Abstract
Recently we have reported that methamphetamine (METH) neurotoxicity in rats depends on the environmental temperature. Here, we evaluate whether a cold environment (4°C) or drugs which affect chloride and glutamate ion channel function block METH neurotoxicity in mice. Adult male CD mice received METH i.p. (4 × 10 mg/kg METH at 23°C along with saline, 2.5 mg/kg ( + )-MK-801, 40 mg/kg phenobarbital or 2.5 mg/kg diazepam and either 4 × 10 or 4 × 20 mg/kg METH at 4°C). Multiple injections of METH (4 × 10 mg/kg, i.p.) at room temperature (23°C) produced a significant depletion of dopamine (DA) in striatum at 24, 72 h, 1 and 2 weeks. Three days post 4 × 10 mg/kg METH at 23°C, an 80% decrease in striatal dopamine (DA) occurred while the same dose at 4°C produced only a 20% DA decrease, and 4 X 20 mg/kg METH at 4°C produced a 54% DA decrease. At 23°C (+)MK-801 completely blocked while phenobarbital (40% decrease) and diazepam (65% decrease) partially blocked decreases in striatal DA produced by 4 × 10 mg/kg METH. Decreases in DOPAC and HVA were similar to the decreases in DA after METH and antagonists. Multiple injections of METH (4 × 10 mg/kg, i.p.) at room temperature also produced a significant depletion of serotonin (5-HT) in striatum at 24, 72 h, 1 and 2 weeks. This depletion of 5-HT at room temperature was blocked either by changing the environmental temperature to 4°C, or by pretreatment with MK-801, diazepam and phenobarbital. A similar pattern in the decreases of the 5-HT metabolite 5-HIAA was observed after METH treatment. Drugs which block METH toxicity, such as haloperidol (D 2 receptors), pentobarbital and phenobarbital (chloride channels) and MK-801 (NMDA/glutamate receptors), do not necessarily have the same mechanism of action but may either induce hypothermia or block induction of hyperthermia. Therefore, it is not clear how much of their protection against METH neurotoxicity is due to the blockade of the hyperthermia produce by METH.
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