Effects of atypical antipsychotics and haloperidol on PC12 cells: only aripiprazole phosphorylates AMP-activated protein kinase

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• 作者：Goro Takami ; Miyuki Ota ; Akira Nakashima ; Yoko S. Kaneko ; Keiji Mori ; Toshiharu Nagatsu and Akira Ota
• 关键词：AMP ; activated protein kinase ; Appetite ; Aripiprazole ; ATP ; ATP ; sensitive K+ channel ; β ; Oxidation
• 刊名：Journal of Neural Transmission
• 出版年：2010
• 出版时间：October 2010
• 年：2010
• 卷：117
• 期：10
• 页码：1139-1153
• 全文大小：600.2 KB

文摘

By converting changes in intracellular energy status to changes in cell membrane polarization, ATP-sensitive K+ (K_ATP) channels in hypothalamic appetite-regulating neurons play a critical role in linking neuronal electrochemical function, metabolic and energy status, and feeding behavior. Most atypical antipsychotics (AAPs) increase the appetite of patients with schizophrenia and thus cause obesity. This study aimed to explain the mechanism underlying AAP-induced appetite stimulation, based on the fact that the efficiency of fatty acid uptake into mitochondria generating ATP through β-oxidation is determined by the rate of fatty acid synthesis. Using PC12 cells exposed to clozapine, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, and haloperidol, we measured intracellular ATP and mRNA and protein expression of enzymes and related substances involved in fatty acid synthesis and K_ATP channel function. Forty-eight-hour treatment of cells with 50 μM aripiprazole in 5.6 mM glucose decreased intracellular ATP. Only 50 μM aripiprazole phosphorylated AMP-activated protein kinase (AMPK); none of the other antipsychotics did so to a detectable level. Expression of carnitine palmitoyltransferase 1a, uncoupling protein 2, and sulfonylurea receptor 1 was unaffected by the antipsychotics, although expression of their mRNA was affected by AAPs. Pyrilamine (H₁ receptor antagonist), ketanserin (5HT₂ receptor antagonist), and raclopride (D₂ receptor antagonist) alone or in combination had no effect on expression of the aforementioned proteins. Therefore, although this study did not differentiate orexigenic and non-orexigenic AAPs, it suggests that aripiprazole is unique in its ability to activate AMPK.