Caractérisation neurochimique de la dyskinésie tardive dans un modèle primate non humain

Tardive dyskinesia (TD) is a debilitating and potentially irreversible motor complication arising in patients chronically exposed to antipsychotic (AP) drugs, used predominantly in the treatment of schizophrenia. Close to 20% of patients under 40 years old treated with AP will develop TD, and this prevalence can rise up to 70% in patients aged 65+ years old. TD is characterised by involuntary movements of the tongue, face, trunk and upper limbs. Even though this neuro-motor side effect is not fatal, it can be disabling, especially in an already vulnerable clientele. Furthermore, the mechanisms of pathophysiology of TD are not fully understood yet. In theory variations in the levels and the activity of neurochemicals elements, principally distributed in the basal ganglia (BG), should be observed in link with AP treatments and the genesis of TD. Therein, various neurochemicals elements have been linked to TD using evidence found in literature. We then used a non-human primate model (Cebus apella) chronically treated with haloperidol (HAL) or clozapine (CLZ) to characterise these potential targets. Thus, an in situ hybridisation, a [35S]GTPγS binding assay to the G proteins of dopamine (DA) receptors stimulated by DA, and bindings assays to transporters, but also serotonin, adenosine and glutamate receptors were performed with this model. Western blots of presynaptic markers and an analysis of residual AP levels in brain tissues of our monkeys have also been accomplished in complement to these assays. A preclinical assay of a D3 antagonist has also been performed on mice, in the treatment of involuntary jaw movements induced by a chronic treatment with HAL, called vacuous chewing movements (VCM). The main purpose of these experiments was to characterize the neurochemical changes that may be associated with TD in primates and then compare them with rodent models and clinical data in humans. In conclusion, the DA transporter (DAT), the vesicular monoamine transporter 2 (VMAT2), the D2, D3, 5-HT2A and the NMDA (NR1/NR2B) receptors were associated with TD in our non-human primate model, at the level of the caudal putamen, either by an alteration of their density or their activity. The 5-HT2C, 5-HT2A, A2A and NMDA (NR1/NR2A) receptor density were not clearly associated with TD. Collectively, these data support the TD theory of DAergic hypersensitivity and maladaptative plasticity. Furthermore, the preclinical assay of a D3 antagonist in the treatment of HAL induced VCM, suggests that rodent models of TD are inadequate in TD studies and the identification of new treatment targets. It also suggest that primate models would be a more reliable option for these purpose. Finally, these data provide essential information for understanding the mechanisms involved in TD induced by AP medication, and may serve to identify potential new therapeutic targets in the treatment of this incapacitating motor side effect.

Keyphrases: Dopamine, Glutamate, Tardive dyskinesia, Antipsychotics, Non-human primate, Basal ganglia, Dopamine, Serotonin, Glutamate, Adenosine, Maladaptative plasticity