Further studies of the role of hyperthermia in methamphetamine neurotoxicity
The depletion of striatal dopamine (DA) that can occur after methamphetamine (METH) administration has been linked to METH-induced hyperthermia. The relationship between METH-induced hyperthermia, neurotoxicity (striatal DA depletions) and compounds that protect against METH neurotoxicity was furthe...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 268; no. 3; pp. 1571 - 1580 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.03.1994
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Subjects | |
Online Access | Get full text |
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Summary: | The depletion of striatal dopamine (DA) that can occur after methamphetamine (METH) administration has been linked to METH-induced
hyperthermia. The relationship between METH-induced hyperthermia, neurotoxicity (striatal DA depletions) and compounds that
protect against METH neurotoxicity was further investigated in this study. Typically, rats exposed to METH die when their
body temperatures exceed 41.3 degrees C but such hyperthermic rats can be saved by hypothermic intervention. Subsequently,
rats saved by hypothermic intervention have greater depletion 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 rats, as assessed by silver degeneration of terminals and increases in the astrocytes that express glial fibrillary
acidic protein immunoreactivity. By contrast, alterations in the number of [3H]dizoclipine (MK-801) binding sites in cortical
or striatal membranes at 1, 3 or 14 days post-METH were not detected. The experiments showed that mean and maximal body temperature
correlated well with striatal DA concentrations 3 days post-METH (r = -0.77, n = 58), which suggests a role for hyperthermia
in METH neurotoxicity. However, hyperthermia (alone or with haloperidol 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 by their inhibition of hyperthermia and increased ambient temperature abolished their neuroprotection.
Although an interleukin-1 receptor antagonist reduced maximal body temperature enough to lower the lethality rate, it did
not reduce the temperature sufficiently to block METH neurotoxicity. It was concluded that short- and long-term decreases
in striatal DA levels depend on the degree of hyperthermia produced during METH exposure but cannot be produced by hyperthermia
alone. In addition, several agents that block DA depletions do so by inhibiting METH-induced hyperthermia. Finally, the results
suggested a role for interleukin-1 in the extreme hyperthermia and lethality produced by METH. |
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ISSN: | 0022-3565 1521-0103 |