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PNAS 104 (9): 3456-3459

Copyright © 2007 by the National Academy of Sciences.

From the Cover

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase

Sangwon F. Kim*, Alex S. Huang*, Adele M. Snowman*, Cory Teuscher{dagger}, and Solomon H. Snyder*,{ddagger},§,¶

*The Solomon H. Snyder Department of Neuroscience, Departments of {ddagger}Pharmacology and Molecular Sciences and §Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205; and {dagger}Departments of Medicine and Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405

Contributed by Solomon H. Snyder, December 21, 2006

Received for publication November 28, 2006.

Abstract: The atypical antipsychotic drugs (AAPDs) have markedly enhanced the treatment of schizophrenias but their use has been hindered by the major weight gain elicited by some AAPDs. We report that orexigenic AAPDs potently and selectively activate hypothalamic AMP-kinase, an action abolished in mice with deletion of histamine H1 receptors. These findings may afford a means of developing more effective therapeutic agents and provide insight into the hypothalamic regulation of food intake.

Key Words: atypical antipsychotic drugs • obesity • hypothalamus

Author contributions: S.F.K. designed research; S.F.K., A.S.H., and A.M.S. performed research; C.T. contributed new reagents/analytic tools; S.F.K., A.S.H., and S.H.S. analyzed data; and S.F.K. and S.H.S. wrote the paper.

The authors declare no conflict of interest.

See Commentary on page 3019.

This article contains supporting information online at www.pnas.org/cgi/content/full/0611417104/DC1.

To whom correspondence should be addressed. E-mail: ssnyder{at}jhmi.edu

© 2007 by The National Academy of Sciences of the USA

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