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The effects of pretreatment with MPTP (1-methyl4-phenyl-1,2,3,6-tetrahydropyridine) on the acute and long-term effects of methamphetamine on striatal dopamine were evaluated in BALB/c mice. Four subcutaneous injections of a non-toxic dose of MPTP (8 mg/kg, at 2 hr intervals) were followed three days later by a toxic regimen of methamphetamine (four injections of 4 mg/kg, at 2 hr intervals) and mice were sacrificed immediately or three days later. Control mice received saline in place of the MPTP or methamphetamine and mice were observed for acute changes in body temperature, self-injurious behaviour, and striatal dopamine metabolites, or long-term changes in striatal dopamine levels, tyrosine hydroxylase immunoreactivity and glial fibrillary acidic protein. It was observed that pretreatment with MPTP protected mice against the acute increase in body temperature caused by the methamphetamine but, at the same time, delayed the occurrence of self-injurious behaviour following the repeated injections of methamphetamine. Likewise, pretreatment with MPTP attenuated the long-term depletion of striatal dopamine induced by the methamphetamine as well as the large increase in glial fibrillary acidic protein and the reduction in tyrosine hydroxylase immunoreactivity. The MPTP-treatment itself did not alter any of these neurotoxic markers. Finally, the acute decrease in 3,4-dihydroxyphenyacetic acid levels and increased ratio of 3-methoxytyramine/dopamine observed 60 min. after a single injection of methamphetamine (4 mg/kg) were also attenuated in MPTP-treated mice. These results are discussed in the context of the hypothesis that the low-dose treatment with MPTP may modify exchange diffusion across the striatal cell membrane thereby altering the acute and long-lasting effects of methamphetamine.

The behavioral and neurochemical effects of high doses of amphetamine administered to BALB/c mice were examined in the presence and absence of co-administered haloperidol (a D2 antagonist), SCH 23390 (a D1 antagonist) and risperidone (a mixed 5-HT2/D2 antagonist). It was observed that mice displayed a dose-dependent increase in stereotypic behavior, oral dyskinesia, and self-injurious behavior (SIB) in response to amphetamine treatment. Furthermore, agents that blocked the SIB reversed the amphetamine-induced release of serotonin. This effect was unrelated to hyperthermia or non-specific sedation (as assessed by measurement of motor activity). These data are interpreted in the context of the underlying basis of murine SIB involving both dopaminergic and serotonergic activation and demonstrate the efficacy of risperidone in treating these behaviors. [Copyright &y& Elsevier]