Antidepressant-like and Beneficial Effects of a Neoponcirin-Beta-Cyclodextrin Inclusion Complex in Mice Exposed to Prolonged Stress.

Neoponcirin causes anxiolytic-like effects in mice when administered intraperitoneally but not orally. Neoponcirin is non-water-soluble and insoluble in solvents, and in medium acid, it isomerizes, reducing its bioavailability. To improve the pharmacological properties of neoponcirin, we formed a neoponcirin complex with beta-cyclodextrin (NEO/ßCD), which was characterized by FT-IR, UV-Vis, and NMR, and their solubility profile. We evaluated the antidepressant-like effects of NEO/ßCD acutely administered to mice orally in the behavioral paradigms, the tail suspension (TST) and the forced swimming (FST) tests. We also analyzed the benefits of repeated oral doses of NEO/ßCD on depression- and anxiety-like behaviors induced in mice by chronic unpredictable mild stress (CUMS), using the FST, hole board, and open field tests. We determined the stressed mice's expression of stress-related inflammatory cytokines (IL-1ß, IL-6, and TNFα) and corticosterone. Results showed that a single or chronic oral administration of NEO/ßCD caused a robust antidepressant-like effect without affecting the ambulatory activity. In mice under CUMS, NEO/ßCD also produced anxiolytic-like effects and avoided increased corticosterone and IL-1ß levels. The effects of the NEO/ßCD complex were robust in both the acute and the stress chronic models, improving brain neurochemistry and recovering immune responses previously affected by prolonged stress.

The intersection between menopause and depression: overview of research using animal models.

Menopausal women may experience symptoms of depression, sometimes even progressing clinical depression requiring treatment to improve quality of life. While varying levels of estrogen in perimenopause may contribute to an increased biological vulnerability to mood disturbances, the effectiveness of estrogen replacement therapy (ERT) in the relief of depressive symptoms remains controversial. Menopausal depression has a complex, multifactorial etiology, that has limited the identification of optimal treatment strategies for the management of this psychiatric complaint. Nevertheless, clinical evidence increasingly supports the notion that estrogen exerts neuroprotective effects on brain structures related to mood regulation. Indeed, research using preclinical animal models continues to improve our understanding of menopause and the effectiveness of ERT and other substances at treating depression-like behaviors. However, questions regarding the efficacy of ERT in perimenopause have been raised. These questions may be answered by further investigation using specific animal models of reduced ovarian function. This review compares and discusses the advantages and pitfalls of different models emulating the menopausal stages and their relationship with the onset of depressive-like signs, as well as the efficacy and mechanisms of conventional and novel ERTs in treating depressive-like behavior. Ovariectomized young rats, middle-to-old aged intact rats, and females treated with reprotoxics have all been used as models of menopause, with stages ranging from surgical menopause to perimenopause. Additionally, this manuscript discusses the impact of organistic and therapeutic variables that may improve or reduce the antidepressant response of females to ERT. Findings from these models have revealed the complexity of the dynamic changes occurring in brain function during menopausal transition, reinforcing the idea that the best approach is timely intervention considering the opportunity window, in addition to the careful selection of treatment according to the presence or absence of reproductive tissue. Additionally, data from animal models has yielded evidence to support new promising estrogens that could be considered as ERTs with antidepressant properties and actions in endocrine situations in which traditional ERTs are not effective.

Developmental programming-ageing effects in muscle strength of obese rat offspring in a sex-dependent manner.

Maternal obesity programs the offspring to metabolic dysfunction. However, the effects of maternal obesity on skeletal muscle programming and ageing have been little explored. To determine if maternal obesity is a detriment to the progress of age-related muscle strength loss in the offspring (F1), we evaluated the indicators of muscle strength, adiposity, and metabolism at young adult and senior adult ages of maternal obesity F1 (MOF1) males and females from a high-fat diet-induced maternal obesity model in rat. Controls were agematched siblings whose mothers were fed a standard maternal diet (CF1). Combinatorial data analysis was performed with body weight (BW), forelimb grip strength (FGS), FGS adjusted with BW, body fat, adiposity index, and serum triacylglycerols, cholesterol, glucose, insulin, and homeostatic model assessment for insulin resistance variables, to identify discriminant traits of variation among F1 groups. During ageing, maternal obesity caused glucose and cholesterol metabolic dysfunctions in male F1, whereas adiposity-associated skeletal strength loss and fatty acid alterations were present in female offspring. In conclusion, offspring programming-ageing effects due to maternal obesity impact metabolism and skeletal muscle strength loss at later ages in a sex-dependent manner.

