Received for publication September 10, 2004.
Revised March 1, 2005.
Accepted for publication March 14, 2005.

Novel gamma-hydroxybutyric acid (GHB) analogs share some, but not all, of the behavioral effects of GHB and GABA_B receptor agonists

Abstract

Gamma-hydroxybutyrate (GHB), a therapeutic for narcolepsy and a drug of abuse, has several mechanisms of action, which involve GHB and GABA_B receptors, metabolism to GABA, and modulation of dopaminergic signaling. The aim of these studies was to examine the role of GHB and GABA_B receptors in the behavioral effects of GHB. Three approaches were used to synthesize GHB analogs that bind selectively to GHB receptors and are not metabolized to GABA-active compounds. Radioligand binding assays identified UMB86, UMB72, UMB73, 2-HPA, 3-HPA, and 4-hydroxy-4-phenylbutyric acid as compounds that displace [³H]NCS-382 from GHB receptors at concentrations that do not markedly affect [³H]GABA binding to GABA_B receptors. In rats and pigeons, GHB discriminative stimulus effects were not mimicked or attenuated by UMB86, UMB72, or 3-HPA, up to doses that decreased responding. In mice, GHB, GHB precursors (GBL and 1,4-BDL), and GABA_B receptor agonists (SKF97541 and baclofen) dose-dependently produced hypolocomotion, catalepsy, ataxia, and loss of righting. The GABA_B receptor antagonist CGP35348 attenuated catalepsy and ataxia that was observed after GHB and GABA_B receptor agonists SKF97541 and baclofen. UMB86, UMB72, UMB73, and 3-HPA, like GHB, produced hypolocomotion, ataxia, and loss of righting; however, catalepsy was never observed with these compounds, which is consistent with the cataleptic effects of GHB being mediated by GABA_B receptors. Ataxia that was observed with UMB86, UMB72, UMB73, and 3-HPA was not antagonized by CGP35348, suggesting that ataxia induced by these analogs is not mediated by GABA_B receptors and might involve GHB receptors.

Key words: GABA, GHB, analog, ataxia, catalepsy, drug discrimination

This article has been cited by other articles:

				R. J. Sevak, W. Koek, A. Galli, and C. P. France Insulin Replacement Restores the Behavioral Effects of Quinpirole and Raclopride in Streptozotocin-Treated Rats J. Pharmacol. Exp. Ther., March 1, 2007; 320(3): 1216 - 1223. [Abstract] [Full Text] [PDF]

				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]