High-dose methamphetamine treatment alters presynaptic GABA and glutamate immunoreactivity

The goal of this study was to determine if high-dose methamphetamine treatm ent altered presynaptic immunoreactivity for the amino acid neurotransmitte rs GABA and glutamate within the basal ganglia. Methamphetamine (15 mg/kg e very 6 h, four doses) treatment in rats resulted in severe hyperthermia and a long-lasting (four weeks) depletion of striatal dopamine content (>80%). Severe dopamine loss correlated with a decrease in the density of presynap tic immunolabeling for GABA one week post-drug, and an increase after four weeks. Although no changes were seen in presynaptic striatal glutamate immu noreactivity, there was a significant increase in the percentage of glutama te-immunopositive terminals associated with perforated postsynaptic densiti es. Rats given the same dose of methamphetamine but prevented from becoming hyperthermic showed less severe dopamine depletions and a lack of ultrastr uctural or immunocytochemical changes. In addition, induction of hypertherm ia in the absence of drug decreased immunolabeling within mitochondria, but had no effect on dopamine content, morphology or nerve terminal immunoreac tivity. Altered presynaptic GABA immunolabeling and terminal size were foun d in both the striatum and globus pallidus, suggesting that dynamic changes occur in the striatopallidal pathway following methamphetamine-induced dop amine loss. In addition, ultrastructural changes in glutamate-positive syna pses which have been correlated with increased synaptic activity were found . These results are similar to changes in GABA and glutamate synapses that fo llow nigrostriatal dopamine loss in 6-hydroxydopamine-lesioned animals and in Parkinson's disease, and provide the first direct evidence that methamph etamine-induced dopamine loss alters the GABAergic striatopallidal pathway. Exposure to either methamphetamine or prolonged hyperpyrexia decreased mit ochondrial immunoreactivity, indicating that hyperthermia may contribute to methamphetamine toxicity by affecting energy stores. (C) 1999 IBRO. Publis hed by Elsevier Science Ltd.