Effects of post-ovariectomy time frame and age on the antidepressant-like actions of estradiol and prolame in female rats.

Estrogen replacement therapy (ERT) is an effective treatment for symptoms associated with climacteric and depression some women experience during perimenopause and menopause. The antidepressant-like effects of ERT may depend on the type of estrogen, age, and time when restitution is initiated after hormonal decline. Prolame is a synthetic steroid with estrogenic and antidepressant-like effects that may produce fewer adverse effects. We hypothesize that such actions of prolame on females depend on age and the duration of hormone deprivation period. We assessed the antidepressant-like effects of 17ß-estradiol (E2) and prolame in young and middle-aged rats across different post-ovariectomy (Ovx) time frames. Independent groups of young adults and middle-aged female rats were tested in the forced swimming test (FST) at 3, 8, 16, and 24 weeks post-Ovx. Prolame and E2 were administered in a sub-chronic schedule consisting of three injections before the FST. Likewise, the utero-trophic effects of these hormones were analyzed. We found that E2 and prolame reduced immobility in young rats 3 and 8 weeks after Ovx; in contrast, only prolame produced this effect in middle-aged rats three weeks post-Ovx. E2 and prolame increased the animals' utero-somatic index at all post-Ovx times, but the action of E2 and prolame produced a greater response in young adult rats. Our findings showed that the antidepressant-like effects of E2 and prolame depend on the post-Ovx time frame, age, and estrogen type. Interestingly, our results indicate that, in contrast to E2, prolame maintained its antidepressant effect in middle-aged rats.

Antidepressant-like effects of acupuncture via modulation of corticosterone, sex hormones, and hippocampal BDNF expression in male rats.

BACKGROUND: Post-weaning social isolated rodents exhibit pathophysiological changes associated with depression including adrenal axis hyperactivity, gonadal hormone level disturbances, molecular alterations in hippocampus, and immobility behavior in the forced swimming test (FST). Although acupuncture by absorbable thread implantation (acu-catgut, AC) elicits antidepressant-like effects in social isolated rats, AC effects on neuroendocrine and hippocampal molecular alterations have been less characterized. OBJECTIVE: To investigate the participation of gonadal hormones, corticosterone, and brain-derived neurotrophic factor (BDNF) hippocampal expression, on the AC antidepressant-like effects in social isolated male rats. METHODS: Sprague-Dawley male rats were raised in social isolation (SI) or standard conditions, for 11 weeks. AC (on Baihui (Du20), Yintang (E X-HN3), Shenshu (BL 23), Pishu (BL 20), Ganshu (BL 18), Xinshu (BL 15) and Guanyuan (Ren 4)), or Sham-AC (puncturing of acupoints without embedding the thread), was applied during the last three weeks of isolation period. Rats were evaluated in the FST; hormones plasmatic levels and hippocampal BDNF content were quantified by ELISA and Western blotting, respectively. RESULTS: Social isolated rats showed more immobility in the FST and had lower testosterone and estradiol levels, higher corticosterone levels, and reduced hippocampal BDNF content than controls. BDNF level in hippocampus inversely correlated to depression-like behavior. AC but not sham-AC normalized immobility behavior, steroid hormone levels, and BDNF content, as in rats raised in a social environment. CONCLUSIONS: AC antidepressant effect could be related to an improvement of hippocampal BDNF protein expression, as well as corticosterone and sex hormones disturbances associated with prolonged exposure to stress caused by social isolation. Present findings have implications for depression treatment in individuals early exposed to stress.

