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

Addict Biol. 2020 Mar;25(2):e12725. doi: 10.1111/adb.12725. Epub 2019 Feb 13.

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 (GABAB ) 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 GABAB drugs, but the rate of tolerance development was increased by SKF 97451 and unaltered in presence of CGP 54626. This indicates that the GABAB 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).

Drosophila melanogaster is an established model for alcohol addiction. We measured alcohol tolerance by recording the change in time in which half of a group of flies is sedated by alcohol vapours (change in ST50). We demonstrate that gamma‐aminobutyric acid receptor B (GABAB) agonist SKF 97541 and antagonist CGP 54626 decreased and increased ethanol sensitivity, respectively. Tolerance still developed in the presence and absence of the GABAB ligands, but its rate was altered. This indicates that GABAB receptors could potentially be a target for pharmacological intervention in alcohol addiction.

Keywords: CGP 54626; Drosophila melanogaster; GABAB receptor; SKF 97541; addiction behaviours; alcohol use disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcoholism / physiopathology*
  • Animals
  • Behavior, Animal / drug effects*
  • Central Nervous System Depressants / pharmacology
  • Disease Models, Animal
  • Drosophila melanogaster
  • Ethanol / pharmacology*
  • GABA-B Receptor Antagonists / administration & dosage*
  • Male
  • Receptors, GABA-B / drug effects
  • Receptors, GABA-B / physiology*

Substances

  • Central Nervous System Depressants
  • GABA-B Receptor Antagonists
  • Receptors, GABA-B
  • Ethanol