Title | 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. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Auteurs | Deslauriers, J, Desmarais, C, Sarret, P, Grignon, S |
Journal | J Mol Neurosci |
Volume | 50 |
Issue | 1 |
Pagination | 134-45 |
Date Published | 2013 May |
ISSN | 1559-1166 |
Keywords | Antipsychotic Agents, Arrestins, beta Catenin, beta-Arrestin 2, beta-Arrestins, Cell Line, Tumor, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Haloperidol, Humans, Oxidative Stress, Phosphorylation, Proto-Oncogene Proteins c-akt, Receptors, Dopamine D2, Signal Transduction, Thioctic Acid, TOR Serine-Threonine Kinases, Transcription, Genetic |
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. |
DOI | 10.1007/s12031-012-9884-4 |
Alternate Journal | J. Mol. Neurosci. |
PubMed ID | 22975849 |
Grant List | / / Canadian Institutes of Health Research / Canada |