GABA A /Benzodiazepine Receptor Complex in the Dorsal Hippocampus Mediates the Effects of Chrysin on Anxiety-Like Behaviour in Female Rats.

Systemic injections of the flavonoid chrysin (5,7-dihydroxyflavone) exert anxiolytic-like effects in ovariectomised and cycling female rats through actions on gamma-aminobutyric acid-A (GABA A ) receptors; however, it is unknown if chrysin directly acts on brain structures that are involved in regulating emotional processes, such as the hippocampus. The present study evaluated the effects of intrahippocampal microinjections of 0.25, 0.5, and 1 µg of chrysin on anxiety-like behaviour in the elevated plus maze (EPM) and locomotor activity test (LAT) in female rats in proestrus and dioestrus. Similar doses of the neurosteroid allopregnanolone were used as a reference GABAergic anxiolytic drug. The participation of the GABA A /benzodiazepine receptor complex was evaluated by administering the antagonists picrotoxin, bicuculline and flumazenil. In proestrus, 0.5 and 1 µg of chrysin and allopregnanolone induced anxiogenic-like behaviour. In dioestrus, chrysin, and allopregnanolone (0.5 µg) induced anxiolytic-like effects. Picrotoxin, bicuculline and flumazenil prevented the effects of chrysin and allopregnanolone in both proestrus and dioestrus. None of the treatments significantly affected locomotor activity. These results indicate that the GABA A /benzodiazepine receptor complex in the dorsal hippocampus regulates the effects of chrysin on anxiety-like behaviour, similar to the actions of allopregnanolone. The divergent effects of treatments across the oestrous cycle phases suggest complex interactions between GABA A receptors and compounds with an anxiolytic potential.

Calea zacatechichi Schltdl. (Compositae) produces anxiolytic- and antidepressant-like effects, and increases the hippocampal activity during REM sleep in rodents.

ETHNOPHARMACOLOGICAL RELEVANCE: Calea zacatechichi is a plant with an extensive popular and ritual use in Mexico. In healthy volunteers, it induces well-being and tranquility senses, and facilitates superficial stages of sleep. However, anxiolytic, and antidepressant-like effects and changes on the sleep-waking stages have not been explored. AIM: To determine anxiolytic and antidepressant-like effects of an aqueous extract of C. zacatechichi (CZ) in rodents and to analyze their effects on hippocampal activity in the rat sleep-waking cycle. MATERIAL AND METHODS: CZ anxiolytic- and antidepressant-like effects were evaluated in several mice and rat behavioral paradigms. CZ effects on temporal distribution of sleep were described, and hippocampus EEG frequency patterns were analyzed during the sleep-waking cycle; absolute and relative powers were analyzed during Rapid Eye Movements (REM) and non-REM sleep stages. CZ chemical analysis was performed by UPLC-ESI-MS. RESULTS: CZ produced specific and robust anxiolytic- and antidepressant-like effects in mice and rats, similar to those of prototypical drugs, at doses ranging from 0.5 to 50 mg/kg. CZ at 100 mg/kg produced visible mild sedative effects in rats, associated with a significant increase in Slow Wave Sleep episodes during a 6 h recording, and enhanced fast frequencies of hippocampus (gamma-band:31-50 Hz) during REM sleep. CONCLUSION: Results could support the well-being and tranquility senses reported by healthy consumers, and to explain the oneiric content during dreams and some improvements in cognitive processes described by consumers. Anxiolytic- and antidepressant-like effects of this species, reported for first time in this study could improve some aspects of mental health.

Age-dependent effects of testosterone on spatial memory in male rats.

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.

Role of Estradiol in the Expression of Genes Involved in Serotonin Neurotransmission: Implications for Female Depression.

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 ß 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.

