The response to prolonged mild stress is dichotomous, has been associated with depression, anxiety and cognitive impairment, and may be modulated by various factors such as sex or GABA-ergic transmission. We investigated in rats the sex-dependent effects of four doses of lipopolysaccharide (LPS) in one week, followed by four weeks of chronic unpredictable mild stress (CUMS), on behavioral parameters assessed in the weekly sucrose preference test and spontaneous locomotor activity, as well as in the behavioral battery (elevated-plus-maze test, resident-intruder test, three-chamber test and forced-swim test) conducted after 7 days of treatment with GL-II-73, a positive allosteric modulator selective for α5 GABAA receptors (LPS/CUMS-GL-II-73), or with solvent (LPS/CUMS-SOL), beginning after the third week of CUMS. At the end of stress, sucrose intake was significantly increased in LPS/CUMS-SOL compared to male controls (CRTL); in females, LPS/CUMS-GL-II-73 showed a significantly higher preference for sucrose than CTRL-SOL. In males, forced swimming time was significantly longer in LPS/CUMS-SOL compared to CTRL-SOL. Social play in the resident-intruder test was reduced in female LPS/CUMS-SOL, and GL-II-73 and GL-II-73 tended to reversed this stress effect. LPS/CUMS-GL-II-73 males showed no significant social recognition in the three-chamber test. Ex vivo tests showed an increase in Gabra5 gene expression in the ventral hippocampus in LPS/CUMS-GL-II-73 compared to CTRL-SOL. The subtle changes in the measured parameters suggest that the clinical benefit of positive modulation of α5 GABAA receptors may result from focusing on the sex-specific niches of behavioral domains affected by prolonged stressors.
