Cyclic estradiol replacement attenuates stress-induced c-Fos expression in the PVN of ovariectomized rats.

Estradiol modulates stress reactions in female rats. Several studies showed anxiolytic effects of estradiol in behavioral tests, but the underlying mechanisms are still unclear. The aim of the current study was to explore how estradiol-treated rats respond to acute and chronic stress compared to ovariectomized rats. Ovariectomized rats received vehicle or 17beta-estradiol injections (10 microg/250 g) once every 4 days, which induced alternating high and low plasma 17beta-estradiol levels. Stress was presented by daily exposure to an adverse environment in which the animals received five footshocks for either 3 or 22 days. Under control conditions no differences were observed, but as soon as stress was applied, reactions of ovariectomized and estradiol-treated rats diverged. Both acute and chronic stress increased the c-Fos protein expression in the paraventricular nucleus (PVN) of the hypothalamus. Cyclic estradiol treatment reduced this stress-induced activation of the PVN, an effect that seems to be dependent on the plasma estradiol levels. No differences in stress-induced corticosterone responses were revealed between the treatment groups. An increase in the number of ERbeta-expressing cells in the PVN of ovariectomized and estradiol-treated rats during chronic stress implied increased ERbeta-mediated mechanisms during these conditions. The dampening effect of estradiol on the excessive stress-induced activity in the PVN may be beneficial for the animal in its response to chronic recurrent stress by reducing the output of the PVN.

Future antidepressants: what is in the pipeline and what is missing?

Monoamine reuptake inhibitors still reign in the treatment of major depression, but possibly not for long. While medicinal chemists have been able to reduce the side effects of these drugs, their delayed onset of action and considerable non-response rate remain problematic. Of late, serious questions have been raised regarding the efficacy of monoamine reuptake inhibitors. The present review presents an inventory of what is (and until recently was) in the antidepressant pipeline of pharmaceutical companies. Novel antidepressant compounds can be categorised into four groups depending on their target(s): (i) monoamine receptors; (ii) non-monoamine receptors; (iii) neuropeptide receptors; and (iv) hormone receptors. Other possible targets include components of post-receptor intracellular processes and elements of the immune system; to date, however, compounds specifically aimed at these targets have not been the subject of clinical trials. Development of several compounds targeted at monoamine receptors has recently been discontinued. At least five neurokinin-1 (NK(1)) receptor antagonists were until recently in phase II of clinical testing. However, the apparent interest in the NK(1) receptor should not be interpreted as representing a departure from the monoamine hypothesis since neurokinins also modulate monoaminergic systems. In the authors' view, development of future antidepressants will continue to rely on the serendipity-based monoamine hypothesis. However, an alternative approach, based on the hypothesis that chronic stress precipitates depressive symptoms, might be more productive. Unfortunately, clinical results using drugs targeted at components of the HPA axis have not been very encouraging to date. In the short run, the authors believe that augmentation strategies offer the best hope for improving the efficacy of antidepressant treatment. Several approaches to improve the efficacy of SSRIs are conceivable, such as concurrent blockade of monoamine autoreceptors and the addition of antipsychotics, neuromodulators or hormones (HPA axis and gender related). In the long-term, however, construction of a scientifically verified conceptual framework will be needed before more effective antidepressants can be developed. It can be argued that it is not depression itself that should be treated, but rather that its duration should be reduced by pharmacological means. Animal models that take this concept into consideration and identify mechanisms for acceleration of recovery from the effects of stress need to be developed.

The effect of n-3 polyunsaturated fatty acid-rich diets on cognitive and cerebrovascular parameters in chronic cerebral hypoperfusion.

Western diets consist to a large part of n-6 polyunsaturated fatty acids (PUFAs). These n-6 PUFAs and their conversion products favor immune and inflammatory reactions and compromise vasoregulation, which can contribute to the development of dementia. Recent epidemiological studies associated dementia, particularly the type accompanied by a vascular component, with high, saturated dietary fat intake. Conversely, high fish consumption (a source of long chain n-3 PUFAs) was related to a reduced risk for cognitive decline. Therefore we studied the effects of long chain n-3 PUFAs in rats with bilateral occlusion of the common carotid arteries (2VO), which mimics cerebral hypoperfusion, a risk factor for dementia. Male Wistar rats received experimental diets with a decreased (n-6)/(n-3) ratio from weaning on. At the age of 3 months, the animals underwent 2VO surgery. The rats were tested in the elevated plus maze, an active avoidance paradigm and the Morris water maze (at different survival times). Following behavioral testing, the animals were sacrificed at the age of 7 months. The frontoparietal cortex was analyzed for capillary ultrastructure with electron microscopy. No effects of cerebral hypoperfusion or diet were found on elevated plus maze and active avoidance, while spatial memory in the Morris maze was compromised due to cerebral hypoperfusion under placebo dietary conditions. n-3 PUFA supplementation in combination with extra additives improved the performance of the 2VO animals. The number of endothelial mitochondria, as well as the ratio of microvessels with degenerative pericytes appeared to be lower due to long chain n-3 PUFAs. These results may indicate an improved condition of the blood-brain barrier.

