Tachyphylaxis has been shown to occur in human cardiovascular responses to cocaine. The present study was designed to establish a response curve for cardiovascular parameters in conscious, chronically instrumented rats and to investigate the degree of tachyphylaxis occurring in these parameters after repeated doses of cocaine. Cardiovascular parameters evaluated included arterial pressure, heart rate (HR), and electrocardiogram (ECG). Administration of low doses (0.0625 mg/kg) of cocaine caused significant increases in arterial pressure. Changes in HR accompanying intravenous (i.v.) cocaine were usually biphasic, characterized by an initial reflex bradycardia, followed by a secondary tachycardia lasting several minutes. Tachyphylaxis was observed in the cardiovascular responses when cocaine was administered repetitively at 5-min intervals. This tachyphylaxis was not apparent when the interval between cocaine infusions was extended to 2 h. The mechanism responsible for the tachyphylaxis is hypothesized to be mediated by the presynaptic alpha 2-receptors. Conscious animals were very sensitive to i.v. cocaine administration, and tachyphylaxis to repeated cocaine administration was observed. Both observations must be considered when interpreting cardiovascular studies using cocaine.