoylecgonine and ecgonine were only weakly inhibitory in the presence of reserpine. Stimulation, rather than additive inhibition, by cocaine was observed in the presence of exogenous dopamine, and amphetamine increased the synthesis in the presence of either reserpine or added dopamine. Pretreatment of rats with reserpine also blocked the stimulation of synthesis by cocaine and WIN 35428. The uptake of labelled substrate was not affected by addition of drug, or by the pretreatment.