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Background:In women, changes in estrogen levels may increase the incidence and/or symptomatology of depression and affect the response to antidepressant treatments. Estrogen therapy in females may provide some mood benefits as a single treatment or might augment clinical response to antidepressants that inhibit serotonin reuptake.Objective:We analyzed the mechanisms of estradiol action involved in the regulation of gene expression that modulates serotonin neurotransmission implicated in depression.Method:Publications were identified by a literature search on PubMed.Results:The participation of estradiol in depression may include regulation of the expression of tryptophan hydroxylase-2, monoamine oxidase A and B, serotonin transporter and serotonin-1A receptor. This effect is mediated by estradiol binding to intracellular estrogen receptor that interacts with estrogen response elements in the promoter sequences of tryptophan hydroxylase-2, serotonin transporter and monoamine oxidase-B. In addition to directly binding deoxyribonucleic acid, estrogen receptor can tether to other transcription factors, including activator protein 1, specificity protein 1, CCAAT/enhancer binding protein β and nuclear factor kappa B to regulate gene promoters that lack estrogen response elements, such as monoamine oxidase-A and serotonin 1A receptor.Conclusion:Estradiol increases tryptophan hydroxylase-2 and serotonin transporter expression and decreases the expression of serotonin 1A receptor and monoamine oxidase A and B through the interaction with its intracellular receptors. The understanding of molecular mechanisms of estradiol regulation on the protein expression that modulates serotonin neurotransmission will be helpful for the development of new and more effective treatment for women with depression.

Decreased spatial memory is common in aging populations and reduces their quality of life. Although its role is still controversial, low testosterone (T) may contribute to impaired cognition in aged men. This study aimed to identify the role of T in age-related deficiencies in spatial memory among male rats. Young adult (3 months old) and aged (21 months old) Wistar rats were assigned to independent groups: intact, orchidectomized, or orchidectomized + subcutaneous pellets of T propionate. The phases of spatial memory acquisition (4 daily trials/4 days) and spatial memory retention (1 trial/day, 3 and 12 days after acquisition) were evaluated using the Barnes maze. Compared with young adults, aged intact rats took longer to find the goal, made more mistakes, and showed only slight improvements in goal sector exploration across the acquisition period. The young orchidectomized rats showed no improvement in performance over the days during the acquisition phase. T treatment in hormonally deprived old rats produced a small improvement in goal sector exploration and number of errors during the acquisition phase. Meanwhile, in young adults, this treatment improved the goal sector searching in the retention phase (12 days after acquisition training). Our results suggested that age-related spatial memory deficits cannot be entirely explained by the decline in T levels; however, this androgen produced subtle and mild beneficial effects on spatial memory in young and old males. Taken together, our findings suggest age differences in the role of T on spatial memory in males.

In preclinical and clinical studies aging has been associated with a deteriorated response to antidepressant treatment. We hypothesize that such impairment is explained by an age-related decrease in brain serotonin transporter (SERT) expression associated with low testosterone (T) levels. The objectives of this study were to establish (1) if brain SERT expression is reduced by aging and (2) if the SERT expression in middle-aged rats is increased by T-restitution. Intact young rats (3–5 months) and gonad-intact middle-aged rats with or without T-restitution were used. The identification of the brain SERT expression was done by immunofluorescence in prefrontal cortex, lateral septum, hippocampus, and raphe nuclei. An age-dependent reduction of SERT expression was observed in all brain regions examined, while T-restitution recovered the SERT expression only in the dorsal raphe of middle-aged rats. This last action seems relevant since dorsal raphe plays an important role in the antidepressant action of selective serotonin reuptake inhibitors. All data suggest that this mechanism accounts for the T-replacement usefulness to improve the response to antidepressants in the aged population.

It has been suggested that old depressed patients require longer antidepressant treatments than their young counterparts. The objective of this study was to establish if aging impairs the response to an antidepressant by using an animal model. For this purpose, young and middle-aged male Wistar rats (of around 4 and 14months, respectively) were exposed to a chronic mild stress schedule for 3weeks. After this period, the animals that developed anhedonia, reflected as a reduction in sucrose solution (1%) intake, were treated with citalopram (10mg/kg/day) during 21days while still maintained under the chronic mild stress schedule. Non-stressed animals were included as controls. In young rats citalopram reversed the reduction in sucrose consumption induced by chronic mild stress after one week of treatment, while in middle-aged animals a similar reversion occurred after three weeks. Citalopram did not importantly modify simple water intake in stressed animals or sucrose consumption in non-stressed rats of both ages. The results imply that young rats have a lower latency of onset to the antidepressant-like effect of citalopram than middle-aged animals. The lower sensitivity of middle-aged animals to citalopram could be underlied by their lower levels of gonadal hormones.

Middle-aged male rats are more vulnerable than young adult ones to develop anhedonia when exposed to chronic mild stress (CMS). Clinical studies support the idea that in aged subjects the low testosterone (T) levels are related with their higher stress vulnerability and that this hormone possesses antidepressant-like actions. In this study we evaluated the role of gonadal hormones — mainly T — on the depressive-like behavior of middle-aged and young adult male rats submitted to CMS. In middle-aged rats we analyzed the effect of T restitution (at the levels of young adult animals) given 3 weeks before (experiment 1) or 3 weeks after (experiment 2) anhedonia development (indicated by a reduction in sucrose solution intake). T restitution before CMS effectively prevented anhedonia but failed to reverse it once installed. In young adult rats we studied if orchidectomy increased stress vulnerability and found that it failed to modify sucrose intake. These results indicate a stress-dependent differential effect of T in middle-aged rats an age differential role of gonadal hormones on the vulnerability to develop anhedonia. The results suggest that T is a resilience factor in middle-aged but not in young adult males.