Failure to down regulate NMDA receptors in the striatum and nucleus accumbens associated with neuroleptic-induced dyskinesia.
The syndrome of vacuous chewing movements (VCMs) in rats is similar in many respects to tardive dyskinesia (TD) in humans. Both syndromes are characterized by delayed onset of persistent orofacial dyskinesias in a sub-group of subjects chronically treated with neuroleptics. Using the rat model, we examined the role of NMDA receptor-mediated corticostriatal neurotransmission in the expression of VCMs. Rats were treated for 36 weeks with haloperidol decanoate or vehicle and then withdrawn for an additional 28 weeks. Chronic persistent VCMs were induced in one subgroup of treated animals (+VCM), but not in another group (-VCM). Rats from +VCM, -VCM groups and vehicle-treated controls were selected for post mortem studies (n = 12 to 14 per group). NMDA receptor levels were assessed using [3H]-MK-801 binding in sections from the mid-striatum and nucleus accumbens. Chronic haloperidol treatment produced a marked reduction of NMDA receptor binding levels throughout the striatum and nucleus accumbens. Post hoc comparisons demonstrated that -VCM rats had lower NMDA receptor binding levels than +VCM and vehicle-treated controls. Ventromedial striatum and nucleus accumbens core were the most affected areas. These findings suggest that down-regulation of striatal NMDA receptor binding levels may protect against the expression of neuroleptic-induced dyskinesia.
Hamid
E H
EH
Clinical Research Services, National Institute of Mental Health, St. Elizabeth's Hospital, Washington, DC, USA.
Hyde
T M
TM
Baca
S M
SM
Egan
M F
MF
D000818:Animals; D014150:Antipsychotic Agents; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D006220:Haloperidol / Q000031:analogs & derivatives*; D008297:Male; D008409:Mastication / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; C033563:haloperidol decanoate; D006220:Haloperidol