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Effects of N-methyl-d-aspartate receptor antagonism on neuroleptic-induced orofacial dyskinesias

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Abstract

Rationale

Tardive dyskinesia is a syndrome of abnormal, involuntary movements, which occurs as a complication of long-term neuroleptic therapy. The pathophysiology of this potentially irreversible syndrome is still an enigma.

Objective

The objective of the present study was to elucidate the role of N-methyl-d-aspartate (NMDA) receptor involvement in neuroleptic-induced orofacial dyskinesia in rats.

Methods

Animals chronically treated with haloperidol for a period of 40 weeks exhibited significantly more vacuous chewing movements (VCMs), as compared to vehicle-treated controls. In a series of acute experiments, rats received: amantadine (10, 20, and 40 mg/kg i.p.), a low-affinity, uncompetitive NMDA-receptor antagonist (open channel blocker); dextrorphan (5, 10, and 20 mg/kg i.p.), an NMDA receptor channel antagonist; ifenprodil (2.5, 5, and 10 mg/kg i.p.), a noncompetitive allosteric NMDA receptor antagonist acting at the polyamine site; and Ro 25-6981 (2.5, 5, and 10 mg/kg i.p.), a potent and selective blocker of NMDA receptors which contain the NR2B subunit.

Results

All the drugs tested, except dextrorphan, reduced VCMs and tongue protrusions with varying efficacies and side effects profiles. Ro 25-6981 was found significantly more potent than amantadine and ifenprodil in reducing VCMs and tongue protrusions at all doses tested, and at the higher dose, it completely eliminated orofacial dyskinesia (p<0.05).

Conclusions

These results suggest that NMDA receptors may play a significant role in the pathophysiology of tardive dyskinesia. Furthermore, antagonists showing selectivity for NMDA receptors containing the NR2B subunit may be particularly efficacious as novel therapeutic agents for the treatment of tardive dyskinesia and deserve further testing.

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Abbreviations

NMDA:

N-methyl-D-aspartate

VCMs:

Vacuous Chewing Movements

TD:

Tardive Dyskinesia

AIMs:

Abnormal Involuntary Movements

MSN:

medium spiny neuron

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Authors and Affiliations

  1. Department of Neurology, University of Ioannina, Medical School University Campus, Ioannina, GR-451 10, Greece

    Spiridon Konitsiotis

  2. Department of Physiology, Medical School, University of Ioannina, Ioannina, Greece

    Christos Tsironis, Dimitrios N. Kiortsis & Angelos Evangelou

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  1. Spiridon Konitsiotis
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  2. Christos Tsironis
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  3. Dimitrios N. Kiortsis
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  4. Angelos Evangelou
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Correspondence to Spiridon Konitsiotis.

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Konitsiotis, S., Tsironis, C., Kiortsis, D.N. et al. Effects of N-methyl-d-aspartate receptor antagonism on neuroleptic-induced orofacial dyskinesias. Psychopharmacology 185, 369–377 (2006). https://doi.org/10.1007/s00213-006-0348-9

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