Differential effects of amisulpride and haloperidol on dopamine D-2 receptor-mediated signaling in SH-SY5Y cells

作者：Park Sung Woo; Seo Mi Kyoung; Cho Hye Yeon; Lee Jung Goo; Lee Bong Ju; Seol Wongi; Kim Young Hoon^*

来源：Neuropharmacology, 2011, 61(4): 761-769.

DOI：10.1016/j.neuropharm.2011.05.022

• Amisulpride
• Haloperidol
• Dopamine D-2 receptors
• beta-Arrestin 2
• Akt/glycogen
• Synthase kinase-3 beta signaling
• Neurite outgrowth

Dopamine D-2 receptors (D2R) are the primary target of antipsychotic drugs and have been shown to regulate Akt/glycogen synthase kinase-3 beta (GSK-3 beta) signaling through scaffolding protein beta-arrestin 2. Amisulpride, an atypical antipsychotic drug, and haloperidol; a typical antipsychotic drug, are both potent D2R antagonists, but their therapeutic effects differ. In the present study, we compared the effects of amisulpride and haloperidol on the beta-arrestin 2-mediated Akt/GSK-3 beta pathway in SH-SY5Y cells. To determine whether these drugs affected neuronal morphology in SH-SY5Y cells, we investigated the effects of amisulpride and haloperidol on neurite outgrowth using immunostaining. We examined the effects of these drugs on Akt and GSK-3 beta and its well-known downstream regulators, CAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), and Bcl-2 levels using Western blot analysis. Amisulpride, but not haloperidol, was found to enhance neurite outgrowth. Small interfering RNA (siRNA) for beta-arrestin 2 knockdown blocked the increase in amisulpride-induced neurite outgrowth. Furthermore, amisulpride increased the levels of Akt and GSK-3 beta phosphorylation, while haloperidol had no effect. The elevation of Akt phosphorylation induced by amisulpride was reduced by beta-arrestin 2 siRNA. Moreover, amisulpride effectively increased the levels of phospho-CREB, BDNF, and Bcl-2. However, haloperidol had no effect on the levels of these proteins. Additionally, wortmannin, a phosphatidylinositol 3-kinase (PI3 K) inhibitor, blocked the stimulatory effect of amisulpride on phosphorylated Akt. Together, these results suggest that regulation of the beta-arrestin 2-dependent pathway via blockade of the D2R in SH-SY5Y cells is one mechanism underlying the neuroprotective effect of amisulpride, but not haloperidol.

• 出版日期2011-9