Tardive dyskinesia is associated with altered putamen Akt/GSK-3β signaling in nonhuman primates

Mov Disord. 2019 May;34(5):717-726. doi: 10.1002/mds.27630. Epub 2019 Jan 24.


Background: Tardive dyskinesia is a delayed and potentially irreversible motor complication arising from chronic exposure to antipsychotic drugs. Interaction of antipsychotic drugs with G protein-coupled receptors triggers multiple intracellular events. Nevertheless, signaling pathways that might be associated with chronic unwanted effects of antipsychotic drugs remain elusive. In this study, we aimed to better understand kinase signaling associated with the expression of tardive dyskinesia in nonhuman primates.

Methods: We exposed capuchin monkeys to prolonged haloperidol (n = 10) or clozapine (n = 6) treatments. Untreated animals were used as controls (n = 6). Half of haloperidol-treated animals (5) developed mild tardive dyskinesia similar to that found in humans. Using Western blots and immunochemistry, we measured putamen total and phosphorylated protein kinase levels associated with canonical and noncanonical signaling cascades of G protein-coupled receptors.

Results: Antipsychotic drugs enhanced pDARPP-32 and pERK1/2, but no difference ws observed in phosphoprotein kinase levels between dyskinetic and nondyskinetic monkeys. On the other hand, comparison of kinase levels between haloperidol-treated dyskinetic and nondyskinetic monkeys indicated that dyskinetic animals had lower GRK6 and β-arrestin2 levels. Levels of pAkt and pGSK-3β were also reduced, but only haloperidol-treated monkeys that developed tardive dyskinesia had reduced pGSK-3β levels, whereas pAkt levels in dyskinetic animals positively correlated with dyskinetic scores. Interestingly, double immunofluorescence labeling showed that putamen dopamine D3 receptor levels were upregulated and that D3/pAkt colocalization was enriched in haloperidol-treated animals displaying tardive dyskinesia.

Conclusions: Our results suggest that upregulation of putamen dopamine D3 receptor and alterations along the noncanonical GRK6/β-arrestin2/Akt/GSK-3β molecular cascade are associated with the development of tardive dyskinesia in nonhuman primates. © 2019 International Parkinson and Movement Disorder Society.

Keywords: antipsychotic; clozapine; dopamine D3 receptor; haloperidol; monkey; striatum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cebus
  • Clozapine / pharmacology*
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / drug effects
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism
  • G-Protein-Coupled Receptor Kinases / drug effects
  • G-Protein-Coupled Receptor Kinases / metabolism
  • Glycogen Synthase Kinase 3 beta / drug effects*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Haloperidol / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / drug effects*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Putamen / drug effects*
  • Putamen / metabolism
  • Receptors, Dopamine D3 / drug effects
  • Receptors, Dopamine D3 / metabolism
  • Signal Transduction
  • Tardive Dyskinesia / metabolism*
  • beta-Arrestin 2 / drug effects
  • beta-Arrestin 2 / metabolism


  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Receptors, Dopamine D3
  • beta-Arrestin 2
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • G-Protein-Coupled Receptor Kinases
  • Clozapine
  • Haloperidol