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Functional alteration by NMDA antagonist: Effects of L-Dopa, neuroleptics drug and postnatal administration


 Antiakinsic effects of the uncompetitive NMDA antagonists, memantine, amantadine and MK-801, and competitive antagonists, CGP 40116, alone or in co-administration with acute subthreshold dose of L-Dopa (5 mg/kg) in MPTP-treated mice, functional alterations induced by acute MK-801 in combinations with neuroleptic compounds or behavioural deficits following postnatal administration of MK-801 were investigated. Memantine and amantadine injected 60 min before the subthreshold dose of L-Dopa (5 mg/kg), induced antiakinesic actions in hypokinesic MPTP-treated mice. Concurrently, higher doses of memantine and MK-801 caused dyskinesic changes, reducing further rearing (10 and 30 mg/kg) and locomotor (30 mg/kg) behaviour of the MPTP mice; MK-801 elevated locomotion (0.1 mg/kg) but reduced rearing (0.3 mg/kg). In control, saline-treated mice, memantine (3, 10 and 30 mg/kg) and MK-801 (0.1 and 0.3 mg/kg) increased locomotor behaviour but decreased rearing behaviour. In rats, MK-801 induced marked increases in locomotor activity and disruptions of circular swim maze acquisition that were to greater or lesser extents blocked or potentiated by neuroleptic compounds: SCH 23390 (0.005 and 0.05 mg/kg) and clozapine (5.0 and 10.0 mg/kg) dose-dependently antagonised MK-801 (0.3 mg/kg) induced locomotor activity whereas raclopride (0.1 mg/kg) and haloperidol (0.1 mg/kg) attenuated it dose-specifically. Amperozide (0.5 mg/kg) attenuated the MK-801 effect but potentiated it at the 2.0 mg/kg dose. In the circular swim maze, raclopride (0.01 mg/kg) and SCH 23390 (0.05 mg/kg) improved the acquisitive performance of rats administered MK-801 (0.03 mg/kg) acutely whereas clozapine (10.0 mg/kg) and amperozide (2.0 mg/kg) deteriorated the performance of MK-801-treated rats. Postnatal administration of MK-801 (0.05 mg/kg, day 11 after birth) induced severe functional alterations in adult mice. At 70 days of age, MK-801 mice showed an initial hypoactivity followed by marked hyperactivity in the motor activity test chambers. These mice showed deficits in habituation, a nonassociative form of learning. Their hyperactivity in the test chambers was reversed by a low dose of d-amphetamine (0.25 mg/kg). Taken together, these findings display a wide range of acute/long-term functional alterations induced by NMDA antagonists, particularly MK-801, associated with animal models of brain disorders.

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Received July 9, 2001 Accepted August 6, 2001 Published online June 17, 2002

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Fredriksson, A., Archer, T. Functional alteration by NMDA antagonist: Effects of L-Dopa, neuroleptics drug and postnatal administration. Amino Acids 23, 111–132 (2002).

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  • Keywords: MPTP
  • Hypokinesia
  • Dyskinesia
  • Locomotion
  • Rearing
  • Memantine
  • Amantadine
  • MK-801
  • L-Dopa
  • 5 mg/kg
  • Co-administration
  • Motor fluctuations
  • C57 BL/6 mice
  • Activity test cages
  • Hypoactivity
  • Hyperactivity
  • Wistar rats
  • Circular swim maze
  • Acquisition performance
  • Clozapine
  • Haloperidol
  • Amperozide
  • SCH 23390
  • Raclopride
  • Antagonism
  • Potentiation
  • Postnatal administration
  • Habituation
  • Neonatal
  • Adult
  • Rats
  • Mice