Risperidone and 5-HT2A Receptor Antagonists Attenuate and Reverse Cocaine-Induced Hyperthermia in Rats

Background: Cocaine (benzoylmethylecgonine) is one of the most widely used illegal psychostimulant drugs worldwide, and mortality from acute intoxication is increasing. Suppressing hyperthermia is effective in reducing cocaine-related mortality, but a definitive therapy has not yet been found. In this study, we assessed the ability of risperidone to attenuate acute cocaine-induced hyperthermia and delineated the mechanism of its action. Methods: Rats were injected i.p. with saline, risperidone, ketanserin, ritanserin, haloperidol, or SCH 23 390 before and after injection of cocaine (30 mg/kg) or with WAY-00 635, SB 206 553, or sulpiride before cocaine injection; thereafter, the rectal temperature was measured every 30 minutes for up to 4 hours. In vivo microdialysis was used to reveal the effect of risperidone on cocaine-induced elevation of dopamine (DA), serotonin (5-HT), and noradrenaline concentrations in the anterior hypothalamus. For post-administration experiments, saline or risperidone (0.5 mg/kg) were injected into rats, and cocaine (30 mg/kg) was injected 15 minutes later. For every 30 minutes thereafter, DA, 5-HT, and noradrenaline levels were measured for up to 240 minutes after cocaine administration. Results: Risperidone, 5-HT2A receptor antagonists, and D1 receptor antagonistic drugs prevented and reversed cocaine-induced hyperthermia. In contrast, receptor antagonists for 5-HT1A, 5-HT2B/2C, and D2 did not alter cocaine-induced hyperthermia. Risperidone treatment further attenuated cocaine-induced elevation of DA. Conclusions: Our results indicate that risperidone attenuates cocaine-induced hyperthermia primarily by blocking the activities of the 5-HT2A and D1 receptors and may be potentially useful for treating cocaine-induced acute hyperthermia in humans.