Erika Estrada-Camarena

Antidepressant-like effect of different estrogenic compounds in the forced swimming test.

The present study evaluated the possible antidepressant-like action of the natural estrogen 17β-estradiol (E2, 2.5–10 μg/rat), the synthetic steroidal estrogen ethinyl-estradiol (EE2, 1.25–10.0 μg/rat), and the nonsteroidal synthetic estrogen, diethyl-stilbestrol (DES, 0.25–1.0 mg/rat) in ovariectomized adult female Wistar rats using the forced swimming test (FST). The behavioral profile induced by the estrogens was compared with that induced by the antidepressants fluoxetine (FLX, 2.5–10 mg/kg) and desipramine (DMI, 2.5–10 mg/kg). In addition, the temporal course of the antidepressant-like action of the estrogenic compounds was analyzed. FLX and DMI induced an antidepressant-like effect characterized by a reduced immobility and increased swimming for FLX and decreased immobility and increased climbing for DMI. Both E2 and EE2 produced a decrease in immobility and an increase in swimming, suggesting an antidepressant-like action. DES did not affect the responses in this animal model of depression at any dose tested. The time course analysis of the actions of E2 (10 μg/rat) and EE2 (5 μg/rat) showed that both compounds induced an antidepressant-like effect observed 1 h after their injection lasting for 2–3 days.

Contribution of estrogen receptors alpha and beta to the effects of estradiol in the brain

Clinical and experimental studies show a modulatory role of estrogens in the brain and suggest their beneficial action in mental and neurodegenerative diseases. The estrogen receptors ERalpha and ERbeta are present in the brain and their targeting could bring selectivity and reduced risk of cancer. Implication of ERs in the effect of estradiol on dopamine, opiate and glutamate neurotransmission is reviewed. The ERalpha agonist, PPT, is shown as estradiol to modulate hippocampal NMDA receptors and AMPA receptors in cortex and striatum of ovariectomized rats whereas the ERbeta agonist DPN is inactive. Striatal DPN activity suggests implication of ERbeta in estradiol modulation of D2 receptors and transporters in ovariectomized rats and is supported by the lack of effect of estradiol in ERbeta knockout (ERKObeta) mice. Both ERalpha and ERbeta agonists modulate striatal preproenkephalin (PPE) gene expression in ovariectomized rats. In male mice PPT protects against MPTP toxicity to striatal dopamine; this implicates Akt/GSK3beta signaling and the apoptotic regulators Bcl2 and Bad. This suggests a role for ERalpha in striatal dopamine neuroprotection. ERKOalpha mice are more susceptible to MPTP toxicity and not protected by estradiol; differences in ERKObeta mice are subtler. These results suggest therapeutic potential for the brain of ER specific agonists.

Interaction of desipramine with steroid hormones on experimental anxiety.

The present study analyzes if estradiol benzoate and/or progesterone interact with desmethylimipramine (DMI) to diminish experimental anxiety. The animal model of anxiety used was the conditioned defensive burying test. Dose response curves for DMI (0.625, 1.25 and 2.5 mg/kg, every 24 h, during 21 days), estradiol benzoate (0.5, 1.0, 2.0 and 4.0 micrograms/rat, 48 h) and progesterone (0.5, 1.0 and 2.0 mg/rat, -4 h) were made in ovariectomized rats. DMI per se decreased dose dependently the cumulative burying time, an effect considered as anxiolytic-like. Progesterone produced a decrease in burying at the highest dose, while estradiol benzoate had no effect on defensive burying. Both, progesterone (0.5 mg/rat) and estradiol benzoate (4.0 micrograms/rat) were able to decrease the cumulative burying behavior when injected with a subthreshold dose of DMI (1.25 mg/kg). In addition, the effect of DMI (1.25 mg/kg) plus the combination of estradiol benzoate and progesterone, sequentially administered (48 h and 4 h before the tests, respectively), also produced a synergistic decrease in burying behavior. In general, the treatments produced no changes in burying behavior latency, neither in spontaneous ambulation or in nociception. It is concluded that DMI synergizes its anxiolytic-like effect when administered with estradiol alone or in combination with progesterone. Present data provide experimental evidence suggesting an interaction between hormones and antidepressants. Results are discussed on the basis of the interaction between steroids and serotonergic or GABAergic receptors.

Participation of the 5-HT1A Receptor in the Antidepressant-Like Effect of Estrogens in the Forced Swimming Test

The aim of the present study was to explore the possible participation of the 5-HT1A receptor in the antidepressant-like action of two estrogenic compounds: 17β-estradiol (E2) and ethynil-estradiol (EE2) in the FST. Ovariectomized female Wistar rats were used in all experiments. As a positive control, the effect of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n)-propil-aminotetraline (8-OH-DPAT; 0.0625, 0.125, 0.25 and 0.5 mg/kg) alone or in combination with WAY 100635 (0.5 and 1.0 mg/kg) was analyzed in the FST. In order to analyze the participation of the 5-HT1A receptor in the antidepressant-like actions of estrogens, the effect of the selective antagonist WAY 100635 (0.5 and 1.0 mg/kg) in combination with E2 (10 μg/rat) and EE2 (5 μg/rat) was studied in the FST. In this case, WAY 100635 was administered either simultaneously with the estrogens (48 h before the FST test) or 30 min before the FST. On the other hand, a suboptimal dose of 8-OH-DPAT (0.0625 mg/kg), combined with a noneffective dose of E2 (2.5 μg/rat) or EE2 (1.25 μg/rat), was tested in the FST. The results showed that 8-OH-DPAT (0.25 and 0.5 mg/kg), E2 (10 μg/rat), and EE2 (5 μg/rat), by themselves, exerted an antidepressant-like action. The antagonist to the 5-HT1A receptor WAY 100635, when applied together with 8-OH-DPAT or E2, blocked their antidepressant-like actions, but not the one induced by EE2. Interestingly, when the antagonist was applied 30 min before the FST, it was able to cancel the actions of EE2 on immobility behavior, and had no effect on the actions of E2. Finally, when a subthreshold dose of 8-OH-DPAT was combined with a noneffective dose of either E2 or EE2, an antidepressant-like action was observed. The results support the notion that the 5-HT1A receptor is one of the mediators of the antidepressant-like action of E2, and could indirectly contribute to the one induced by EE2.

Chronic treatment with desipramine induces an estrous cycle-dependent anxiolytic-like action in the burying behavior, but not in the elevated plus-maze test.

The effect of chronic desipramine (DMI, 2.5 mg/kg x 21-26 days) treatment in female rats in two anxiety paradigms was assessed: the burying behavior (BB) and the elevated plus-maze (EPM) tests. In the BB test DMI produced a significant decrease in burying in ovariectomized rats, an effect considered as anxiolytic-like. In cycling females, DMI also reduced the cumulative BB most notably in proestrus rats. However, in diestrus rats no anxiolytic-like actions were observed. In addition, DMI increased BB latencies in proestrus and estrus rats. In the EPM test, DMI produced anxiolytic-like actions only in ovariectomized rats, while no significant actions were found in cycling females. Finally, the chronic treatment with DMI produced a general reduction in the ambulatory behavior of rats in all estrous cycle phases. Results are discussed on the basis of the differences between both anxiety paradigms and the probable relationship between the steroids secreted during proestrus and chronic DMI treatment.

Facilitating antidepressant-like actions of estrogens are mediated by 5-HT1A and estrogen receptors in the rat forced swimming test

Previous studies have shown that 17beta-estradiol (E2) induces antidepressant-like actions per se and potentiates those produced by fluoxetine (FLX) in the forced swimming test (FST). The aim of the present work was to explore the participation of serotonin 1A receptors (5-HT1A) and estrogen receptors (ERs) in the antidepressant-like actions of E2, FLX or their combination in the FST. Although all antidepressants reduce behavioral immobility, antidepressants that modulate serotonergic neurotransmission increase swimming behavior whereas those that modulate the catecholaminergic neurotransmission increase climbing behavior. Thus, using this animal model, it is possible to infer which neurotransmitter system is modulating the action of an antidepressant compound. Ovariectomized female Wistar rats were used in all experiments. In the first experiment, an effective dose of E2 (10 microg/rat, -48 h) was combined with several doses (0.5, 1.0 and 2 mg/kg) of RU 58668 (a pure ER antagonist) 48 h previous to the FST. The second experiment evaluated the action of (1 mg/kg, -48 h or -23, -5 and -1 h) WAY 100635 (5-HT1A receptor antagonist) on the antidepressant-like action of FLX (10 mg/kg, -23, -5 and -1 h). In the third experiment, the effect of RU 58668 (2 mg/kg, -48) or WAY 100635 (1 mg/kg, -48 h) on the antidepressant-like action of the combination of a sub-optimal dose of E2 (2.5 microg/rat, -48 h) plus a non-effective dose of FLX (2.5 mg/kg, -23,-5 and -1 h) was evaluated. The results showed that RU 58668, the antagonist to the ER, canceled the antidepressant-like action of E2 in a dose-dependent manner. The antagonist to the 5-HT1A receptor blocked the antidepressant action of FLX only when administered simultaneously with FLX, i.e. -23, -5 and -1 h before the FST. Finally, the administration of both RU 58668, and WAY100635 canceled the antidepressant-like action of the combination of E2/FLX. These results imply that both 5-HT1A receptors and ERs participate in the facilitating actions of E2 on the antidepressant-like action of FLX in the FST.

