Estrogens have numerous beneficial effects on brain health; they impact learning, memory, and mood. We utilized the latter effect of estrogens to study an estrogenic compound’s antidepressant-like effect in experimental animals upon systemic (subcutaneous) drug administration.
The Porsolt Swim Test (PST) is a well-known model to survey the antidepressant-like effect of potential CNS agents. In this model, a mouse is placed in a water-filled container for a set period of time. When the animal ceases swimming and only makes enough movement to keep its head above the water, also known as immobility, this corresponds to a “depressive mood.” We used 30 ovariectomized CD-1 mice lacking endogenous estrogens to avoid inference with the exogenously added estrogenic compound. The mice were divided into 5 groups of 6, with one group being designated as the control. Test agent was administered at various doses to the other 4 groups in corn oil vehicle for 5 days daily, and experiment started 30 minutes after the last injection for each mouse. At the highest dose, ICI 182,780 (an estrogen antagonist) was also co-administered. The movement of the animals were taped for 6 minutes. Two blinded observers independently determined the immobility times for the last 4 minutes of the videotaped experiment. At the end of the experiment, the mice were sacrificed and tissues were harvested for future drug quantification. Uterus wet weights were also measured. Mice were only exposed to these experimental conditions on the day of the experiment.
Compared to the corn oil vehicle control, a dose-dependent and statistically significant reductions in immobility time were observed in animals treated with the estrogenic compounds. ICI 182,780 completely reversed the antidepressant-like effect of the test agent. Wet uterus weights were also statistically significantly different from those measured for the control group, indicating the uterotropic effect of the estrogenic test compound.
We have showed that an estrogenic test compound produced a dose-dependent antidepressant-like effect in PST, and this effect was completely reversible by the co-administration of an estrogen antagonist, implicating that the genomic effect of the estrogenic compound played a pivotal role in the observed CNS effect. At the same time, we also showed that the uterus of animals receiving the estrogenic test compound became very large due to fluid imbibition, which is a typical detrimental peripheral side-effect of estrogens exogenously administered for the purpose of neurotherapy. In the future, drug content in the brain and blood of the experimental animals will be determined and correlated with the obtained neuropharmacological effect.
Research reported in this publication was supported in part by the National Heart, Lung, and Blood Institute and the National Cancer Institute of the National Institutes of Health under Award Numbers R25HL125447 (to Dr. J.K. Vishwanatha) and R01CA215550 (to L.P.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.||