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Synergistic interactions between NMDA-antagonists and L-dopa on activity in MPTP-treated mice
A Fredriksson1, C Gentsch, T Archer
1Department of Psychiatry, University of Uppsala, Sweden.
Abstract:
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.
Insights
NMDA-antagonists, like CGP40116, can potentiate L-Dopa
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Parkinson's disease is characterized by motor deficits, including akinesia.
- Levodopa (L-Dopa) is a primary treatment, but its efficacy can be limited by dosage and side effects.
- NMDA receptors are implicated in motor control and may represent a therapeutic target.
Purpose of the Study:
- To investigate if NMDA receptor antagonists can enhance the motor activity effects of L-Dopa in a mouse model of Parkinson's disease.
- To evaluate the potential of specific NMDA antagonists, MK-801 and CGP40116, in combination with L-Dopa.
Main Methods:
- MPTP-treated mice, a model for Parkinson's disease, were used to assess motor activity (locomotion and rearing).
- Experiments involved administering L-Dopa alone, NMDA antagonists (MK-801, CGP40116, CGP40117) alone, and combinations thereof.
- Behavioral responses were measured using an automated activity monitoring system.
Main Results:
- L-Dopa alone showed anti-akinesia effects at higher doses (10 and 20 mg/kg) but not at 5 mg/kg.
- The NMDA antagonist MK-801 increased locomotion in MPTP-treated mice when combined with 5 mg/kg L-Dopa.
- The active NMDA antagonist CGP40116, but not its inactive isomer CGP40117, produced anti-akinesia effects when co-administered with 5 mg/kg L-Dopa, suggesting NMDA receptor involvement.
Conclusions:
- The competitive NMDA antagonist CGP40116, at doses below those causing side effects, synergistically enhanced the anti-akinesia effect of a sub-therapeutic L-Dopa dose.
- This potentiation suggests a therapeutic strategy for Parkinson's disease treatment by reducing L-Dopa dosage and associated side effects.
- The findings support the role of NMDA receptors in modulating L-Dopa's therapeutic effects in Parkinsonism.