Long-term l-Dopa pretreatment of mice: Central receptor subsensitivity or supersensitivity?

Abstract

The effect of acute and repeated treatments with l-Dopa in oral doses of 200 mg/kg plus benserazide (50 mg/kg) was studied using locomotor activity in mice as a model of central catecholaminergic function. Mice pretreated with l-Dopa once daily for 1, 4 or 10 days responded to a challenge dose of l-Dopa (same dose as above) 1 day later with a more pronounced increase in motor activity than vehiclepretreated animals. Dexamphetamine-induced (0.5, 1.0 or 2.0 mg/kg) stimulation was found not to be significantly different in the two pretreatment groups when mice were challenged 1 day after one or four pretreatment doses of l-Dopa. However, a reduced response to dexamphetamine was observed in l-Dopa-pretreated mice (compared to vehicle-treated mice) on withdrawal of the mice from a 10-day l-Dopa pretreatment schedule. One day after one l-Dopa dose, with or without premedication with α-methyl-p-tyrosine (200 mg/kg) plus reserpine (10 mg/kg), mice responded to apomorphine (1.0 mg/kg) with significantly less activity than vehicle-pretreated mice. In contrast, 1 day after ten doses of l-Dopa, there was a shift to the left of the dose-response curve to apomorphine, which did not, however, occur 4 days after withdrawal. Hence, marked dopamine receptor sensitivity changes seem not to be of primary importance for l-Dopa hyperactivity in l-Dopa-pretreated mice. The present study also suggests that dopaminergic changes are not of consequence in the activity induced by dexamphetamine in l-Dopa-pretreated animals.