Antipsychotic-Induced DRD2 Upregulation and Its Prevention by α-Lipoic Acid in SH-SY5Y Neuroblastoma Cells

Most antipsychotic (AP) drugs are dopamine (DA) D2 receptor (DRD2) antagonists and remain the main pharmacological treatment of schizophrenia. Long-term AP use can give rise to tardive dyskinesia. It has been reported that chronic treatment with APs induces DRD2 upregulation and oxidative stress, which have been associated with tardive dyskinesia. We showed previously that H2O2-induced oxidative stress increased DRD2 expression in human SH-SY5Y neuroblastoma cells. We report here the effects of AP drugs on DRD2 expression levels in the same cell line and the effects of the inhibition of oxidative phenomena by (+/-)-alpha-lipoic acid treatment. Haloperidol, a first-generation AP, induced an increase in DRD2 protein and mRNA levels, whereas amisulpride, a second-generation AP, had no significant effect. (+/-)-alpha-Lipoic acid pretreatment reversed the haloperidol-induced DRD2 upregulation in mRNA, and protein levels. Furthermore, haloperidol induced a larger increase of oxidative stress biomarkers (protein carbonylation, lipid peroxidation, and superoxide anion production) than amisulpride. (+/-)-alpha-Lipoic acid also attenuated AP-induced oxidative stress. Inhibition of catecholamine synthesis by alpha-methyl-DL-tyrosine (AMPT) increased DRD2 expression and prevented further increase by APs. Our results suggest that haloperidol-induced DRD2 upregulation is linked to oxidative stress and provide potential mechanisms by which (+/-)-alpha-lipoic acid can be considered as a therapeutic agent to prevent and treat side effects related to the use of first-generation APs. Synapse 65:321-331, 2011. (C) 2010 Wiley-Liss, Inc.