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 the phosphorylation of AMPK, which enhances its kinase activity. 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 earlier reports that that the potency of AAPDs in blocking the histamine H1 receptor (H1R) correlated with their tendency to stimulate weight gain, the authors showed that clozapine blocked the ability of histamine to decrease the phosphorylation of AMPK in hypothalamic slices. Moreover, clozapine failed to stimulate AMPK phosphorylation in mice lacking the H1R. Thus, they conclude that the orexigenic effects of AAPDs probably involve blockade of the H1R and an associated activation of hypothalamic AMPK. -- EMA
Proc. Natl. Acad. Sci. U.S.A. 104, 3456 (2007).
