Effects of N-methyl-D-aspartate receptor antagonism on neuroleptic-induced orofacial dyskinesias.
BACKGROUND
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.
Konitsiotis
Spiridon
S
Department of Neurology, University of Ioannina, Medical School University Campus, Ioannina, GR-451 10, Greece. skonitso@cc.uoi.gr
Tsironis
Christos
C
Kiortsis
Dimitrios N
DN
Evangelou
Angelos
A
D000494:Allosteric Regulation; D000547:Amantadine / Q000627:therapeutic use; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D003917:Dextrorphan / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D006220:Haloperidol / Q000009:adverse effects*; D008297:Male; D010636:Phenols / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D014150:Antipsychotic Agents; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D003917:Dextrorphan; D000547:Amantadine; D006220:Haloperidol; C010739:ifenprodil