Pharmacological targeting of the GABA_B receptor alters Drosophila's behavioural responses to alcohol

Abstract

When exposed to ethanol, Drosophila melanogaster display a variety of addiction-like behaviours similar to those observed in mammals. Sensitivity to ethanol can be quantified by measuring the time at which 50% of the flies are sedated by ethanol exposure (ST50); an increase of ST50 following multiple ethanol exposures is widely interpreted as development of tolerance to ethanol. Sensitivity and tolerance to ethanol were measured after administration of the gamma-aminobutyric acid receptor B (GABA B ) agonist (SKF 97541) and antagonist (CGP 54626), when compared with flies treated with ethanol alone. Dose-dependent increases and decreases in sensitivity to ethanol were observed for both the agonist and antagonist respectively. Tolerance was recorded in the presence of GABA B drugs, but the rate of tolerance development was increased by SKF 97451 and unaltered in presence of CGP 54626. This indicates that the GABA B receptor contributes to both the sensitivity to ethanol and mechanisms by which tolerance develops. The data also reinforce the usefulness of Drosophila as a model for identifying the molecular components of addictive behaviours and for testing drugs that could potentially be used for the treatment of alcohol use disorder (AUD). KEYWORDS addiction behaviours, alcohol use disorder, CGP 54626, Drosophila melanogaster, GABA B receptor, SKF 97541

The Neurotransmitters Involved in Drosophila Alcohol-Induced Behaviors

“…These effects persisted for 4 days. Additionally, the SKF 97541-fed flies still developed alcohol tolerance and actually became much more tolerant than controls on the fourth day of exposure (Ranson et al, 2020). When repeating these experiments using the GABA B antagonist CGP 54626, flies became significantly less sensitive to alcohol than controls.…”

“…When repeating these experiments using the GABA B antagonist CGP 54626, flies became significantly less sensitive to alcohol than controls. However, these manipulations did not affect the development of tolerance, suggesting that GABA B receptors are just one of several receptor systems contributing to tolerance development (Ranson et al, 2020). These results suggest that GABA B receptors mediate ethanol sensitivity and the development of tolerance (Ranson et al, 2020; see Figure 2).…”

“…Feeding flies the GABA B agonist SKF 97541 increases their sensitivity to sedation when exposed to ethanol vapor (Ranson et al, 2020). These effects persisted for 4 days.…”

Unraveling the Mechanisms of Behaviors Associated With AUDs Using Flies and Worms

“…Interspecies transcriptomic and proteomic analyses combined with behavioral mutant analyses will help to narrow the list of crucial regulators of AUDs. In the future, Drosophila and C. elegans can be used as screening platforms to test the efficacy of pharmacological compounds to disrupt alcohol‐related behaviors (Koyyada et al., ; Ranson et al., ; Scott et al., ,b). Finally, the use of Drosophila and C. elegans as genetic model organisms can also be extended to study other drugs of abuse, such as nicotine or cocaine (reviewed by Dupuis et al., ; Engleman et al., ; Haydon et al., ; Kaun et al., ; Kudelska et al., ; Lowenstein and Velazquez‐Ulloa, ; Matta et al., ).…”

G-protein αq gene expression plays a role in alcohol tolerance in Drosophila melanogaster

“…Short horizontal bars represent mean values. et al, 2018) and GABA B receptor (Ranson et al, 2019). An earlier extensive review of mammalian studies of the effect of psychostimulants on G-protein expression (Kitanaka et al, 2008) highlighted that only limited work had been focused on ethanolinduced changes in any animal models, with only one study reporting a reduction in G-protein b1 in rat hippocampus (Saito et al, 2002).…”