Distinct sex-dependent behavioral responses induced by two positive allosteric modulators of alpha 5 subunit-containing GABAA receptors
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 pr...
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Published in | Behavioural brain research Vol. 428; p. 113832 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Elsevier B.V
25.06.2022
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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. |
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AbstractList | 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. |
ArticleNumber | 113832 |
Author | Santos-Silva, Thamyris Cook, James M. Pedrazzi, João Francisco C. Del-Bel, Elaine A. Mian, Md Yeunus Souza, Adriana Jesus Li, Guanguan Guimarães, Francisco S. Domingos, Luana B. Braga, Matheus Silva Silva, Nicole R. Gomes, Felipe V. Resstel, Leonardo B.M. Cortez, Isadora L. Sharmin, Dishary |
Author_xml | – sequence: 1 givenname: Adriana Jesus surname: Souza fullname: Souza, Adriana Jesus organization: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Brazil – sequence: 2 givenname: Isadora L. surname: Cortez fullname: Cortez, Isadora L. organization: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Brazil – sequence: 3 givenname: Nicole R. surname: Silva fullname: Silva, Nicole R. organization: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Brazil – sequence: 4 givenname: João Francisco C. surname: Pedrazzi fullname: Pedrazzi, João Francisco C. organization: Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Brazil – sequence: 5 givenname: Luana B. surname: Domingos fullname: Domingos, Luana B. organization: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Brazil – sequence: 6 givenname: Matheus Silva surname: Braga fullname: Braga, Matheus Silva organization: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Brazil – sequence: 7 givenname: Thamyris surname: Santos-Silva fullname: Santos-Silva, Thamyris organization: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Brazil – sequence: 8 givenname: Elaine A. surname: Del-Bel fullname: Del-Bel, Elaine A. organization: Department of Physiology, Ribeirão Preto Dentistry School, University of São Paulo, Brazil – sequence: 9 givenname: Leonardo B.M. surname: Resstel fullname: Resstel, Leonardo B.M. organization: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Brazil – sequence: 10 givenname: Guanguan surname: Li fullname: Li, Guanguan organization: Department of Chemistry and Biochemistry, University of Wisconsin Milwaukee, USA – sequence: 11 givenname: Md Yeunus surname: Mian fullname: Mian, Md Yeunus organization: Department of Chemistry and Biochemistry, University of Wisconsin Milwaukee, USA – sequence: 12 givenname: Dishary surname: Sharmin fullname: Sharmin, Dishary organization: Department of Chemistry and Biochemistry, University of Wisconsin Milwaukee, USA – sequence: 13 givenname: Francisco S. surname: Guimarães fullname: Guimarães, Francisco S. organization: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Brazil – sequence: 14 givenname: James M. surname: Cook fullname: Cook, James M. organization: Department of Chemistry and Biochemistry, University of Wisconsin Milwaukee, USA – sequence: 15 givenname: Felipe V. surname: Gomes fullname: Gomes, Felipe V. email: gomesfv@usp.br organization: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Brazil |
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Keywords | SH-053–2′F-R-CH3 Schizophrenia Depression Excitatory-inhibitory balance Anxiety GL-II-73 GABAA receptors |
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