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Science 302 (5649): 1412-1415

Copyright © 2003 by the American Association for the Advancement of Science

Diverse Psychotomimetics Act Through a Common Signaling Pathway

Per Svenningsson,1 Eleni T. Tzavara,2 Robert Carruthers,1 Ilan Rachleff,1 Sigrid Wattler,3 Michael Nehls,3 David L. McKinzie,2 Allen A. Fienberg,1,4 George G. Nomikos,2 Paul Greengard1*

Abstract: Three distinct classes of drugs: dopaminergic agonists (such as D-amphetamine), serotonergic agonists (such as LSD), and glutamatergic antagonists (such as PCP) all induce psychotomimetic states in experimental animals that closely resemble schizophrenia symptoms in humans. Here we implicate a common signaling pathway in mediating these effects. In this pathway, dopamine- and an adenosine 3',5'-monophosphate (cAMP)–regulated phospho-protein of 32 kilodaltons (DARPP-32) is phosphorylated or dephosphorylated at three sites, in a pattern predicted to cause a synergistic inhibition of protein phosphatase–1 and concomitant regulation of its downstream effector proteins glycogen synthesis kinase–3 (GSK-3), cAMP response element–binding protein (CREB), and c-Fos. In mice with a genetic deletion of DARPP-32 or with point mutations in phosphorylation sites of DARPP-32, the effects of D-amphetamine, LSD, and PCP on two behavioral parameters—sensorimotor gating and repetitive movements—were strongly attenuated.

1 Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021, USA.
2 Eli Lilly and Company, Lilly Corporate Center, Neuroscience Discovery Research, Indianapolis, IN 46285–0510, USA.
3 Lexicon Genetics Inc., The Woodlands, TX 77381–1160, USA.
4 Intra-Cellular Therapies Inc., Audubon Biomedical Science and Technology Park, New York, NY 10032, USA.

* To whom correspondence should be addressed. E-mail: greengd{at}mail.rockefeller.edu


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