α-Lipoic acid interaction with dopamine D2 receptor-dependent activation of the Akt/GSK-3ß signaling pathway induced by antipsychotics: potential relevance for the treatment of schizophrenia.

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-3ß (GSK-3ß) signaling pathway in antipsychotic action. These findings led us to examine whether the Akt/GSK-3ß 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-3ß, and additive effects were observed with (±)-α-lipoic acid. GSK-3ß inhibitors reversed haloperidol-induced overexpression of D2R mRNA levels but did not affect haloperidol-induced oxidative stress. Sustained antipsychotic treatment increased ß-arrestin-2 and D2R receptor interaction. Regarding Akt/GSK-3ß downstream targets, antipsychotics increased ß-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-3ß 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-3ß signaling cascade is not involved in the preventive effect of (±)-α-lipoic acid on antipsychotics-induced D2R upregulation.