HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 43, 42006-42011, October 24, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/43/42006    most recent M304238200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ren, X. Articles by Mody, I. Search for Related Content PubMed PubMed Citation Articles by Ren, X. Articles by Mody, I. Social Bookmarking                      What's this?

-Hydroxybutyrate Reduces Mitogen-activated Protein Kinase Phosphorylation via GABA_B Receptor Activation in Mouse Frontal Cortex and Hippocampus^*

Xiuhai Ren and Istvan Mody

From the Departments of Neurology and Physiology, The David Geffen School of Medicine, UCLA, Los Angeles, California 90095

-Hydroxybutyrate (GHB) naturally occurs in the brain, but its exogenous administration induces profound effects on the central nervous system in animals and humans. The intracellular signaling mechanisms underlying its actions remain unclear. In the present study, the effects of GHB on the activation (phosphorylation) of mitogen-activated protein kinases (MAP kinases), extracellular signal-regulated kinase 1 and 2 (ERK1/2), were investigated. Acute administration of GHB (500 mg/kg, intraperitoneal) induced a fast and long lasting inhibition of MAP kinase phosphorylation in both frontal cortex and hippocampus. The reduced MAP kinase phosphorylation was observed in the CA1 and CA3 areas but not in the dentate gyrus. Pretreatment with the specific -aminobutyric acid, type B (GABA_B), receptor antagonist CGP56999A (20 mg/kg, intraperitoneal) prevented the action of GHB, and the effect of GHB was mimicked by baclofen, a selective GABA_B receptor agonist, whereas the high affinity GHB receptor antagonist NCS-382 (200 mg/kg, intraperitoneal) had no effect on GHB-inhibited MAP kinase phosphorylation. Moreover, the GHB dehydrogenase inhibitor valproate (500 mg/kg, intraperitoneal), which inhibits the conversion of GHB into GABA, failed to block the effect of GHB on MAP kinase phosphorylation. Altogether, these data suggest that GHB, administered in vivo, reduces MAP kinase phosphorylation via a direct activation of GABA_B receptors by GHB. In contrast, GHB (10 mM for 15 min) was found ineffective on MAP kinase phosphorylation in brain slices, indicating important differences in the conditions required for the second messenger activating action of GHB.

Received for publication, April 22, 2003 , and in revised form, August 13, 2003.

^* This work was supported by National Institutes of Health Grant DA14947 (to I. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Neurology, RNRC 3-155, The David Geffen School of Medicine, UCLA, 710 Westwood Plaza, Los Angeles, CA 90095. Tel.: 310-206-4481; Fax: 310-825-0033; E-mail: mody{at}ucla.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				P. Wellendorph, S. Hog, J. R. Greenwood, A. de Lichtenberg, B. Nielsen, B. Frolund, L. Brehm, R. P. Clausen, and H. Brauner-Osborne Novel Cyclic {gamma}-Hydroxybutyrate (GHB) Analogs with High Affinity and Stereoselectivity of Binding to GHB Sites in Rat Brain J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 346 - 351. [Abstract] [Full Text] [PDF]

				O. C. Snead and K. M. Gibson {gamma}-Hydroxybutyric Acid N. Engl. J. Med., June 30, 2005; 352(26): 2721 - 2732. [Full Text] [PDF]

				L. P. Carter, H. Wu, W. Chen, M. M. Matthews, A. K. Mehta, R. J. Hernandez, J. A. Thomson, M. K. Ticku, A. Coop, W. Koek, et al. Novel {gamma}-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABAB Receptor Agonists J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1314 - 1323. [Abstract] [Full Text] [PDF]