Factors producing a menopausal depressive-like state in mice following ovariectomy

Rationale: Bilateral ovariectomy in female mice produces a menopausal depressive-like state but the factors responsible for the phenomenon are unknown. Objectives: We elucidated methodological issues related to establishing this mouse model and investigated a possible mechanism underlying the depressive-like state of ovariectomized mice. Methods: We removed both ovaries of female ICR mice at 9 weeks of age. Changes in the immobility time during the forced swimming test as a function of the time interval between ovariectomy and behavioral testing were determined on nine different days after surgery. To assess behavioral specificity, the elevated plus-maze (EPM) behavior and spontaneous activity were measured. With respect to the effect of ovariectomy on the immobility time, we compared ICR mice with three other strains of mice (C57BL/6J, DBA/2N, and CD-1). Finally, we investigated the effects of (-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and (+/-)-8-hydroxy-2-(N,N-di-n-propylamino) tetralin (8-OH-DPAT) on the immobility time of ovariectomized mice. Results: A significant effect on the prolongation of immobility was observed between 12 and 18 days after ovariectomy. Ovariectomy did not alter either the EPM behavior or spontaneous activity. Of the four strains of mice, only DBA mice did not show any significant prolongation of immobility after ovariectomy. Acute or chronic treatment with DOI (0.5 or 1.0 mg kg(-1)) significantly prevented the prolongation of immobility time, whereas acute and chronic treatments with 8-OH-DPAT (0.05, 0.5, or 1.0 mg kg(-1) stop) were ineffective. Conclusion: The present findings have potentially important implications for evaluating a candidate substance for the management of mood disorders in menopausal women.