Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 21 November 2003:
Vol. 302. no. 5649, pp. 1412 - 1415
DOI: 10.1126/science.1089681
Prev | Table of Contents | Next

Reports

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*

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

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
ADX47273 [S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: A Novel Metabotropic Glutamate Receptor 5-Selective Positive Allosteric Modulator with Preclinical Antipsychotic-Like and Procognitive Activities.
F. Liu, S. Grauer, C. Kelley, R. Navarra, R. Graf, G. Zhang, P. J. Atkinson, M. Popiolek, C. Wantuch, X. Khawaja, et al. (2008)
J. Pharmacol. Exp. Ther. 327, 827-839
   Abstract »    Full Text »    PDF »
Antipsychotic Drugs: Comparison in Animal Models of Efficacy, Neurotransmitter Regulation, and Neuroprotection.
J. A. Lieberman, F. P. Bymaster, H. Y. Meltzer, A. Y. Deutch, G. E. Duncan, C. E. Marx, J. R. Aprille, D. S. Dwyer, X.-M. Li, S. P. Mahadik, et al. (2008)
Pharmacol. Rev. 60, 358-403
   Abstract »    Full Text »    PDF »
Dopamine Modulation of Prefrontal Cortex Interneurons Occurs Independently of DARPP-32.
H. Trantham-Davidson, S. Kroner, and J. K. Seamans (2008)
Cereb Cortex 18, 951-958
   Abstract »    Full Text »    PDF »
The B''/PR72 subunit mediates Ca2+-dependent dephosphorylation of DARPP-32 by protein phosphatase 2A.
J.-H. Ahn, J. Y. Sung, T. McAvoy, A. Nishi, V. Janssens, J. Goris, P. Greengard, and A. C. Nairn (2007)
PNAS 104, 9876-9881
   Abstract »    Full Text »    PDF »
From prediction error to psychosis: ketamine as a pharmacological model of delusions.
P.R. Corlett, G.D. Honey, and P.C. Fletcher (2007)
J Psychopharmacol 21, 238-252
   Abstract »    PDF »
Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs?.
C. H. Large (2007)
J Psychopharmacol 21, 283-301
   Abstract »    PDF »
Biochemical and Behavioral Evidence for Antidepressant-Like Effects of 5-HT6 Receptor Stimulation.
P. Svenningsson, E. T. Tzavara, H. Qi, R. Carruthers, J. M. Witkin, G. G. Nomikos, and P. Greengard (2007)
J. Neurosci. 27, 4201-4209
   Abstract »    Full Text »    PDF »
Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56{delta} subunit.
J.-H. Ahn, T. McAvoy, S. V. Rakhilin, A. Nishi, P. Greengard, and A. C. Nairn (2007)
PNAS 104, 2979-2984
   Abstract »    Full Text »    PDF »
DARPP-32 Involvement in the Photic Pathway of the Circadian System.
L. Yan, J. M. Bobula, P. Svenningsson, P. Greengard, and R. Silver (2006)
J. Neurosci. 26, 9434-9438
   Abstract »    Full Text »    PDF »
Cocaine self-administration in mice is inversely related to phosphorylation at Thr34 (protein kinase A site) and Ser130 (kinase CK1 site) of DARPP-32..
Y. Zhang, P. Svenningsson, R. Picetti, S. D. Schlussman, A. C. Nairn, A. Ho, P. Greengard, and M. J. Kreek (2006)
J. Neurosci. 26, 2645-2651
   Abstract »    Full Text »    PDF »
Cannabinoid Action Depends on Phosphorylation of Dopamine- and cAMP-Regulated Phosphoprotein of 32 kDa at the Protein Kinase A Site in Striatal Projection Neurons.
M. Andersson, A. Usiello, A. Borgkvist, L. Pozzi, C. Dominguez, A. A. Fienberg, P. Svenningsson, B. B. Fredholm, E. Borrelli, P. Greengard, et al. (2005)
J. Neurosci. 25, 8432-8438
   Abstract »    Full Text »    PDF »
Comparative and Interactive Human Psychopharmacologic Effects of Ketamine and Amphetamine: Implications for Glutamatergic and Dopaminergic Model Psychoses and Cognitive Function.
J. H. Krystal, E. B. Perry Jr, R. Gueorguieva, A. Belger, S. H. Madonick, A. Abi-Dargham, T. B. Cooper, L. MacDougall, W. Abi-Saab, and D. C. D'Souza (2005)
Arch Gen Psychiatry 62, 985-994
   Abstract »    Full Text »    PDF »
cAMP and Extracellular Signal-Regulated Kinase Signaling in Response to D-Amphetamine and Methylphenidate in the Prefrontal Cortex in Vivo: Role of {beta}1-Adrenoceptors.
V. Pascoli, E. Valjent, A.-G. Corbille, J.-C. Corvol, J.-P. Tassin, J.-A. Girault, and D. Herve (2005)
Mol. Pharmacol. 68, 421-429
   Abstract »    Full Text »    PDF »
Predictors of schizophrenia--a review.
P. Maki, J. Veijola, P. B. Jones, G. K. Murray, H. Koponen, P. Tienari, J. Miettunen, P. Tanskanen, K.-E. Wahlberg, J. Koskinen, et al. (2005)
Br. Med. Bull. 73-74, 1-15
   Abstract »    Full Text »    PDF »
From The Cover: Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum.
E. Valjent, V. Pascoli, P. Svenningsson, S. Paul, H. Enslen, J.-C. Corvol, A. Stipanovich, J. Caboche, P. J. Lombroso, A. C. Nairn, et al. (2005)
PNAS 102, 491-496
   Abstract »    Full Text »    PDF »
Ethologically Based Resolution of D2-Like Dopamine Receptor Agonist-versus Antagonist-Induced Behavioral Topography in Dopamine- and Adenosine 3',5'-Monophosphate-Regulated Phosphoprotein of 32 kDa "Knockout" Mutants Congenic on the C57BL/6 Genetic Background.
R. E. Nally, A. Kinsella, O. Tighe, D. T. Croke, A. A. Fienberg, P. Greengard, and J. L. Waddington (2004)
J. Pharmacol. Exp. Ther. 310, 1281-1287
   Abstract »    Full Text »    PDF »
Comment on "Diverse Psychotomimetics Act Through a Common Signaling Pathway".
P. Seeman (2004)
Science 305, 180c
   Full Text »    PDF »
Response to Comment on "Diverse Psychotomimetics Act Through a Common Signaling Pathway".
P. Svenningsson, G. G. Nomikos, and P. Greengard (2004)
Science 305, 180d
   Full Text »    PDF »
Phactrs 1-4: A family of protein phosphatase 1 and actin regulatory proteins.
P. B. Allen, A. T. Greenfield, P. Svenningsson, D. C. Haspeslagh, and P. Greengard (2004)
PNAS 101, 7187-7192
   Abstract »    Full Text »    PDF »
Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade.
J.-M. Beaulieu, T. D. Sotnikova, W.-D. Yao, L. Kockeritz, J. R. Woodgett, R. R. Gainetdinov, and M. G. Caron (2004)
PNAS 101, 5099-5104
   Abstract »    Full Text »    PDF »
Psychotomimetic Effects of Drugs -- A Common Pathway to Schizophrenia?.
D. J. Gerber and S. Tonegawa (2004)
N. Engl. J. Med. 350, 1047-1048
   Full Text »    PDF »
Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum.
K. Chergui, P. Svenningsson, and P. Greengard (2004)
PNAS 101, 2191-2196
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)