Piper auritum Kunth (Piperaceae) improves the sexual performance of sluggish male rats through enhancing ejaculation.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper auritum Kunth is employed as an aphrodisiac in the traditional medicine, but corroborative evidence for such effect is scarce. AIM OF THE STUDY: The pro-sexual effect of an aqueous extract of P. auritum and its possible mechanisms were analyzed in two paradigms of male sexual function. MATERIAL AND METHODS: Effects of an aqueous extract of P. auritum (PA, single administration) were investigated in the fictive ejaculation, and copulatory behavior paradigms in sexually sluggish male rats. WAY 100635 (antagonist of 5-HT1A receptors), atosiban (antagonist of oxytocinergic receptors), L-NAME (inhibitor of the nitric oxide synthase) and baclofen (antagonist of GABAB receptors) were used as pre-treatments in order to investigate the role of different neurotransmitter systems in PA actions. Chemical profile of PA was determined by Gases Chromatography and Ultra Performance Chromatography-Electrospray Ionization-Masses Spectrometry (UPLC-ESI-MS). RESULTS: In males with retarded ejaculation, PA stimulated ejaculatory behavior and recovered electromyographic activity of pelvic musculature participating in seminal emission and ejaculation. All pre-treatments blocked stimulating effects of PA on the fictive ejaculation; additionally WAY 100635 interfered with PA actions on ejaculatory behavior. Safrol, apigenin dimethylether, myristicin, vaccihein A, sakuranin and sakuranetin flavonoids, were main constituents of PA, with possible participation in its pro-sexual effects. CONCLUSIONS: Pro-sexual effects of P. auritum elicited at level of ejaculation were mediated by several neurotransmitter systems, among which serotonin and its 5-HT1A receptors play an important role. Present findings support P. auritum reputation as an aphrodisiac, with potential use in delayed ejaculation disorder.

Forced ethanol ingestion by Wistar rats from a juvenile age increased voluntary alcohol consumption in adulthood, with the involvement of orexin-A.

Human adolescents who drink alcohol are more likely to become alcoholics in adulthood. Alcohol administration (intraperitoneally) or drinking (in a 2-bottle free choice paradigm) during the juvenile/adolescent age of rats promotes voluntary alcohol consumption in adulthood. On the other hand, there is growing evidence that the orexinergic system plays a role in several rewarded behaviors, including alcohol ingestion. Since it is unknown what effect is exerted in adulthood by forced oral ethanol intake and/or administration of orexin-A (OX-A) in juvenile rats, the present study aimed to evaluate this question. A group of male Wistar rats was forced to drink ethanol (10% v/v) as the only liquid in the diet from weaning (postnatal day 21) to postnatal day 67 (46 days), followed by a forced withdrawal period. An age-matched group was raised drinking tap water (control). OX-A or its vehicle was microinjected intracerebroventricularly (i.c.v.) (1 nmol/0.6 µL) to explore its effect as well. Locomotor activity and voluntary ethanol consumption were later assessed in all groups. The rats forced to consume ethanol early in life showed an elevated level of ambulation and alcohol ingestion in adulthood. A single injection of OX-A increased locomotor activity and acute ethanol intake in rats with or without prior exposure to alcohol at the juvenile stage. In conclusion, forced ethanol consumption in juvenile rats led to increased voluntary alcohol drinking behavior during adulthood, an effect likely facilitated by OX-A.

Antidepressant effects of acupoint stimulation and fluoxetine by increasing dendritic arborization and spine density in CA1 hippocampal neurons of socially isolated rats.

Given the importance of depression and the adverse effects of conventional treatment, it is necessary to seek complementary therapies. In a rat model of depression, this study aimed to assess the behavioral and morphological effects of embedding absorbable thread in acupoints (acu-catgut), and compare the results to those of fluoxetine treatment and the corresponding control groups. Therefore, depressive-like behavior was evaluated with the forced swimming test, and dendritic morphology (in the CA1 hippocampal region) with the Golgi-Cox technique and Sholl analysis. After weaning, male Sprague-Dawley rats were housed in social isolation for 8 weeks to induce depressive-like behavior. They were then given a 21-day treatment by stimulating acupoints with acu-catgut (AC) or fluoxetine (FX) (2 mg/kg). Rats were divided into six groups: Control (socially housed), social isolation (SI), SI + AC, SI + Sham (sham embedding of thread), SI + FX and SI + VH (vehicle). Compared to fluoxetine, acu-catgut treatment was more effective in reversing depressive-like behavior elicited by SI. The SI-induced reduction in dendritic length and spine density in hippocampal CA1 pyramidal neurons was attenuated after prolonged treatment with acu-catgut or fluoxetine. Hence, both treatments proved capable of reversing depressive-like alterations caused by SI, likely due to dendritic remodeling in the hippocampus.

