Implication of the ERK/MAPK Pathway in Antipsychotics-induced Dopamine D2 Receptor Upregulation and in the Preventive Effects of (±)-α-lipoic acid in SH-SY5Y Neuroblastoma Cells
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Chronic administration of antipsychotics (APs) has been associated with dopamine D2 receptor (D2R) upregulation and tardive dyskinesia. We previously showed that haloperidol, a first-generation AP, exerted a more robust increase in D2R expression than amisulpride, a second-generation AP and that (±)-α-lipoic acid pre-treatment reversed the AP-induced D2R upregulation. We also demonstrated that the Akt/GSK-3β/β-catenin pathway is involved in the control of D2R expression levels, but is unlikely implicated in the preventive effects of (±)-α-lipoic acid since co-treatment with haloperidol and (±)-α-lipoic acid exerts synergistic effects on Akt/GSK-3β activation. These findings led us to examine whether the ERK/MAPK signaling pathway may be involved in D2R upregulation elicited by APs, and in its reversal by (±)-α-lipoic acid, in SH-SY5Y human neuroblastoma cells. Our results revealed that haloperidol, in parallel with an elevation in D2R mRNA levels, induced a larger increase of ERK (p42/p44) phosphorylation than amisulpride. Pre-treatment with the selective ERK inhibitor U0126 attenuated haloperidol-induced increase in D2R upregulation. Furthermore, (±)-α-lipoic acid prevented AP-induced ERK activation. These results show that (1) the ERK/MAPK pathway is involved in haloperidol-induced D2R upregulation; (2) the preventive effect of (±)-α-lipoic acid on haloperidol-induced D2R upregulation is in part mediated by an ERK/MAPK-dependent signaling cascade. Taken together, our data suggest that (±)-α-lipoic acid exerts synergistic effects with haloperidol on the Akt/GSK-3β pathway, potentially involved in the therapeutic effects of APs, and antagonism of ERK activation and D2R upregulation, potentially involved in tardive dyskinesia and treatment resistance.
KeywordsAntipsychotics Lipoic acid Dopamine D2 receptor ERK SH-SY5Y
This work was supported by an unrestricted educational grant from Novartis Pharma Canada to the Department of Psychiatry, Université de Sherbrooke, and by the Centre des Neurosciences de Sherbrooke. Philippe Sarret, PhD is recipient of the Canada Research Chair in Neurophysiopharmacology of Chronic Pain and director of the Sherbrooke’s Neuroscience Centre. Philippe Sarret, PhD and Sylvain Grignon, MD, PhD are members of the FRSQ-funded Centre de Recherche Clinique Étienne Lebel. Jessica Deslauriers, MSc is recipient of a FRQS doctoral training award.
The authors have no financial conflict of interest to declare.
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