Methamphetamine-induced neurotoxicity in rats: Effects on neostriatal monoamines and glial fibrillary acidic protein

In order to investigate methamphetamine (MA)-induced neurotoxicity, two studies were carried out. In the first study, MA-induced neostriatal monoamine depletions in male and female Sprague-Dawley CD rats were studied under conditions in which the magnitude of MA-induced hyperthermia was comparable between the sexes. MA (5 or 10 mgikg) or saline (3 ml/kg) was administered S.C. four times at two hr intervals. Rectal temperatures were monitored for 9 hours in a room with an ambient temperature of 23 ± 2°C. Animals were sacrificed three days post-treatment for the determination of dopamine (DA) and serotonin (5-HT). MA induced significant monoamine reductions but the magnitude of these reductions and of the hyperthermic responses were not significantly different between males and females. Unlike reports in mice, gender does not play a role in MA-induced monoamine reductions in rat neostriatum when MA-induced hyperthermia is comparable across sexes. In the second study, the neurotoxic effects of a single administration of MA were investigated. After a single dose of MA (10, 20, 30, or 40 mgikg, s.c.) or saline (3 ml/kg) to Sprague-Dawley CD male rats, rectal temperatures were monitored for 9 hours. Neostriatal DA, 5-HT, tyrosine hydroxylase (TH), and glial fibrillary acidic protein (GFAP) were assayed 3 days following MA treatment. MA induced significant dose-dependent hyperthermia. MA also induced dose-dependent reductions of DA, 5-HT and TH, and increases of GFAP. These results demonstrate that a single-dose of MA can be as effective as the widely used four-dose regimen, provided ambient temperature is modestly increased. A single-dose model offers advantages for mechanistic studies, especially those employing antagonists or other agents thought to be neuroprotective.