Isolation stress and chronic mild stress induced immobility in the defensive burying behavior and a transient increased ethanol intake in Wistar rats.

Stress can be experienced with or without adverse effects, of which anxiety and depression are two of the most important due to the frequent comorbidity with alcohol abuse in humans. Historically, stress has been considered a cause of drug use, particularly alcohol abuse due to its anxiolytic effects. In the present work we exposed male Wistar rats to two different stress conditions: single housing (social isolation, SI), and chronic mild stress (CMS). We compared both stressed groups to group-housed rats and rats without CMS (GH) to allow the determination of a clear behavioral response profile related to their respective endocrine stress response and alcohol intake pattern. We found that SI and CMS, to a greater extent, induced short-lasting increased sucrose consumption, a transient increase in serum corticosterone level, high latency/immobility, and low burying behavior in the defensive burying behavior (DBB) test, and a transient increase in alcohol intake. Thus, the main conclusion was that stress caused by both SI and CMS induced immobility in the DBB test and, subsequently, induced a transient increased voluntary ethanol intake in Wistar rats with a free-choice home-cage drinking paradigm.

Corrigendum to "Young-Adult Male Rats' Vulnerability to Chronic Mild Stress Is Reflected by Anxious-Like instead of Depressive-Like Behaviors".

[This corrects the article DOI: 10.1155/2016/5317242.].

Age-related changes in the antidepressant-like effect of desipramine and fluoxetine in the rat forced-swim test.

Some reports suggest that older patients are less responsive to antidepressants than young adults, but this idea has not been fully supported. Here, we investigated the role of aging in the behavioral effects of the antidepressants, desipramine (DMI) (5, 10, and 20 mg/kg) and fluoxetine (FLX) (5, 10, and 20 mg/kg) in young adults (3-5 months), middle-aged (MA, 12-15 months), and senescent (SE, 23-25 months) male rats in the forced-swim test. In addition, locomotor activity and motor coordination were assessed as side-effects. DMI and fluoxetine produced an antidepressant-like effect in YA and MA animals, although in the latter group, a shift to the right in the dose-response curve was found for DMI. Importantly, neither drug was effective in SE animals. Motor side-effects were produced mainly by DMI in MA and SE rats. Therefore, a decrease in the antidepressant-like effect is associated strongly with senescence as well as an increased vulnerability to motor side-effects, particularly of tricyclics. This study is significant because SE animals are scarcely studied in pharmacological screening tests, and our findings might be useful for improving antidepressant treatments for the increasing aged population.

Chronic stress induces structural alterations in splenic lymphoid tissue that are associated with changes in corticosterone levels in wistar-kyoto rats.

Major depressive disorder patients present chronic stress and decreased immunity. The Wistar-Kyoto rat (WKY) is a strain in which the hypothalamic-pituitary-adrenal axis is overactivated. To determine whether chronic stress induces changes in corticosterone levels and splenic lymphoid tissue, 9-week-old male rats were subject to restraint stress (3 h daily), chemical stress (hydrocortisone treatment, 50 mg/Kg weight), mixed stress (restraint plus hydrocortisone), or control treatment (without stress) for 1, 4, and 7 weeks. The serum corticosterone levels by RIA and spleens morphology were analyzed. Corticosterone levels as did the structure, size of the follicles and morphology of the parenchyma (increase in red pulp) in the spleen, varied depending on time and type of stressor. These changes indicate that chronic stress alters the immune response in the spleen in WKY rats by inducing morphological changes, explaining in part the impaired immunity that develops in organisms that are exposed to chronic stress.

Brain SERT Expression of Male Rats Is Reduced by Aging and Increased by Testosterone Restitution.

