Stimulation of [ 35 S]GTPγS binding by GABA B receptor agonists and positive modulators in different mouse brain regions

GHB is used to treat narcolepsy, but is also abused. Its mechanism of action likely involves GABA B receptors because it shares many behavioral effects with the GABA B receptor agonist baclofen. To further examine the role of these receptors, effects of GHB in different mouse brain regions were compared with those of baclofen and the GABA B receptor positive modulators CGP7930 and BHFF. Agonist‐stimulated [ 35 S]GTPγS binding was measured using quantitative autoradiography to examine drug effects in prefrontal and anterior cingulate cortex, and in hippocampus (CA1, CA2/3, dentate gyrus). Baclofen concentration‐dependently stimulated [ 35 S]GTPγS binding in hippocampal and cortical regions. GHB did not stimulate [ 35 S]GTPγS binding in any region examined. CGP7930 and BHFF stimulated [ 35 S]GTPγS binding in all regions examined. The maximal effects of CGP7930 were smaller than those of baclofen, but those of BHFF were similar to those of baclofen. A concentration of the GABA B receptor antagonist CGP35348 that blocked the effects of baclofen did not appear to attenuate the effects of CGP7930 and BHFF. These results suggest that GHB has lower efficacy than baclofen at GABA B receptors. The results further suggest that the positive GABA B receptor modulators CGP7930 and BHFF exert agonist activity that may not result from potentiation of endogenous GABA at GABA B receptors. Supported by MH052369(JGH), DA15692(WK).