FURTHER-STUDIES OF THE ROLE OF HYPERTHERMIA IN METHAMPHETAMINE NEUROTOXICITY

The depletion of striatal dopamine (DA) that can occur after methamphe tamine (METH) administration has been linked to METH-induced hyperther mia. The relationship between METH-induced hyperthermia, neurotoxicity (striatal DA depletions) and compounds that protect against METH neur otoxicity was further investigated in this study. Typically, rats expo sed to METH die when their body temperatures exceed 41.3 degrees C but such hyperthermic rats can be saved by hypothermic intervention. Subs equently, rats saved by hypothermic intervention have greater depletio n of striatal DA at an earlier time of onset (18 hr or less post-METH) than do METH-exposed rats that do not attain such high temperatures. Striatal damage was present 3 days post-METH in these hyperthermic rat s, as assessed by silver degeneration of terminals and increases in th e astrocytes that express glial fibrillary acidic protein immunoreacti vity. By contrast, alterations in the number of [H-3]dizoclipine (MK-8 01) binding sites in cortical or striatal membranes at 1, 3 or 14 days post-METH were not detected. The experiments showed that mean and max imal body temperature correlated well with striatal DA concentrations 3 days post-METH (r = -0.77, n = 58), which suggests a role for hypert hermia in METH neurotoxicity. However, hyperthermia (alone or with hal operidol present) induced by high ambient temperatures did not deplete striatal DA in the absence of METH. Haloperidol, diazepam and MK-801 all reduced METH-induced striatal DA depletion to a degree predicted b y their inhibition of hyperthermia and increased ambient temperature a bolished their neuroprotection. Although an interleukin-1 receptor ant agonist reduced maximal body temperature enough to lower the lethality rate, it did not reduce the temperature sufficiently to block METH ne urotoxicity. It was concluded that short- and long-term decreases in s triatal DA levels depend on the degree of hyperthermia produced during METH exposure but cannot be produced by hyperthermia alone. In additi on, several agents that block DA depletions do so by inhibiting METH-i nduced hyperthermia. Finally, the results suggested a role for interle ukin-1 in the extreme hyperthermia and lethality produced by METH.