Objective: To investigate the neurochemical basis of tardive dyskinesia (TD) in an experimental primate model.

Background: TD is a potentially irreversible motor complication occurring in one third of subjects during long-term exposure to centrally acting dopamine D2/3 receptor antagonists such as antipsychotic drugs. The induction and maintenance mechanisms remain elusive. We previously documented an upregulation of striatal D3 (not D2) receptors specific to TD-expressing monkeys in direct medium spiny neurons. Multiple kinase pathways are modulated by antipsychotic drugs, but the distinct impact of conventional vs. atypical drugs and their involvement in TD are unknown.

Methods: Under animal research ethics approval, we chronically exposed capuchins to haloperidol (N=11) or clozapine (N=6). Six unmedicated animals served as controls. Using Western blots, total and phosphorylated protein kinase levels (normalized over GAPDH or tubulin protein levels) were measured in the putamen in cAMP-dependent and -independent pathways associated with dopamine D2/3 receptor signaling. An immunofluorescence technique was used to reveal the differential expression of phospho[Ser473]Akt (pAkt) in D3+ cells.

Results: Five haloperidol-treated animals developed typical TD, and no TD was observed in the clozapine group. Total protein kinase levels were not altered by any treatment. While haloperidol enhanced phospho[Thr202/Tyr204]-p44/42 ERK1/2 levels by 3.4 fold, no difference was observed between TD-expressing and TD-free monkeys. Phospho[Thr34]-DARPP-32 levels were elevated 1.7 fold only in TD animals. Haloperidol specifically reduced putamen GRK6 (64%), β-arrestin2 (57%), and phospho[Ser9]GSK-3β (69%) levels in TD animals. Levels of pAkt were generally reduced (46%) by haloperidol, and were higher in TD-expressing (+47%) relative to TD-free animals. Further, pAkt/D3 colocalization was increased (40%) in the putamen of TD monkeys compared to TD-free animals. Phosphorylated protein kinases levels in the clozapine group were similar to controls, but GRK6 protein levels were upregulated 1.7 fold.

Conclusions: Our results suggest that failure to up-regulate striatal GRK6 and inactivate GSK-3β signaling may contribute to striatal D3 receptor upregulation and development of experimental TD. If confirmed, these changes may offer novel avenues for preventing or palliating TD. Supported by the Canadian Institutes for Health Research.

References: 1. Mahmoudi S, Lévesque D, Blanchet PJ. Upregulation of dopamine D3, not D2, receptors correlates with tardive dyskinesia in a primate model. Mov Disord 2014;29:1125–1133. 2. Lévesque C, Hernandez G, Mahmoudi S, Calon F, Gasparini F, Gomez-Mancilla B, Blanchet PJ, Lévesque D. Deficient striatal adaptation in aminergic and glutamatergic neurotransmission is associated with tardive dyskinesia in non-human primates exposed to antipsychotic drugs. Neuroscience 2017;361:43-57.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/abnormal-signaling-along-the-non-canonical-molecular-cascade-grk6-%ce%b2-arrestin2-akt-gsk-3%ce%b2-in-the-putamen-is-associated-with-tardive-dyskinesia-following-chronic-haloperidol-exposure-in-a-prim/