title: 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.
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.
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12e avenue Nord, Sherbrooke, QC, Canada, J1H 5N4.
authors.forename: Jessica
authors.initials: J
authors.lastname: Deslauriers
authors.forename: Christian
authors.initials: C
authors.lastname: Desmarais
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
authors.forename: Sylvain
authors.initials: S
authors.lastname: Grignon
mesh_terms: D000077582:Amisulpride; D014150:Antipsychotic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D006220:Haloperidol / Q000494:pharmacology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D013469:Sulpiride / Q000031:analogs & derivatives / Q000494:pharmacology; D008063:Thioctic Acid / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D014150:Antipsychotic Agents; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D008063:Thioctic Acid; D013469:Sulpiride; D000077582:Amisulpride; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006220:Haloperidol