MPTP‐Induced Hypoactivity in Mice: Reversal by L‐Dopa

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Abstract
Three experiments were performed to study the subchronic effects of treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 2 × 40 mg/kg subcutaneously two weeks before testing) in C57 BL/6 mice upon spontaneous motor activity and the reversal of the long-term behavioural changes by acute treatment with L-Dopa. Mice treated with MPTP showed a drastic reduction of striatal dopamine levels (-88%) associated with reductions of all three parameters of spontaneous motor activity, i.e. locomotion, rearing and total activity, during both the initial, exploratory, stage (first 90 min), and later stages of the 3- or 4-hr test periods. L-Dopa (5–80 mg/kg subcutaneously) injected 60 min. after the start of testing dose-dependently improved all three parameters studied in MPTP treated mice with 10 mg/kg being the lowest dose causing a significant effect, while doses above 20 mg/kg caused hyperactivity. During the initial period, rearing activity in MPTP mice was to a variable degree suppressed by the L-Dopa treatment (20–80 mg/kg); these reductions were followed by enormous increases in motor activity by the 40 mg/kg (locomotion) and 80 mg/kg (total activity) L-Dopa groups. Both the degree and duration of the L-Dopa-induced hypoactivity for locomotor behaviour increased dose-dependently in control mice. No suppressive effects of L-Dopa were obtained for total activity in control mice, although the 80 mg/kg L-Dopa doses evoked hyperactivity for up to 90 min. following treatment for both locomotion and total activity. At the 20–80 mg/kg doses, significant reductions were even obtained in MPTP mice during the initial period after administration, for locomotor activity; In saline-treated control mice, the higher doses of L-Dopa (20–80 mg/kg) by which caused considerable reductions in locomotor activity followed again by large increases in activity may have been caused an initial dopamine autoreceptor action, which appears also for the MPTP treated mice as reflected by the locomotion data of the 20–80 mg/kg L-Dopa groups. The results indicate that the MPTP-treated mouse model may provide an important drug screen of compounds of potential therapeutic importance for at least some symptoms of Parkinson's illness.