Tolerance to a suprathreshold dose of L-Dopa in MPTP mice: effects of glutamate antagonists

Summary.

Three experiments were performed to study the development and manipulation of tolerance to a suprathreshold dose of L-Dopa (20 mg/kg, s.c.) in MPTP-treated and control (saline-injected) C57 Bl/6 mice. The motor activity reinstatement effect of this dose of L-Dopa upon MPTP-treated mouse behaviour deteriorated from the 13th injection (Test Day 8) of L-Dopa onwards and reached basal level (i.e. no stimulatory effects of the drug) by the 16th administration (Test Day 10). Administration of L-Dopa to control mice reduced locomotor and rearing activity throughout the tolerance development period (Test Days 1–12) during the first hour after injection, and then increased locomotor activity during the second hour. The effects of combining either a noncompetitive, MK-801, or a competitive, CGP 40116, glutamate antagonist with L-Dopa, following tolerance development, were assessed in MPTP mice on the 23rd day of L-Dopa administration (Test Day 13). MK-801 (0.1 mg/kg, s.c.) reinstated the locomotory and rearing behaviour induced by L-Dopa; CGP 40116 did so also to a greater extent in the dose range 0.01 to 0.03 mg/kg. These results indicate that MPTP-treated mice continue to offer a useful parkinsonian model also for the examination of different aspects of the "wearing-off" phenomenon of L-Dopa tolerance and in particular the putative glutamatergic involvement. The clinical consequences may be far-reaching for the utility of L-Dopa in Parkinson's disease, whether the effects demonstrated be of a reinstatement or synergistic na-ture, once therapeutically adequate glutamate antagonists are more readily available.