Increased depression-like behaviors in corticotropin-releasing factor receptor-2-deficient mice: sexually dichotomous responses

Abstract

Depressive disorders affect nearly 19 million American adults, making depression and the susceptibility for developing depression a critical focus of mental health research today. Females are twice as likely to develop depression as males. Stress is a known risk factor for developing depression, and recent hypotheses suggest an involvement of an overactive stress axis. As mediators of the stress response, corticotropin-releasing factor (CRF) and its receptors (CRFR1 and CRFR2) have been implicated in the propensity for developing stress-related mood disorders. Mice deficient in CRFR2 display increased anxiety-like behaviors and a hypersensitive stress response. As a possible animal model of depression, these mice were tested for depression-like behaviors in the forced swim test. Comparisons were made between wild-type and mutant animals, as well as between sexes. Male and female CRFR2-mutant mice showed increased immobility as an indicator of depression compared with wild-type mice of the same sex. In addition, mutant and wild-type female mice demonstrated increased immobile time compared with males of the same genotype. Treatment of CRFR2-deficient mice with the CRFR1 antagonist antalarmin decreased immobile time and increased swim time in both sexes. We found a significant effect of sex for both time spent immobile and swimming after antalarmin treatment. Because differences in behaviors in the forced swim test are good indicators of serotonergic and catecholaminergic involvement, our results may reveal an interaction of CRF pathways with other known antidepressant systems and may also support an involvement of CRF receptors in the development of depression such that elevated CRFR1 activity, in the absence of CRFR2, increases depression-like behaviors.

Figure 1.

Measurement of depression-like behaviors in forced swim test. A, Both male and female mutant (Mut) mice showed increased immobile time during 5 min forced swim compared with wild-type (Wt) mice (n = 10). Overall, females showed significantly greater immobile time compared with their respective males of the same genotype. ^*p < 0.05 compared with wild-type males; ^**p < 0.01 compared with wild-type males; ^***p < 0.001 compared with wild-type females and male mutant mice; ANOVA and Fisher's post hoc test. B, Both male and female mutant mice demonstrated decreased swim time compared with wild-type littermates (n = 10). ^*p < 0.05 compared with wild-type males; ^**p < 0.01 compared with wild-type females; ^***p < 0.001 compared with wild-type males; ANOVA and Fisher's post hoc test. C, Female mice deficient for CRFR2 spent significantly less time climbing during the forced swim test compared with female wild-type littermates;^***p < 0.001;ANOVA and Fisher'spost hoc test.

Figure 2.

Forced swim test results after pretreatment with antalarmin in female CRFR2-deficient mice. A, Female mutant mice treated with antalarmin (7.5 mg/kg) 1 hr before testing showed decreased immobile time compared with vehicle-treated mutant mice (n = 10). ^***p < 0.001. This effect remained evident 24 (n = 5) and 72 (n = 5) hr after treatment. ^***p < 0.001; ANOVA and Fisher's post hoc test. + indicates basal wild-type female immobile levels for comparison. B, Female mutant mice treated with antalarmin displayed increased swim time compared with vehicle-treated mutant females 1 (n = 10), 24 (n = 5), and 72 (n = 5) hr after treatment. ^*p < 0.05; ^***p < 0.001; ANOVA and Fisher's post hoc test. + indicates basal wild-type female swim levels for comparison. C, Female mutant mice treated with antalarmin showed increased climbing time 24 hr (n = 5) after treatment compared with vehicle-treated females. ^*p < 0.05. No difference was detected in climbing time 1 hr after treatment (n = 10); ANOVA and Fisher's post hoc test. + indicates basal wild-type female climbing levels for comparison.

Figure 3.

Forced swim test results after pretreatment with antalarmin in male CRFR2-deficient mice. A, Male mutant mice treated with antalarmin (7.5 mg/kg) 1 hr before testing showed decreased immobile time compared with vehicle-treated mutant mice (n = 10). ^***p < 0.001. This effect remained evident 24 hr (n = 5) after treatment. ^**p < 0.01. No difference in immobile time was detected 72 hr (n = 5) after treatment; ANOVA and Fisher's post hoc test. + indicates basal wild-type male immobile levels for comparison.B, Male mutant mice treated with antalarmin 1 hr before testing showed increased swim time compared with vehicle-treated mutant mice (n = 10). ^***p < 0.001. This effect remained evident 24 hr (n = 5) after treatment. ^*p < 0.05. No difference in swim time was detected 72 hr (n = 5) after treatment; ANOVA and Fisher's post hoc test. + indicates basal wild-type male swim levels for comparison. C, Male mutant mice treated with antalarmin showed increased climbing time 24 hr (n = 5) after treatment compared with vehicle-treated males. ^*p < 0.05. No difference was detected between antalarmin and vehicle-treated males in climbing time 1 hr (n = 10) or 72 hr (n = 5) after treatment; ANOVA and Fisher's post hoc test. + indicates basal wild-type male climbing levels for comparison.