title: Sex-Dependent Anti-Stress Effect of an α5 Subunit Containing GABAAReceptor Positive Allosteric Modulator.
abstract: Rationale:Current first-line treatments for stress-related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells.Objectives:The present study evaluates whether SH-053-2'F-R-CH3 (denoted "α5-PAM"), a positive allosteric modulator selective for α5-subunit containing GABAAreceptors found predominantly on cortical pyramidal cell dendrites, has anti-stress effects.Methods:Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with α5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally.Results:Acute and chronic α5-PAM treatments produce a pattern of decreased stress-induced behaviors (denoted as "behavioral emotionality") across various tests in female, but not in male mice. BehavioralZ-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic α5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to α5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of theGabra5gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with α5-PAM in females only, and these expression changes correlated with behavioral emotionality.Conclusion:We showed that acute and chronic positive modulation of α5 subunit-containing GABAAreceptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.
authors.affiliation: Center for Neuroscience, University of PittsburghPittsburgh, PA, USA; Department of Psychiatry, University of PittsburghPittsburgh, PA, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Piantadosi
authors.affiliation: Department of Psychiatry, University of Pittsburgh Pittsburgh, PA, USA.
authors.forename: Beverly J
authors.initials: BJ
authors.lastname: French
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee Milwaukee, WI, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Poe
authors.affiliation: Department of Pharmacology, University of Belgrade Belgrade, Serbia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Timić
authors.affiliation: Department of Pharmaceutical Chemistry, University of Belgrade Belgrade, Serbia.
authors.forename: Bojan D
authors.initials: BD
authors.lastname: Marković
authors.affiliation: Neurobiology of Depression and Aging, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health Toronto, ON, Canada.
authors.forename: Mohan
authors.initials: M
authors.lastname: Pabba
authors.affiliation: Department of Psychiatry, University of Pittsburgh Pittsburgh, PA, USA.
authors.forename: Marianne L
authors.initials: ML
authors.lastname: Seney
authors.affiliation: Center for Neuroscience, University of PittsburghPittsburgh, PA, USA; Department of Psychiatry, University of PittsburghPittsburgh, PA, USA; Neurobiology of Depression and Aging, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental HealthToronto, ON, Canada.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Oh
authors.affiliation: Department of Anesthesia-Department of Physiology, University of Toronto Toronto, ON, Canada.
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
authors.affiliation: Department of Pharmacology, University of Belgrade Belgrade, Serbia.
authors.forename: Miroslav M
authors.initials: MM
authors.lastname: Savić
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee Milwaukee, WI, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.affiliation: Center for Neuroscience, University of PittsburghPittsburgh, PA, USA; Department of Psychiatry, University of PittsburghPittsburgh, PA, USA; Neurobiology of Depression and Aging, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental HealthToronto, ON, Canada; Department of Psychiatry- Department of Pharmacology and Toxicology, University of TorontoToronto, ON, Canada.
authors.forename: Etienne
authors.initials: E
authors.lastname: Sibille
keywords: GABA; Gabra5; PAM; alpha5; depression; interneurons