Synergistic interactions between NMDA-antagonists and L-dopa on activity in MPTP-treated mice.
Four experiments were performed to investigate whether or not coadministration of NMDA-antagonists potentiate the effect of an ineffective dose of L-Dopa on motor activity in hypoactive MPTP-treated mice. Motor activity was measured in an automated system recording both locomotion (horizontal) and rearing (vertical) activity. L-Dopa alone, at doses of 10 and 20 mg/kg, but not 5 mg/kg, expressed an anti-akinesia effect in MPTP-treated mice. The non-competitive NMDA-antagonist MK-801 (0.03, 0.1, and 0.3 mg/kg) increased by itself both locomotion (0.1 and 0.3 mg/kg) and rearing (0.03 mg/kg) in control (saline-treated) mice whereas no effect was seen in the MPTP-treated mice. Combined with 5 mg/kg L-Dopa, MK-801 (0.1 mg/kg) increased locomotion in MPTP-treated mice. There was no interaction seen between L-Dopa and MK 801 in the control mice. CGP40116 and CGP40117, the active D- and the inactive L-stereoisomer of the competitive NMDA-inhibitor CGP37849, respectively, were also administered together with 5 mg/kg L-Dopa. Both doses (0.003 and 0.03 mg/kg) of CGP40116 in contrast to CGP40117, produced anti-akinesia effect in MPTP-treated mice. CGP40116 (0.0001 to 0.1 mg/kg) together with 5 mg/kg L-Dopa did not affect behaviour in control mice but produced (0.01 mg/kg CGP40116 and 5 mg/kg L-Dopa) in the MPTP-treated mice an anti-akinesia effect. Our findings indicate that the non-competitive NMDA-antagonist MK-801, at doses with reported side-effects, only increase locomotion while rearing remained unaltered in MPTP-treated mice when combined with 5 mg/kg L-Dopa. Only the active stereoisomer CGP40116 in contrast to CG40117, at doses far below reported side-effects, dose-dependently modulated the anti-akinesia effect of a subthreshold dose of L-Dopa. Such data thus support the notion that this behavioural modulation was regulated via NMDA-receptors. The synergism between L-Dopa and the competitive NMDA-antagonist CGP40116 has a potential in treatment of Parkinson's disease to reduce the side-effects of doses of L-Dopa that are used today.
Fredriksson
A
A
Department of Psychiatry, University of Uppsala, Sweden.
Gentsch
C
C
Archer
T
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013237:Stereoisomerism
D016194:Receptors, N-Methyl-D-Aspartate; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D007980:Levodopa; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine