Maternal separation induces long-term effects on monoamines and brain-derived neurotrophic factor levels on the frontal cortex, amygdala, and hippocampus: differential effects after a stress challenge.

The maternal separation (MS) paradigm is a well-known animal model that resembles the stress of early adverse life experiences and produces structural and functional abnormalities when animals are adults. The present study analyzed the effect of MS, in adult mice, on brain-derived neurotrophic factor (BDNF), serotonin (5-HT), and dopamine (DA) levels, and the turnover rate in the hippocampus, frontal cortex, and amygdala, and brain regions that are associated with emotion. Also, the effects of MS in depression-like responses in adult mice were studied. The results showed that MS from postnatal day 8-21 induces depression-like behaviors. In MS mice, the three brain areas showed differential responses in 5-HT, DA, and BDNF concentrations both in basal levels and when animals were challenged with an acute stressor in adulthood. Specifically, under basal conditions, MS increased monoamine and BDNF levels in the hippocampus and amygdala, but decreased these levels in the frontal cortex. In MS, but not in control mice, the amygdala responded to the stress challenge, whereas the frontal cortex showed no response. Finally, the hippocampus showed increased 5-HT and DA activity, but not increased BDNF after the stress challenge in MS mice. The present results support the theory of the hypofunctionality of the frontal cortex and hyperactivity of mesolimbic areas in depression-like conditions.

Antidepressant effects of estrogens: a basic approximation.

The use of estrogenic compounds as antidepressants or as coadjuvants to facilitate the effect of antidepressants has reported controversial results, suggesting that many factors could influence their actions. This review analyzes, from a basic research perspective, the possible factors that may underlie the antidepressant action of estrogens alone or in combination. The possible mechanisms of action of estrogens alone and in combination with the selective serotonin reuptake inhibitor, fluoxetine, the selective noradrenaline reuptake inhibitor, desipramine, and the mixed serotonin/noradrenaline reuptake inhibitor, venlafaxine are reviewed, focusing on monoaminergic systems and estrogen receptors as main targets. The antidepressant effect of estrogens depends on the type of estrogen, treatment duration, doses, sex, time after ovariectomy, and age. Estrogens potentiate the antidepressant-like action of fluoxetine, venlafaxine, and desipramine and drastically shorten their latency of action. The antidepressant-like effect of estrogens alone or in combination with antidepressants seems to be mediated by monoaminergic and classic estrogen receptors, as WAY100635, an antagonist to the serotonin 1A receptor, idaxozan, an antagonist to alpha2 adrenergic receptors, and RU 58668, an estrogen receptor antagonist, blocked their antidepressant-like effect. In conclusion, estrogens produce antidepressant-like actions by themselves and importantly facilitate the action of clinically used antidepressants.

Synergistic effect of estradiol and fluoxetine in young adult and middle-aged female rats in two models of experimental depression.

The antidepressant effect of estrogens combined with antidepressants is controversial: some preclinical data showed that estrogens facilitate the effect of antidepressants in the forced swimming test (FST) in young adult rats, while others failed to find such effect in middle-aged rats in the chronic mild stress (CMS) model. In clinics similar differences were reported and may be due to the compounds, the depression model or type of depression, the experimental design, and the age of the subjects or the women's menopause stage. The objective of this study was to analyze the antidepressant-like effect of the combination of 17ß-estradiol (E(2)) and fluoxetine (FLX) in young adults (2-4 months) and middle-aged (12-14 months) ovariectomized (OVX) rats in two experimental models: FST and CMS. E(2) (5 and 10 µg/rat) and FLX (2.5 and 10 mg/kg) per se dose-dependently reduced immobility in both age groups and, in young adults both compounds increased swimming, whereas in middle-aged rats they increased swimming and climbing. Analysis of the antidepressant-like effect of the combination of suboptimal doses of FLX (1.25 mg/kg) and E(2) (2.5 µg/rat) showed a decrease in immobility and an increase in swimming in both age groups. In the CMS, chronic E(2) (2.5 µg/rat) with FLX (1.25 mg/kg) augmented relative sucrose intake, but middle-aged rats responded 2 weeks earlier than young adults. These results show that the antidepressant-like effect of the combination of E(2) and FLX in young adult and middle-aged female rats is evidenced in the two animal models of depression: FST and CMS.