Distinct sex-dependent behavioral responses induced by two positive allosteric modulators of alpha 5 subunit-containing GABAA receptors.

Abstract

Dysregulation of GABAergic neurotransmission has long been implicated in several psychiatric disorders, including schizophrenia, depression, and anxiety disorders. Alpha 5 subunit-containing GABAA receptors (α5-GABAAR), which are expressed mainly by pyramidal neurons in the hippocampus, have been proposed as a potential target to treat these psychiatric disorders. Here, we evaluated the effects produced by GL-II-73 and SH-053-2'F-R-CH3 (1, 5, and 10 mg/kg), two positive allosteric modulators of α5-GABAAR in behavioral tests sensitive to drugs with anxiolytic, antidepressant, and antipsychotic properties in male and female C57BL/6 mice. In both males and females, GL-II-73 produced an anxiolytic-like effect in the elevated plus-maze (EPM) and novelty-suppressed feeding and a rapid and sustained antidepressant-like effect in the forced swim test. GL-II-73 also induced antipsychotic-like effects in males indicated by attenuating MK-801-induced hyperlocomotion and prepulse inhibition (PPI) disruption. However, GL-II-73 per se increased locomotor activity and impaired fear memory extinction in males and females and PPI in males. On the other hand, SH-053-2'F-R-CH3 induced anxiolytic-like effects in the EPM and facilitated fear memory extinction in males. Contrary to GL-II-73, SH-053-2'F-R-CH3 attenuated MK-801-induced hyperlocomotion and PPI disruption in females but not in males. Neither of these drugs induced rewarding effects or impaired motor coordination. These findings suggest that GL-II-73 and SH-053-2'F-R-CH3 cause distinct sex-dependent behavioral responses and support continued preclinical research on the potential of positive allosteric modulators of α5-GABAAR for the treatment of psychiatric disorders.

• Authors: Adriana Jesus Souza, Isadora L Cortez, Nicole R Silva, João Francisco C Pedrazzi, Luana B Domingos, Matheus Silva Braga, Thamyris Santos-Silva, Elaine A Del-Bel, Leonardo B M Resstel, Guanguan Li, Md Yeunus Mian, Dishary Sharmin, Francisco S Guimarães, James M Cook, Felipe V Gomes
• Journal: Behavioural brain research (Behav Brain Res) Vol. 428 Pg. 113832 (06 25 2022) ISSN: 1872-7549 [Electronic] Netherlands
• PMID: 35259414 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022. Published by Elsevier B.V.

Chemical References

• Anti-Anxiety Agents
• Antipsychotic Agents
• Receptors, GABA-A
• Benzodiazepines
• gamma-Aminobutyric Acid
• Dizocilpine Maleate

Topics

• Animals
• Anti-Anxiety Agents (pharmacology)
• Antipsychotic Agents
• Benzodiazepines (pharmacology)
• Dizocilpine Maleate
• Female
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Receptors, GABA-A
• gamma-Aminobutyric Acid