Blockade of nigral and pallidal opioid receptors suppresses vacuous chewing movements in a rodent model of tardive dyskinesia.
Chronic neuroleptic treatment leads to the development of tardive dyskinesia in 20-30% of patients. While the pathogenesis of tardive dyskinesia remains elusive, altered opioid peptide function in striatal projection pathways of the basal ganglia has been implicated. Using a rodent model of vacuous chewing movements induced by chronic neuroleptic administration, we investigated regional involvement of opioid transmission in tardive dyskinesia. We examined the role of dynorphin in the direct striatonigral pathway by infusing nor-binaltorphimine, a selective kappa opioid receptor antagonist, into the substantia nigra pars reticulata. As well, infusions of naloxone (a non-specific opioid receptor antagonist), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP; a mu opioid receptor antagonist) or naltrindole (a delta opioid receptor antagonist) into the globus pallidus were used to establish the contribution of the striatopallidal pathway. Chronic fluphenazine treatment (25 mg/kg i.m. every 3 weeks for 18 weeks) resulted in a robust increase in vacuous chewing movements. Infusion of nor-binaltorphimine (5.0 nmol) into the substantia nigra pars reticulata significantly attenuated vacuous chewing movements. Infusion of naloxone (0.5 and 2.0 nmol) into the globus pallidus also significantly attenuated vacuous chewing. Infusion of naltrindole into the globus pallidus blocked vacuous chewing at all doses administered (0.5, 1.0, 2.0 nmol) while CTOP was only effective at the two higher doses. From these results we suggest that increases in dynorphin in the direct striatonigral pathway and enkephalin in the indirect striatopallidal pathway following chronic neuroleptic administration are both likely to contribute to tardive dyskinesia.
McCormick
S E
SE
Pacific Parkinson's Research Centre, Faculty of Medicine, University of British Columbia, Vancouver, Canada V6T 2B5.
Stoessl
A J
AJ
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism*; D005476:Fluphenazine / Q000494:pharmacology; D005917:Globus Pallidus / Q000378:metabolism*; D008297:Male; D008409:Mastication / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013378:Substantia Nigra / Q000378:metabolism*
D009292:Narcotic Antagonists; D011957:Receptors, Opioid; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D009270:Naloxone; C051844:norbinaltorphimine; D013004:Somatostatin; D009271:Naltrexone; D004399:Dynorphins; C055382:naltrindole; D005476:Fluphenazine