Pharmacological evidence for GABAergic regulation of specific behaviors in Drosophila melanogaster.

Abstract

We have identified several GABAergic-modulated behaviors in Drosophila melanogaster by employing a pharmacological approach to disrupt GABA transporter function in vivo. Systemic treatment of adult female flies with the GABA transport inhibitors DL-2,4-diaminobutyric acid (DABA) or R,S-nipecotic acid (NipA), resulted in diminished locomotor activity, deficits in geotaxis, and the induction of convulsive behaviors with a secondary loss of the righting reflex. Pharmacological evidence suggested that the observed behavioral phenotypes were specific to disruption of GABA transporter function and GABAergic activity. The effects of GABA reuptake inhibitors on locomotor activity were dose dependent, pharmacologically distinct, and paralleled their known effects in mammalian systems. Recovery of normal locomotor activity and the righting reflex in DABA- and NipA-treated flies was achieved by coadministration of bicuculline (BIC), a GABA receptor antagonist that supresses GABAergic activity in mammals. Recovery of these behaviors was also achieved by coadministration of gabapentin, an anticonvulsant agent that interacts with mammalian GABAergic systems. Finally, behavioral effects were selective because other specific behaviors such as feeding activity and female sexual receptivity were not affected. Related pharmacological analyses performed in vitro on isolated Drosophila synaptic plasma membrane vesicles demonstrated high affinity, saturable uptake mechanisms for [3H]-GABA; further competitive inhibition studies with DABA and NipA demonstrated their ability to inhibit [3H]-GABA transport. The existence of experimentally accessible GABA transporters in Drosophila that share conserved pharmacological properties with their mammalian counterparts has resulted in the identification of specific behaviors that are modulated by GABA.