Drosophila GABA(B) receptors are involved in behavioral effects of gamma-hydroxybutyric acid (GHB).
Gamma-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 gamma-aminobutyric acid (GABA) GABA(B) 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 GABA(B) receptors. The evidence for this was obtained by pharmacological antagonism of GABA(B) receptors with CGP54626 and by RNA interference (RNAi)-induced knockdown of the GABA(B(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 GABA(B) receptors. These receptors do not have a Drosophila orthologue. Whether Drosophila express a different GHB receptor should be explored.
Dimitrijevic
Nikola
N
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, MC912, Chicago, Illinois 60612, USA.
Dzitoyeva
Svetlana
S
Satta
Rosalba
R
Imbesi
Marta
M
Yildiz
Sevim
S
Manev
Hari
H
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001567:Benzocycloheptenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists; D006885:Hydroxybutyrates / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D009943:Organophosphorus Compounds / Q000494:pharmacology; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
D001567:Benzocycloheptenes; D058788:GABA-B Receptor Antagonists; D006885:Hydroxybutyrates; D009943:Organophosphorus Compounds; D012330:RNA, Double-Stranded; D018080:Receptors, GABA-B; C066471:NCS 382; C107353:CGP 54626; C111420:4-hydroxybutyric acid; D000431:Ethanol