Journal of Molecular Neuroscience

, Volume 52, Issue 3, pp 378–383

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

Authors

  • Jessica Deslauriers
    • Department of Physiology and Biophysics, Faculty of Medicine and Health SciencesUniversité de Sherbrooke
  • Christian Desmarais
    • Department of Physiology and Biophysics, Faculty of Medicine and Health SciencesUniversité de Sherbrooke
  • Philippe Sarret
    • Department of Physiology and Biophysics, Faculty of Medicine and Health SciencesUniversité de Sherbrooke
    • Department of Physiology and Biophysics, Faculty of Medicine and Health SciencesUniversité de Sherbrooke
    • Department of PsychiatryCentre Hospitalier Universitaire de Sherbrooke
    • Department of PsychiatryCHUS Hôtel-Dieu
Article

DOI: 10.1007/s12031-013-0158-6

Cite this article as:
Deslauriers, J., Desmarais, C., Sarret, P. et al. J Mol Neurosci (2014) 52: 378. doi:10.1007/s12031-013-0158-6

Abstract

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

Keywords

AntipsychoticsLipoic acidDopamine D2 receptorERKSH-SY5Y

Supplementary material

12031_2013_158_MOESM1_ESM.pdf (305 kb)
ESM 1(PDF 305 kb)

Copyright information

© Springer Science+Business Media New York 2013