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PNAS 107 (24): 11086-11091

Copyright © 2010 by the National Academy of Sciences.

From the Cover

BIOLOGICAL SCIENCES / NEUROSCIENCE

RGS inhibition at G{alpha}i2 selectively potentiates 5-HT1A–mediated antidepressant effects

Jeffery N. Talbota,b, Emily M. Jutkiewicza,c, Steven M. Gravesa, Crystal F. Clemansb, Melanie R. Nicolb, Richard M. Mortensend, Xinyan Huanga, Richard R. Neubiga,e, and John R. Traynora,c,1

aDepartment of Pharmacology, University of Michigan, Ann Arbor, MI 48109; bDepartment of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, OH 45810; and cDrug Abuse Research Center and dDepartments of Physiology and eInternal Medicine, University of Michigan, Ann Arbor, MI 48109

Edited by Leslie Lars Iversen, University of Oxford, Oxford, United Kingdom, and approved May 11, 2010 (received for review January 1, 2010)

Abstract: Elevating serotonin (5-HT) levels with selective serotonin reuptake inhibitors (SSRIs) is the most widely used treatment for depression. However, current therapies are ineffective, have delayed benefit, or cause side effects in many patients. Here, we define a mechanism downstream of 5-HT1A receptors that mediates antidepressant-like behavior and is profoundly and selectively enhanced by genetic disruption of regulators of G protein signaling (RGS) activity at G{alpha}i2. Animals rendered insensitive to RGS protein regulation through a mutation in G{alpha}i2 (G184S) exhibited spontaneous antidepressant- and anxiolytic-like behaviors. Mice expressing RGS-insensitive G{alpha}i2 also exhibited increased cortical and hippocampal phosphorylation of glycogen synthase kinase-3β, a constitutively active proapoptotic kinase that is inhibited through phosphorylation in response to serotonin, SSRIs, and 5-HT1 receptor agonists. Both behavioral and biochemical phenotypes were blocked by treatment with WAY 100635, a 5-HT1A–selective antagonist. RGS-insensitive mice were also 5–10 times more responsive to the antidepressant-like effects of the SSRI fluvoxamine and 5-HT1A–selective agonist 8-hydroxy-2-dipropylaminotetralin. In contrast, the antidepressant potency of agents acting through nonserotonergic mechanisms was unchanged as was 5-HT1A action on body temperature. The findings point to a critical role for endogenous RGS proteins to suppress the antidepressant-like effects of 5-HT1A receptor activation. By selectively enhancing the beneficial effects of serotonin, inhibition of RGS proteins represents a therapeutic approach for the treatment of mood disorders.

Key Words: 5-HT1A receptors • depression • G protein • regulator of G protein signaling proteins • transgenic mouse

Author contributions: J.R.T. designed research; J.N.T., E.M.J., S.M.G., C.F.C., and M.R.N. performed research; R.M.M., X.H., and R.R.N. contributed new reagents/analytic tools; J.N.T., E.M.J., and J.R.T. analyzed data; and J.N.T. and J.R.T. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1000003107/-/DCSupplemental.

1To whom correspondence should be addressed. E-mail: jtraynor{at}umich.edu.

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