@article{0629ac8dbe1d4545a6be75a2b031d135,
title = "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 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",
author = "Troppoli, {Timothy A.} and Panos Zanos and Polymnia Georgiou and Gould, {Todd D.} and Uwe Rudolph and Thompson, {Scott M.}",
note = "Funding Information: This work was supported by grants from the National Institutes of Health (Grant Nos. R01 MH086828 [to SMT], R01-MH107615 [to TDG], R01MH095905-01A1 [to UR], and R01GM128183-01A1 [to UR]), The Kahlert Foundation (to SMT), US Department of Veterans Affairs Merit Awards (Grant Nos. 101BX004062 and 101BX003631 [to TDG]), a NARSAD Distinguished Investigator grant (Grant No. 25623 [to UR]), and a P&S Fund Investigator (to UR). The contents of this manuscript do not represent the views of the United States Department of Veterans Affairs or the United States Government. TAT and SMT conceived and designed the project and wrote the manuscript. TAT, PZ, and PG performed all behavioral experiments. TAT performed all electrophysiological experiments. PZ, PG, and TDG assisted with design and performance of behavioral and electroencephalography experiments. UR provided α5 knockout mice and assisted with genotyping. All authors contributed to the editing of the manuscript. We thank Mackenzie Nelson for training in electroencephalogram transmitter implantation, Brent Stewart for assistance with electroencephalogram signal analysis and spectrogram generation, and Maxwell Madden for facilitating 3D printing of restraint tubes. Data from this manuscript were previously shown in posters at 2020 meetings of The Society for Neuroscience and American College of Neuropsychopharmacology under the title of “The GABAAR α5 subunit is required for the fast antidepressant-like actions of MRK-016 on stress-induced anhedonia and weakened synaptic function.”, The University of Maryland Baltimore has a patent pending (USPTO application No. 15/300,984), on which SMT is listed as an inventor, covering the use of α5-selective GABA-NAMs to treat psychiatric disease. TDG is listed as a coauthor of patent applications related to the pharmacology and use of (2R,6R)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorder. TDG has received research funding from Allergan and Roche Pharmaceuticals and served as a consultant for FSV7 LLC during the preceding 3 years. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by grants from the National Institutes of Health (Grant Nos. R01 MH086828 [to SMT], R01-MH107615 [to TDG], R01MH095905-01A1 [to UR], and R01GM128183-01A1 [to UR]), The Kahlert Foundation (to SMT), US Department of Veterans Affairs Merit Awards (Grant Nos. 101BX004062 and 101BX003631 [to TDG]), a NARSAD Distinguished Investigator grant (Grant No. 25623 [to UR]), and a P&S Fund Investigator (to UR). Funding Information: The University of Maryland Baltimore has a patent pending (USPTO application No. 15/300,984), on which SMT is listed as an inventor, covering the use of α5-selective GABA-NAMs to treat psychiatric disease. TDG is listed as a coauthor of patent applications related to the pharmacology and use of (2R,6R)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorder. TDG has received research funding from Allergan and Roche Pharmaceuticals and served as a consultant for FSV7 LLC during the preceding 3 years. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: {\textcopyright} 2021 Society of Biological Psychiatry",
year = "2022",
month = aug,
day = "1",
doi = "10.1016/j.biopsych.2021.11.024",
language = "English (US)",
volume = "92",
pages = "216--226",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "3",
}