Participation of the lateral septal nuclei (LSN) in the antidepressant- like actions of progesterone in the forced swimming test (FST)

The possible participation of lateral septal nuclei (LSN) in the antidepressant-like actions of progesterone was evaluated. The effect of different concentrations of progesterone (0.001, 0.01 and 0.1 M) or saline solution injected directly into the LSN of ovariectomised rats was determined using the forced swimming test (FST). In addition, the temporal course of progesterone (0.1 M) antidepressant-like actions was compared with that of the classical antidepressant imipramine (0.1 M). Finally, in order to establish the possible participation of the GABA(A) receptor in the antidepressant-like action of progesterone, the effect of pre-treatment with the GABA(A) antagonist picrotoxin (0.125 mg/kg, i.p.) was evaluated. Intraseptally administered progesterone produced a concentration-dependent decrease in immobility behaviour but did not modify locomotor activity. These antidepressant-like actions lasted 4 h, while those of imipramine lasted 72 h. Finally, progesterone-induced anti-immobility effect could be blocked by the systemic injection of picrotoxin. Present results reveal that LSN play a role in the antidepressant-like actions of progesterone that appear to be mediated by the GABA(A) receptor.

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 α2 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.

Long-term ovariectomy modulates the antidepressant-like action of estrogens, but not of antidepressants

Controversial results related to effectiveness of estrogen replacement therapy (ERT) to alleviate depression are frequently reported. The discrepancies could be related to (a) time when ERT is initiated after the beginning of menopause and/or (b) type of estrogen used. Furthermore, estrogens modulate the antidepressant effect of different compounds; therefore, the effectiveness of antidepressant drugs could also depend on the menopausal status. The aim of the present study was to analyze whether the time after estrogen decline can influence antidepressant-like effects of two estrogens and/or two antidepressants. Thus, the antidepressant-like actions of 17β-estradiol (E2), 17α-ethynyl-estradiol (EE2), fluoxetine (FLX) and desipramine (DMI) were studied at different periods (1, 3 and 12 weeks) after ovariectomy (OVX), using the forced swimming test (FST). Results showed that OVX increased depressive-like behavior only 1 week after OVX. The antidepressant-like actions of E2, but not those of EE2, were cancelled 12 weeks after OVX. Conversely, antidepressant-like actions of FLX and DMI were observed at 1, 3 and 12 weeks after OVX. In conclusion, while the antidepressant-like effects of estrogens depended on the time at which treatment is initiated after OVX as well as on the estrogenic compound used, antidepressant-like effects of FLX and DMI were not blocked by OVX.

Environmental enrichment induces neuroplastic changes in middle age female BalbC mice and increases the hippocampal levels of BDNF, p-Akt and p-MAPK1/2

Hippocampus is one of the brain regions in which neuroplastic changes occur. Paradigms such as environmental enrichment (ENR) have been used to prevent or delay the neuroplastic changes of the hippocampus during aging. Here, we investigated the beneficial effects of ENR on dendritic spines and hippocampal neurogenesis in middle age Balb/c mice. ENR increased the number of dendritic spines, cell survival, and intermediate stages of the hippocampal neurodevelopment process. Also, ENR alters the distribution of cells involved in the neurogenic process along the dorsal-ventral dentate gyrus. In addition, ENR increased the proportion of cells with more mature dendritic morphology and net hippocampal neurogenesis. Whole-hippocampus protein extracts revealed that ENR increases the levels of BDNF, phospho-Akt and phospho-MAPK1/2, suggesting that the positive effects of ENR on neuroplasticity in middle age Balb/c mice involve the participation of these key-signaling proteins. Our results suggest that ENR is a relevant strategy to prevent neuroplastic decline by increasing the formation of both dendritic spines and new neurons in the hippocampus during middle age.