METHAMPHETAMINE-INDUCED HYPERTHERMIA IN MICE - EXAMINATION OF DOPAMINE DEPLETION AND HEAT-SHOCK-PROTEIN INDUCTION

Methamphetamine (METH) is a common drug of abuse and a clinical anoret ic which is known to cause neurotoxicity in rodents as evidenced by a depletion of dopamine (DA) and by decreased numbers of DA uptake sites in the striatum. It is also known to cause hyperthermia which is beli eved to induce the production of the 72-kDa heat shock protein (HSP-72 ). In the present study, we evaluated whether METH induced the product ion of HSP-72 in both the mouse hippocampus and striatum and also atte mpted to correlate this induction with monoamine depletion. Adult male C57BL/6N mice received METH (20 mg/kg, i.p.) in an ambient temperatur e of 27 degrees C and body temperatures were monitored up to 240 min a fter treatment. Animals were sacrificed 12, 18, 24, 39, and 48 h after treatment. One striatum was examined for DA, DOPAC, and HVA levels us ing HPLC-EC and the contralateral striatum, along with the hippocampus , was prepared for immunoblotting. HPLC-EC analysis revealed a signifi cant depletion of DA, DOPAC, and HVA at all time points. There was, ho wever, a significant increase in DA at 48 vs. 39 h. A biphasic product ion of HSP-72, in both the hippocampus and striatum, was detected by i mmunoblot. HSP-72 production was strong at 12 h which corresponds to n euronal induction. However, at Is h in the striatum and 24 h in the hi ppocampus, the induction appears to be reduced. A second phase of HSP- 72 induction occurred at 39 h in both regions. In a second experiment, mice were dosed according to the same paradigm and were perfused at 1 8 h after treatment for immunohistochemical analysis. HSP-72 immunorea ctivity was found in neurons of the CA1 and CA4 regions of the hippoca mpus; however, no detectable response was evident in the striatum. In conclusion, these data demonstrate that a single injection of METH can lead to hyperthermia which may then result in both the induction of H SP-72 and depletion of DA concentration. (C) 1997 Elsevier Science B.V .