Atypical Antipsychotics Activate Hypothalamic AMPK

Abstract

Although atypical antipsychotic drugs (AAPDs) are currently the most commonly used treatments for schizophrenia, some of them stimulate a substantial weight gain--largely associated with increased food intake--that can lead to the development of diabetes and cardiovascular disease. Noting that activation of hypothalamic adenosine 5'-monophosphate-activated protein kinase (AMPK) is associated with increased food intake, Kim et al . explored the effects of AAPDs on AMPK phosphorylation (and thereby activation). Clozapine and olanzapine, two AAPDs that elicit weight gain, stimulated phosphorylation of AMPK in mouse hypothalamic slices, as did quetiapine, whereas antipsychotic drugs with less effect on appetite did not. Furthermore, clozapine stimulated the phosphorylation and catalytic activity of hypothalamic AMPK in intact mice. After confirming reports that the potency of AAPDs in blocking the histamine H 1 receptor (H1R) correlated with their tendency to stimulate weight gain (determined from the clinical literature), the authors showed that clozapine blocked the ability of histamine to decrease phosphorylation of AMPK in hypothalamic slices. Moreover, clozapine failed to stimulate AMPK phosphorylation in mice lacking the H1R. Thus, the authors conclude that the orexigenic effects of AAPDs likely involve blockade of the H1R and an associated activation of hypothalamic AMPK. In a thoughtful commentary, Meltzer notes that the first modern antipsychotic, chlorpromazine, was initially developed in a search for antihistamines. S. F. Kim, A. S. Huang, A. M. Snowman, C. Teuscher, S. H. Snyder, Antipsychotic drug-induced weight gain mediated by histamine H 1 receptor-linked activation of hypothalamic AMP-kinase. Proc. Natl. Acad. Sci. U.S.A. 104 , 3456-3459 (2007). [Abstract] [Full Text] H. Y. Meltzer, Illuminating the molecular basis for some antipsychotic drug-induced metabolic burden. Proc. Natl. Acad. Sci. U.S.A. 104 , 3019-3020 (2007). [Full Text]