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.

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 GABA_A (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 GABA_A 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 =

SUBMITTER: Troppoli TA 

PROVIDER: S-EPMC9198111 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature