Implication of the ERK/MAPK Pathway in Antipsychotics-induced Dopamine D2 Receptor Upregulation and in the Preventive Effects of (+/-)-alpha-lipoic acid in SH-SY5Y Neuroblastoma Cells

作者：Deslauriers Jessica; Desmarais Christian; Sarret Philippe; Grignon Sylvain^*

来源：Journal of Molecular Neuroscience, 2014, 52(3): 378-383.

DOI：10.1007/s12031-013-0158-6

• Antipsychotics
• Lipoic acid
• Dopamine D2 receptor
• ERK
• SH-SY5Y

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 (+/-)-alpha-lipoic acid pre-treatment reversed the AP-induced D2R upregulation. We also demonstrated that the Akt/GSK-3 beta/beta-catenin pathway is involved in the control of D2R expression levels, but is unlikely implicated in the preventive effects of (+/-)-alpha-lipoic acid since co-treatment with haloperidol and (+/-)-alpha-lipoic acid exerts synergistic effects on Akt/GSK-3 beta 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 (+/-)-alpha-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, (+/-)-alpha-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 (+/-)-alpha-lipoic acid on haloperidol-induced D2R upregulation is in part mediated by an ERK/MAPK-dependent signaling cascade. Taken together, our data suggest that (+/-)-alpha-lipoic acid exerts synergistic effects with haloperidol on the Akt/GSK-3 beta 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.

• 出版日期2014-3