[Show abstract][Hide abstract] ABSTRACT: 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 (H(1) receptor antagonist), ketanserin (5HT(2) receptor antagonist), and raclopride (D(2) 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.
No preview · Article · Oct 2010 · Journal of Neural Transmission
[Show abstract][Hide abstract] ABSTRACT: Electrophysiological and immunohistochemical studies have demonstrated that glucose-sensing neurons in the hypothalamus contain both ATP-sensitive K(+) (K(ATP)) and tandem-pore K(+) (TASK1 and TASK3) channels and that glucose-induced depolarization or hyperpolarization of these neurons function as an important link between glucose-excited or glucose-inhibited neurons and feeding behavior. Medication with atypical antipsychotics increases the appetite of schizophrenic patients and thus causes increases in body weight. Therefore, the present study investigates mRNA expression levels of the genes encoding the components of these K(+) channel subsets in PC12 cells cultured with risperidone (an atypical antipsychotic) and in the hypothalami of rats subcutaneously injected for 21 consecutive days with 0.1 or 0.01 mg/kg/day of risperidone. The mRNA expression levels of various genes were not obviously altered in rat hypothalami. However, the mRNA expression levels for sulfonylurea receptor 1, a component affording nucleotide-binding folds to K(ATP) channels, and TASK1 were down-regulated in PC12 cells cultured with 50 microM risperidone for 24h, but the amount of intracellular ATP in these cells was not affected by the drug. Collectively, these results indicate that the amplitude of the current through these K(+) channels in PC12 cells might be modulated as a pharmacological effect of risperidone.
No preview · Article · Mar 2007 · Neuroscience Letters
[Show abstract][Hide abstract] ABSTRACT: This study was undertaken to find an answer to the discrepancy between enhanced leptin mRNA expression level in white adipose tissue and its normal serum level in the rats given risperidone of 0.1 mg/kg/day (an equivalent dose to the standard one used for patients) for 21 consecutive days. In the white adipose tissues of rats injected with risperidone, mRNA expression levels of the genes encoding truncated a form of leptin receptor (Ob-Ra) and suppressor of cytokine signaling-3 (SOCS-3) were up-regulated; α 1c-adrenergic receptor subtype mRNA expession level was down-regulated. On the contrary, the mRNA expression levels of the genes encoding long form of leptin receptor (Ob-Rb), Ob-Ra, SOCS-3, and neuropeptides known to regulate the appetite were not altered in the hypothalamus, a target site of leptin, obtained from the rats injected with risperidone for 21 consecutive days. These data indicate the importance of the adaptation that occurred in the white adipose tissue of the rats injected with risperidone for semi-chronic duration.