Tolerance to a suprathreshold dose of L-Dopa 283 J Neural Transm (1999) 106: 283–300 Tolerance to a suprathreshold dose of L-Dopa in MPTP mice: effects of glutamate antagonists A. Fredriksson 1 , T. Palomo 2 , T. Chase 3 , and T. Archer 4 1 Department of Psychiatry, University of Uppsala, Uppsala, Sweden 2 Servicio de Psiquiatriá, Hospital 12 de Octubre, Carretera de Andalucia, Madrid, Spain 3 NIH, Experimental Therapeutics Branch, Bethesda, MD, USA 4 Department of Psychology, University of Göteborg, Göteborg, Sweden Received May 19, 1998; accepted September 7, 1998 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 develop- ment 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 conse- quences 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. Keywords: C57 Bl/6 mice, MPTP, suprathreshold, L-Dopa -20 mg/kg, chronic injections, tolerance, NMDA antagonists, MK-801, CGP 40116, rein- statement, synergism, parkinsonism.