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.

Participación de las hormonas gonadales en el efecto de los fármacos antidepresivos en la rata macho / Participation of gonadal hormones in the effect of antidepressant drugs in male rats

It has been proposed that gonadal hormones participate in regulation of mood and emotion in men as well as in the effect of psychoactive drugs, such as antidepressants. However, evaluation of this type of interactions has been poorly studied in clinic and basic studies. The objective of the present study was to determine the role of gonadal hormones, testosterone (T) and 17β-estradiol (E2), one of its main metabolites, in the effect of two antidepressant drugs: desipramine and fluoxetine. The former is a tricyclic antidepressant that inhibits noradrenaline reuptake in a preferential manner, while the second is a serotonin selective reup-take inhibitor (SSRI) and the most prescribed antidepressant. Behavioral evaluations were conducted in adult male rats, intact or orchidectomized (Orx), treated with T (0-2 mg/rata), E2 (0-40 µg/rata), desipramine (0-20 mg/kg), fluoxetine (0-20 mg/kg) and their combinations. Forced swimming test was used as an animal model to detect antidepressant-like effect induced by treatments, on the basis of its predictive validity. We found that desipramine and fluoxetine produced an anti-depressant-like effect in gonadally intact male rats. However, the antidepressant-like effect of both treatments was cancelled in Orx males. Treatment with E2, but not with T, produced antidepressant-like actions in Orx males. Interestingly, treatment with E2 restored the antidepressant-like effect of desipramine and fluoxetine, while supplementation with T only reestablished the antidepressant-like action of desipramine, evidencing that gonadal hormones have a differential participation in regulation of neurotransmitter systems involving in the antidepressant effect. In conclusion, the main testicular androgen T, participates in the expression of the effect of antidepressant drugs, mainly via conversion to its estrogenic metabolite E2. These results give support to the idea that a combined therapy of gonadal hormones and antidepressant drugs may be more convenient to treat depressive disorders in hypogonadal men resistant to conventional antidepressant drugs.

Se ha propuesto que las hormonas gonadales participan en la regulación del estado de ánimo en los varones, y en el efecto de los fármacos psicoactivos, tales como los antidepresivos. Sin embargo, la evaluación de este tipo de interacciones ha sido estudiada escasamente. El objetivo del presente trabajo fue determinar el papel que cumplen las hormonas testosterona (T) y 17β-estradiol (E2), uno de sus principales metabolitos, en el efecto de dos fármacos antidepresivos utilizados en la práctica clínica, desipramina y fluoxetina. El primero es un tricíclico con acciones sobre el sistema noradrenérgico, mientras que la fluoxetina es un inhibidor selectivo de la recaptura de serotonina. Las evaluaciones se llevaron a cabo utilizando ratas macho adultas jóvenes, gonadalmente intactas u orquidectomizadas (Orx), bajo tratamiento con T (0-1 mg/rata), E2 (0-40 µg/rata), desipramina (0-20 mg/kg), fluoxetina (0-20 mg/kg) y sus respectivas combinaciones. Se utilizó la prueba de nado forzado (PNF) para detectar las acciones antidepresivas de los tratamientos. Encontramos que desipramina y fluoxetina redujeron la conducta de depresión en los machos gonadalmente intactos; sin embargo, el efecto de ambos tratamientos fue abolido por la orquidectomía. El tratamiento de restitución hormonal con E2, pero no con T, indujo acciones antidepresivas en los machos Orx. A su vez, cuando los animales Orx recibieron la restitución con T se produjo la recuperación del efecto antidepresivo de la desipramina, mientras que el E2 restableció las acciones antidepresivas de ambos fármacos. En conclusión, el principal andrógeno de origen testicular, la T, participa en la expresión del efecto de los fármacos antidepresivos explorados en el presente estudio, principalmente a través de su metabolito estrogénico, el E2. Estos resultados apoyan la idea de que una terapia adjunta de tratamientos hormonales y antidepresivos sería de beneficio para varones hipogonadales que cursen con depresión resistente a los fármacos antidepresivos convencionales.