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

• Published in: Behavioural brain research Vol. 428; p. 113832
• Main Authors: Souza, Adriana Jesus, Cortez, Isadora L, Silva, Nicole R, Pedrazzi, João Francisco C, Domingos, Luana B, Braga, Matheus Silva, Santos-Silva, Thamyris, Del-Bel, Elaine A, Resstel, Leonardo B M, Li, Guanguan, Mian, Md Yeunus, Sharmin, Dishary, Guimarães, Francisco S, Cook, James M, Gomes, Felipe V
• Format: Journal Article
• Language: English
• Published: Netherlands 25.06.2022
• Subjects: Animals; Anti-Anxiety Agents - pharmacology; Antipsychotic Agents; Benzodiazepines - pharmacology; Dizocilpine Maleate; Female; gamma-Aminobutyric Acid; Humans; Male; Mice; Mice, Inbred C57BL; Receptors, GABA-A; GABA(A) receptors; SH-053–2′F-R-CH3; Schizophrenia; Depression; Anxiety; Excitatory-inhibitory balance; GL-II-73

Dysregulation of GABAergic neurotransmission has long been implicated in several psychiatric disorders, including schizophrenia, depression, and anxiety disorders. Alpha 5 subunit-containing GABA receptors (α5-GABA R), 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-GABA R 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-GABA R for the treatment of psychiatric disorders.