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

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Jesus Souza, Adriana ; Cortez, Isadora L. ; Silva, Nicole R. ; Pedrazzi, Joao Francisco C. ; Domingos, Luana B. ; Silva Braga, Matheus ; Santos-Silva, Thamyris ; Del-Bel, Elaine A. ; Resstel, Leonardo B. M. ; Li, Guanguan ; Yeunus Mian, Md ; Sharmin, Dishary ; Guimaraes, Francisco S. ; Cook, James M. ; Gomes, Felipe, V

• Document type: Journal article
• Source: Behavioural Brain Research; v. 428, p. 11-pg., 2022-06-25.

Abstract

Dysregulation of GABAergic neurotransmission has long been implicated in several psychiatric disorders, including schizophrenia, depression, and anxiety disorders. Alpha 5 subunit-containing GABA(A) receptors (alpha 5GABA(A)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 SH053-2' F-R-CH3 (1, 5, and 10 mg/kg), two positive allosteric modulators of alpha 5-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, SH053-2' 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 alpha 5-GABA(A)R for the treatment of psychiatric disorders. (AU)

• FAPESP's process: 18/17597-3 - The impact of stress on the dopamine system depends on the state of the critical period of neuroplasticity: implications for depression and schizophrenia and for the study of new drug targets
• Grantee: Felipe Villela Gomes
• Support Opportunities: Research Grants - Young Investigators Grants