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

Timothy A. Troppoli, Panos Zanos, Polymnia Georgiou, Todd D. Gould, Uwe Rudolph, Scott M. Thompson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)216-226
Number of pages11
JournalBiological Psychiatry
Volume92
Issue number3
DOIs
StatePublished - Aug 1 2022

Keywords

  • Antidepressant
  • Depression
  • GABA
  • Gamma
  • Hippocampus
  • Ketamine

ASJC Scopus subject areas

  • Biological Psychiatry

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