Effects of two estradiol regimens on anxiety and depressive behaviors and trophic effects in peripheral tissues in a rodent model

Abstract

Background: With aging and menopause, which are associated with decreases in ovarian steroids such as 17beta-estradiol (E(2)), women might experience negative psychological symptoms, including anxiety and depression. Some women use E(2)-based therapies to alleviate these symptoms, but E(2) has been associated with trophic effects that might increase vulnerability to some steroid-sensitive cancers, such as breast cancer, in both premenopausal and postmenopausal women.

Objective: This study investigated the relationships between the possible beneficial effects of E(2) on anxiety and depressive behaviors concurrent with trophic effects using an animal model of E(2) decline and replacement.

Methods: Dose-dependent effects of E(2) on affective, sexual, and motor behavior of young adult rats were studied. Ovariectomized (OVX) rats were administered the chemical carcinogen 7,12-dimethylbenz(a) anthracene (DMBA) 1.25 mg or inactive vehicle (vegetable oil; control) by gavage. E(2) (0.03 or 0.09 mg/kg) or vehicle was administered subcutaneously 44 to 48 hours before assessments of anxiety (light-dark transition), depression (forced swim test), sexual (lordosis), and motor (activity monitor) behaviors. Fourteen weeks after carcinogen exposure, E(2) concentrations in plasma and brain regions (cortex, hippocampus, and hypothalamus) were determined. Incidences and numbers of tumors and uterine weight were analyzed.

Results: Administration of E(2) (0.09 mg/kg) was associated with significant increases in antianxiety-like behavior in the light-dark transition task, antidepressant-like behavior in the forced swim test, and physiologic circulating and central E(2) concentrations compared with E(2) (0.03 mg/kg) and vehicle. Compared with vehicle, E(2) (0.9 > 0.3 mg/kg) was associated with significant increases in lordosis and uterine weight. Administration of DMBA was associated with significant increases in the incidences and numbers of tumors; this effect was augmented by E(2)administration.

Conclusions: Based on the findings in this rat model, the hypothesis that E(2) may be effective in reducing anxiety and depressive behaviors and enhance sexual behavior in OVX rats, concurrent with trophic effects in the periphery, was supported. Moderate physiologic levels of E(2) might have beneficial effects on affective and sexual behaviors in female rodents, but regimens including E(2) might increase tumorigenic capacity.

Figure 1

Time spent on the light side of the light–dark transition chamber in ovariectomized rats administered the chemical carcinogen 7,12-dimethylbenz(a)anthracene or inactive vehicle, followed by weekly priming with estradiol (E₂) or inactive vehicle (control). *P ≤ 0.05 versus control.

Figure 2

Time spent immobile in the forced swim test in ovariectomized rats administered the chemical carcinogen 7,12-dimethylbenz(a)anthracene or inactive vehicle, followed by weekly priming with estradiol (E₂) or inactive vehicle (control). *P ≤ 0.05 versus control.

Figure 3

Lordosis ratings (LRs) in ovariectomized rats administered the chemical carcinogen 7,12-dimethylbenz(a)anthracene or inactive vehicle, followed by weekly priming with estradiol (E₂) or inactive vehicle (control). *P = 0.01 versus control.

Figure 4

(A) Incidence of tumors in experimental rats and (B) number of tumors in ovariectomized rats administered the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) or inactive vehicle (no DMBA), followed by weekly priming with estradiol (E₂) or inactive vehicle (control). *P ≤ 0.01 versus control; ^†P ≤ 0.05 versus no DMBA.

Figure 5

Uterine weight in ovariectomized rats administered the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) or inactive vehicle (no DMBA), followed by weekly priming with estradiol (E₂) or inactive vehicle (control). *P ≤ 0.01 versus control.