Negative Allosteric Modulation of Gamma-Aminobutyric Acid A Receptors at α5 Subunit-Containing Benzodiazepine Sites Reverses Stress-Induced Anhedonia and Weakened Synaptic Function in Mice

Biol Psychiatry. 2022 Aug 1;92(3):216-226. doi: 10.1016/j.biopsych.2021.11.024. Epub 2021 Dec 15.

Abstract

Background: Abnormal reward processing, typically anhedonia, is a hallmark of human depression and is accompanied by altered functional connectivity in reward circuits. Negative allosteric modulators of GABAA (gamma-aminobutyric acid A) receptors (GABA-NAMs) have rapid antidepressant-like properties in rodents and exert few adverse effects, but molecular targets underlying their behavioral and synaptic effects remain undetermined. We hypothesized that GABA-NAMs act at the benzodiazepine site of GABAA receptors containing α5 subunits to increase gamma oscillatory activity, strengthen synapses in reward circuits, and reverse anhedonia.

Methods: Anhedonia was induced by chronic stress in male mice and assayed by preferences for sucrose and female urine (n = 5-7 mice/group). Hippocampal slices were then prepared for electrophysiological recording (n = 1-6 slices/mouse, 4-6 mice/group). Electroencephalography power was quantified in response to GABA-NAM and ketamine administration (n = 7-9 mice/group).

Results: Chronic stress reduced sucrose and female urine preferences and hippocampal temporoammonic-CA1 synaptic strength. A peripheral injection of the GABA-NAM MRK-016 restored hedonic behavior and AMPA-to-NMDA ratios in wild-type mice. These actions were prevented by pretreatment with the benzodiazepine site antagonist flumazenil. MRK-016 administration increased gamma power over the prefrontal cortex in wild-type mice but not α5 knockout mice, whereas ketamine promoted gamma power in both genotypes. Hedonic behavior and AMPA-to-NMDA ratios were only restored by MRK-016 in stressed wild-type mice but not α5 knockout mice.

Conclusions: α5-Selective GABA-NAMs exert rapid anti-anhedonic actions and restore the strength of synapses in reward regions by acting at the benzodiazepine site of α5-containing GABAA receptors. These results encourage human studies using GABA-NAMs to treat depression by providing readily translatable measures of target engagement.

Keywords: Antidepressant; Depression; GABA; Gamma; Hippocampus; Ketamine.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anhedonia
  • Animals
  • Benzodiazepines* / pharmacology
  • Female
  • Humans
  • Ketamine* / pharmacology
  • Male
  • Mice
  • N-Methylaspartate
  • Receptors, GABA
  • Receptors, GABA-A / physiology
  • Sucrose
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • gamma-Aminobutyric Acid

Substances

  • Receptors, GABA
  • Receptors, GABA-A
  • Benzodiazepines
  • gamma-Aminobutyric Acid
  • Sucrose
  • N-Methylaspartate
  • Ketamine
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid