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

Mov Disord. 2014 Aug;29(9):1125-33. doi: 10.1002/mds.25909. Epub 2014 May 16.


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.

Keywords: antipsychotic drugs; basal ganglia; dopamine receptors; tardive dyskinesia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology
  • Brain / drug effects
  • Brain / metabolism*
  • Cebus
  • Clozapine / pharmacology
  • Disease Models, Animal
  • Dopamine Antagonists / toxicity
  • Enkephalins / genetics
  • Enkephalins / metabolism
  • Female
  • Haloperidol / toxicity
  • Iodine Radioisotopes / pharmacokinetics
  • Movement Disorders / etiology
  • Movement Disorders / metabolism
  • Movement Disorders / pathology
  • Movement Disorders / physiopathology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Ovariectomy
  • Protein Binding / drug effects
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D3 / genetics
  • Receptors, Dopamine D3 / metabolism*
  • Sulpiride / analogs & derivatives
  • Sulpiride / pharmacokinetics
  • Tetrahydronaphthalenes / pharmacokinetics
  • Up-Regulation / drug effects
  • Up-Regulation / physiology*


  • Antipsychotic Agents
  • Dopamine Antagonists
  • Enkephalins
  • Iodine Radioisotopes
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Tetrahydronaphthalenes
  • iodosulpride
  • 7-hydroxy-2-(N-n-propyl-N-(3-iodo-2'-propenyl)-amino)tetralin
  • Sulpiride
  • Clozapine
  • Haloperidol