Extracellular microelectrode studies were conducted to test the effects of cocaine HCl on the activity of spontaneously firing single serotonergic dorsal raphe (DRN), noradrenergic locus coeruleus (LC) and dopaminergic ventral tegmental (VTA) and zona compacta (ZC) neurons, and cerebellar Purkinje neurons (PC) in urethane anesthetized rats in vivo. Cocaine (0.0625-4 mg/kg) predominantly inhibited all of the central monoaminergic neurons and predominantly activated cerebellar Purkinje neurons. Cocaine (1 mg/kg, IV) failed to potentiate the inhibitory effects of LC stimulation on PC neurons. The temporal effects of intravenous cocaine on arterial pressure (i.e., pressor response) were not directly correlated with the effects on neurons. Cocaine did not decrease the amplitude or slope of neuron action potentials, and the effects of cocaine on firing rate were not shared by similar doses of procaine. Reserpine pretreatment (10 mg/kg, IP) attenuated the effects of cocaine (1 mg/kg, IV) on DRN, LC, and PC neurons. Specific adrenoceptor antagonists antagonized the inhibitory effects of cocaine on LC (piperoxane, yohimbine) and VTA (haloperidol) neurons. These results suggest that the central effects of cocaine on presynaptic monoaminergic neurons may in part be mediated by augmented monoamine neurotransmission at autoreceptors and that the effects of cocaine on postsynaptic target cells (PC) may be more complex, requiring the analysis of both pre- and postsynaptic elements.