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. 1. Introduction Clinical studies propose a delayed response of aged patients to antidepressants as compared to young ones [1, 2]. Accordingly, we recently found in the chronic mild stress paradigm that middle-aged male rats (MA, 13–15 months) responded slower than young adults to the antidepressant treatment with citalopram (a selective serotonin reuptake inhibitor—SSRI—) [3]. The serotonin transporter (SERT) is the primary target of SSRIs and has a polymorphism in the promoter region of its gene with two variants: long (l) and short (s), interestingly, the s-variant has been associated to a reduced SERT expression and low serotonin uptake [4–7]. Patients carrying the s-variant (associated to low SERT expression) displayed a retarded response to SSRIs [8–10], suggesting a relationship between therapeutic response and number of SERTs [9, 11, 12]. On the other hand, it has been shown that in aged subjects there is deterioration of serotoninergic fibers in the rat forebrain [13] and reduced binding of [11C](+)McN5652 to SERT in several brain areas of Rhesus monkey, such as prefrontal cortex and hippocampus [14], a structure involved in the response to antidepressants [15]. On these bases we hypothesize that the impaired antidepressant-like response of MA rats to citalopram [3] is associated with an age-related reduction of brain SERT expression. The mechanisms underlying the
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