The neurotoxic potential of cocaine when administered under conditions conducive to the initiation of hyperthermia was investigated. Rats were administered cocaine at ambient temperatures of 22 degrees C or 30 degrees C. To determine the thermal response, body temperatures were measured every 30 min and the total thermal response (TTR), representing the area under the temperature vs. time curve, was calculated. Saline administered at 22 degrees C or 30 degrees C resulted in a normal thermal response (TTR = 9.8+/-0.9 and 11.2+/-0.9, respectively). Cocaine administration resulted in ambient temperature-dependent hyperthermia. Cocaine (4 x 25 mg/kg) administered at 22 degrees C resulted in a TTR of 15.1+/-0.9 whereas cocaine (4 x 15 or 25 mg/kg) administered at 30 degrees C resulted in TTRs of 22.2+/-0.9 and 21.9+/-0.8, respectively. Regardless of the dose or thermal response, cocaine administration did not result in depletion of dopamine (DA) or serotonin (5-HT) in the caudate-putamen. Cocaine administration also failed to induce an increase in the concentration of glial fibrillary acidic protein (GFAP), a marker for neurotoxicity. These results demonstrate that hyperthermia does not promote cocaine-induced neurotoxicity in the rat caudate-putamen.