Drosophila GABAB receptors are involved in behavioral effects of γ-hydroxybutyric acid (GHB)

γ-hydroxybutyric acid (GHB) can be synthesized in the brain but is also a known drug of abuse. Although putative GHB receptors have been cloned, it has been proposed that, similar to the behavior-impairing effects of ethanol, the in vivo effects of pharmacological GHB may involve metabotropic γ-aminobutyric acid (GABA) GABAB receptors. We developed a fruitfly (Drosophila melanogater) model to investigate the role of these receptors in the behavioral effects of exogenous GHB. Injecting GHB into male flies produced a dose-dependent motor impairment (measured with a computer-assisted automated system), which was greater in ethanol-sensitive cheapdate mutants than in wild-type flies. These effects of pharmacological concentrations of GHB require the presence and activation of GABAB receptors. The evidence for this was obtained by pharmacological antagonism of GABAB receptors with CGP54626 and by RNA interference (RNAi)-induced knockdown of the GABAB(1) receptor subtype. Both procedures inhibited the behavioral effects of GHB. GHB pretreatment diminished the behavioral response to subsequent GHB injections; i.e., it triggered GHB tolerance, but did not produce ethanol tolerance. On the other hand, ethanol pretreatment produced both ethanol and GHB tolerance. It appears that in spite of many similarities between ethanol and GHB, the primary sites of their action may differ and that recently cloned putative GHB receptors may participate in actions of GHB that are not mediated by GABAB receptors. These receptors do not have a Drosophila orthologue. Whether Drosophila express a different GHB receptor should be explored.