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α-Lipoic Acid Interaction with Dopamine D2 Receptor-Dependent Activation of the Akt/GSK-3β Signaling Pathway Induced by Antipsychotics: Potential Relevance for the Treatment of Schizophrenia

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Abstract

Chronic administration of antipsychotics has been associated with dopamine D2 receptor (D2R) upregulation and tardive dyskinesia. We have previously shown that haloperidol, a first-generation antipsychotic (FGA), exerted an increase in D2R expression and oxidative stress and that (±)-α-lipoic acid reversed its effect. Previous studies have implicated the Akt/glycogen synthase kinase-3β (GSK-3β) signaling pathway in antipsychotic action. These findings led us to examine whether the Akt/GSK-3β pathway was involved in D2R upregulation and oxidative stress elicited by antipsychotics and, in (±)-α-lipoic acid-induced reversal of these phenomena, in SH-SY5Y cells. Antipsychotics increased phosphorylation of Akt and GSK-3β, and additive effects were observed with (±)-α-lipoic acid. GSK-3β inhibitors reversed haloperidol-induced overexpression of D2R mRNA levels but did not affect haloperidol-induced oxidative stress. Sustained antipsychotic treatment increased β-arrestin-2 and D2R receptor interaction. Regarding Akt/GSK-3β downstream targets, antipsychotics increased β-catenin levels, whereas (±)-α-lipoic acid induced an elevation of mTOR activation. These results suggest (1) that the effect of antipsychotics on the Akt/GSK-3β pathway in SH-SY5Y cells is reminiscent of their in vivo action, (2) that (±)-α-lipoic acid partially synergizes with antipsychotic drugs (APDs) on the same pathway, and (3) that the Akt/GSK-3β signaling cascade is not involved in the preventive effect of (±)-α-lipoic acid on antipsychotics-induced D2R upregulation.

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Acknowledgments

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 a CIHR investigator. Philippe Sarret, PhD and Sylvain Grignon, MD, PhD are members of the FRSQ-funded Centre de Recherche Clinique Étienne Lebel.

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  1. Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12e avenue Nord, Sherbrooke, QC, J1H 5N4, Canada

    Jessica Deslauriers, Christian Desmarais, Philippe Sarret & Sylvain Grignon

  2. Department of Psychiatry, Centre Hospitalier Universitaire de Sherbrooke, 580 Bowen Sud, Sherbrooke, QC, J1G 2E8, Canada

    Sylvain Grignon

  3. Department of Psychiatry, CHUS Hôtel-Dieu, 580 rue Bowen Sud, Sherbrooke, QC, J1G 2E8, Canada

    Sylvain Grignon

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Deslauriers, J., Desmarais, C., Sarret, P. et al. α-Lipoic Acid Interaction with Dopamine D2 Receptor-Dependent Activation of the Akt/GSK-3β Signaling Pathway Induced by Antipsychotics: Potential Relevance for the Treatment of Schizophrenia. J Mol Neurosci 50, 134–145 (2013). https://doi.org/10.1007/s12031-012-9884-4

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