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Upregulation of dopamine D3, not D2, receptors correlates with tardive dyskinesia in a primate model

Authors

  • Souha Mahmoudi PhD,

    1. Faculty of Pharmacy, Universite de Montreal, Montreal, Quebec, Canada
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  • Daniel Lévesque PhD,

    1. Faculty of Pharmacy, Universite de Montreal, Montreal, Quebec, Canada
    2. CNS Research Group (GRSNC), Universite de Montreal, Canada
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  • Pierre J. Blanchet MD, FRCPC, PhD

    Corresponding author
    1. Faculty of Dental Medicine, Department of Stomatology, Universite de Montreal, Canada
    2. CNS Research Group (GRSNC), Universite de Montreal, Canada
    • Correspondence to: Dr. Pierre Blanchet, Faculty of Dental Medicine, Universite de Montreal, P.O. Box 6128, Succ. Centre-ville, Montreal (QC), H3C 3J7, Canada. E-mail: pierre.j.blanchet@umontreal.ca

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  • Funding agencies: This study was supported by grants from the Canadian Institutes for Health Research (CIHR, MOP-81321). S.M. held a doctoral studentship from “Fonds de Recherche du Québec en Santé (FRQ-S)”.

  • Relevant conflicts of interest/financial disclosures: Dr. Blanchet reports having received lecture fees from Novartis Pharma Canada Inc., and consultation fees from UCB Pharma. Dr. Mahmoudi and Dr. Lévesque declare no potential conflicts of interest.

  • Full financial disclosures and author roles may be found in the online version of this article.

ABSTRACT

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication arising in patients chronically exposed to centrally active dopamine D2 receptor antagonists, including antipsychotic drugs and metoclopramide. The classical dopamine D2 receptor supersensitivity hypothesis in TD, which stemmed from rodent studies, lacks strong support in humans. To investigate the neurochemical basis of TD, we chronically exposed adult capuchin monkeys to haloperidol (median, 18.5 months; n = 11) or clozapine (median, 6 months; n = 6). Six unmedicated animals were used as controls. Five haloperidol-treated animals developed mild TD movements, and no TD was observed in the clozapine group. Using receptor autoradiography, we measured striatal dopamine D1, D2, and D3 receptor levels. We also examined the D3 receptor/preprotachykinin messenger RNA (mRNA) co-expression, and quantified preproenkephalin mRNA levels, in striatal sections. Unlike clozapine, haloperidol strongly induced dopamine D3 receptor binding sites in the anterior caudate-putamen, particularly in TD animals, and binding levels positively correlated with TD intensity. Interestingly, the D3 receptor upregulation was observed in striatonigral neurons. In contrast, D2 receptor binding was comparable to controls, and dopamine D1 receptor binding was reduced in the anterior putamen. Enkephalin mRNA widely increased in all animals, but to a greater extent in TD-free animals. These results suggest for the first time that upregulated striatal D3 receptors correlate with TD in nonhuman primates, adding new insights to the dopamine receptor supersensitivity hypothesis. The D3 receptor could provide a novel target for drug intervention in human TD. © 2014 International Parkinson and Movement Disorder Society

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