Effect of risperidone on acute methamphetamine-induced hyperthermia in rats

The abuse of methamphetamine (METH) is popular in many parts of the world. The number of fatal cases related to METH-induced hyperthermia is increasing, but no definitive therapy has yet been found. In the present study, we investigated the ability of risperidone to attenuate acute METH-induced hyperthermia and the mechanism of its action. When administered before and after a single high METH dose (10 mg/kg), risperidone significantly suppressed acute METH-induced hyperthermia in a dose-dependent manner. The same effect was produced by dopamine-1 (DA(1)) and serotonin-2A (5-HT(2A)) receptor blockers, but not by D₂, 5-HT(1A), 5-HT(2B/2C), or 5-HT(2C) receptor blockers, demonstrating that risperidone suppressed METH-induced hyperthermia by blocking the D(1) and 5-HT(2A) receptors. A microdialysis study showed that when METH (10 mg/kg) was subcutaneously injected into rats, the levels of DA, 5-HT, glutamate, and the nitric oxide (NO) metabolites NOx (NO₂⁻+ NO₃⁻) in the anterior hypothalamus increased. Risperidone pretreatment significantly attenuated increases in the levels of DA, 5-HT, glutamate, and NOx. The present study indicates that risperidone may be an effective drug for treating METH-induced hyperthermia in humans and that METH influences the DA and 5-HT neuron systems as well as other neuron systems, including the glutamate and NO systems.