Brain temperature fluctuates biphasically in response to repeated, intravenous (i.v.) cocaine injections, perhaps reflecting cocaine's inhibiting effect on both dopamine (DA) transporters and Na+ channels. By using a DA receptor blockade, one could separate these actions and determine the role of DA-dependent and DA-independent mechanisms in mediating this temperature fluctuation. Rats were chronically implanted with thermocouple probes in the brain, a non-locomotor head muscle and subcutaneously. Temperature fluctuations associated with ten repeated i.v. cocaine injections (1 mg/kg with 8-min inter-injection intervals) were examined after a combined, systemic administration of selective D1-like and D2-like receptor blockers (SCH-23390 and eticlopride) at doses that effectively inhibit DA transmission. In contrast to the initial temperature increases and subsequent biphasic fluctuations (decreases followed by increases) seen with repeated cocaine injections in saline-treated control, brain and muscle temperatures during DA receptor blockade decreased with each repeated cocaine injection. DA receptor blockade had no effects on skin temperature, which tonically decreased and biphasically fluctuated (decreases followed by increases) during repeated cocaine injections in both conditions. DA receptor blockade by itself slightly increased brain and muscle temperatures, with no evident effect on skin temperature. DA antagonists also strongly decreased spontaneous movement activity and completely blocked the locomotor activation normally induced by repeated cocaine injections. Although our data confirm that cocaine's inhibitory action on presynaptic DA uptake is essential for its ability to induce metabolic and behavioral activation, they also suggest that the physiological effects of this drug cannot be explained through this system alone. The continued hypothermic effect of cocaine points to its action on other central systems (particularly blockade of Na+ channels) that may be important for the development of cocaine abuse and adverse effects of this drug.