Increased stress vulnerability after a prefrontal cortex lesion in female rats.

Neuroimaging studies in patients suffering from affective disorders have shown decreased volume and reduced regional cerebral blood flow in multiple areas of the prefrontal cortex, including the medial prefrontal cortex and the orbitofrontal cortex. This aberrant brain activity is among other things attributed to chronic stress. Affective disorders occur more often in women than in men. In the current experiment, female mPFC-lesioned and non-lesioned rats were subjected to 3 weeks of chronic unpredictable stress in order to determine the role of the mPFC in dealing with chronic stress, and the consequences of mPFC damage for coping with consecutive stressful events. mPFC damage in female rats intensified the stress-induced activation of the dorsomedial nucleus of the hypothalamus and the paraventricular nucleus of the hypothalamus as measured with Fos expression changes and markedly increased plasma catecholamine levels after 3 weeks of unpredictable stress. Additionally, an mPFC lesion significantly reduced the time of appearance of stress-induced behavioral changes in the open field. Altogether, mPFC dysfunction affects the way female rats react to chronic stress, it not only increased the activation of brain regions involved in neuroendocrine and autonomic responses to stress but it also significantly reduced the time of onset of behavioral changes.

Sex differences in stress responses: focus on ovarian hormones.

Women in the reproductive age are more vulnerable to develop affective disorders than men. This difference may attribute to anatomical differences, hormonal influences and environmental factors such as stress. However, the higher prevalence in women normalizes once menopause is established, suggesting that ovarian hormones may play an important role in the development of depression in women. Ovarian hormones such as estrogen can pass the brain-blood barrier and bind to cytoplasmatic estrogen receptor (ER)-alpha and ER-beta in different areas of the limbic system. During stress, estrogen can modulate the behavioral and neurobiological response depending on the concentrations of estrogen. In this review we present evidence for disparate effects of chronic stress on neuroplasticity and brain activity in male and female rats. Furthermore, we will demonstrate that effects of social support on coping with stress can be mimicked by social housing of rats and that this model can be used for identification of underlying neurobiological mechanisms, including behavior, phosphorylation of CREB and ERK1/2, and brain activity changes as measured with fos expression. Using cyclic administration of estrogen in ovariectomized female rats we could specifically address effects of different plasma estrogen levels and antidepressants on stress-induced neuroplasticity and activity changes. In this model we also studied effects of estrogen on recovery after chronic stress. We conclude that the female brain has a different innate strategy to handle stress than the male brain and that female animal models are necessary for studying the underlying mechanisms and options for treatment.

Stress-induced sensitization of the limbic system in ovariectomized rats is partly restored by cyclic 17beta-estradiol administration.

Chronic stress induces neurobiological alterations which have consequences for subsequent stress handling. In the current experiment, ovariectomized rats were subjected daily to a stressor for 21 days. Thereafter, the rats were treated for 21 days with 17beta-estradiol benzoate (10 microg/250 g, once every 4 days) or mirtazapine (10 mg/kg, daily). In this way, we were able to evaluate the ability of these compounds to reverse chronic stress-induced changes in the activity of the limbic system. After 21 days of recovery and treatment, the rats were re-exposed to the adverse environment of the initial stressor and perfused 2 h later. Ovariectomized rats displayed increased numbers of c-Fos-positive nuclei, after re-exposure to the stressor, in the paraventricular nucleus of the hypothalamus, dentate gyrus, medial prefrontal cortex and central and medial amygdala. Cyclic estradiol treatment attenuated the sensitization of the paraventricular nucleus and central amygdala. Mirtazapine increased the number of c-Fos-positive nuclei in the central amygdala and dentate gyrus. Long-term transcriptional changes induced by chronic stress were determined with DeltaFosB immunoreactivity. The medial prefrontal cortex showed an increased number of DeltaFosB-positive nuclei after chronic stress and this was not affected by estradiol or mirtazapine administration during recovery. In conclusion, cyclic estradiol administration reversed chronic stress-induced sensitization in the limbic system, the paraventricular nucleus and central amygdala of female rats, output regions of the limbic system involved in fear responses. Mirtazapine did not achieve this reversal of stress-induced aberrations in the limbic system after 21 days of treatment.