GABAergic regulation of locomotion before and during an ethanol exposure in Drosophila melanogaster

Ethanol at low doses induces a locomotor stimulant response across a range of phylogenetically diverse species. In rodents, this response is commonly used as an index of ethanol's disinhibitory, anxiolytic, or reinforcing effects, and its expression is regulated by signaling through a number of conserved neurotransmitter systems. In the current experiments, we asked whether ethanol-induced locomotor stimulation in the fruit fly Drosophila melanogaster might be mediated by ionotropic GABA receptors. We measured basal and ethanol-stimulated locomotion in flies expressing RNAi directed against three known subunits of ionotropic GABA receptors, and also examined the effects of picrotoxin feeding on these behaviors. We found that RNAi-mediated knockdown of a subunit of fly ionotropic GABA receptors, RDL, in all neurons resulted in an increased ethanol-induced locomotor stimulant response, while knockdown of two other subunits, LCCH3 and GRD, did not affect the responses. The effect of pan neuronal RDL knockdown was recapitulated with selective RDL knockdown in cholinergic neurons, and increased ethanol-induced locomotor stimulation was also seen by feeding the GABA_A antagonist picrotoxin to flies prior to behavioral testing. However, the increase in ethanol-stimulated locomotion in each of these experiments was largely accounted for by decreased baseline activity. Our results indicate that ionotropic GABA receptors might be a conserved mediator of the locomotor stimulant effects of ethanol, but that alternative experimental approaches will be necessary to disentangle effects of GABAergic manipulations on baseline and ethanol-stimulated locomotion in flies.