Increased limbic phosphorylated extracellular-regulated kinase 1 and 2 expression after chronic stress is reduced by cyclic 17beta-estradiol administration.

Chronic stress induced neuronal changes that may have consequences for subsequent stress responses. For example, chronic stress in rats rearranges dendritic branching patterns and disturbs the phosphorylation of extracellular-regulated kinase 1 and 2 (ERK) 1/2 throughout the limbic system. Stress-induced psychopathology occurs more often in women, however, most of studies have been done in male rats. Therefore, we studied the effect of stress in female rats. Other studies show that estradiol can modulate neuronal plasticity and might protect against stress-induced aberrations. To investigate the role of estradiol in stress responses we manipulated the hormone levels. Ovariectomized rats were cyclically treated with vehicle or with 17beta-estradiol-benzoate (1x in 4 days, 10 microg/250 g, s.c.) and subjected to either acute (3 days) or chronic (22 days) stress. In ovariectomized rats, the number of c-Fos positive cells in the infralimbic and prelimbic cortex of the prefrontal cortex and in the medial and basolateral amygdala was increased after acute stress. Moreover, acute stress reduced the number of phosphorylated ERK1/2 positive neurons in the prefrontal cortex of ovariectomized rats. Chronic stress, on the other hand, abolished normal patterns of c-Fos immunoreactivity in the prefrontal cortex and amygdala and increased the prefrontocortical phosphorylation of ERK1/2 in ovariectomized rats. Cyclic estradiol treatment preserved the neuronal reactivity in the infralimbic cortex after chronic stress and prevented sustained accumulation of phosphorylated ERK1/2. Therefore, cyclic estradiol administration apparently preserves the integrity of signal transduction cascades in limbic structures, which may protect against the harmful consequences of recurrent stress.

Unique patterns of FOS, phospho-CREB and BrdU immunoreactivity in the female rat brain following chronic stress and citalopram treatment.

Affective disorders are common psychiatric illnesses characterized by marked gender-related prevalence. Recent evidence links chronic stress and dysregulation of neurotrophin signaling with the development of depression, while novel theories suggest that antidepressants may act by promoting intracellular adaptations linked to neuroplasticity. Although selective serotonin reuptake inhibitors (SSRIs) efficaciously improve a variety of dysfunctions in males, their neuroendocrine effects and intracellular signaling patterns in females are not well determined. Here we show that chronic footshock stress (21 days) promotes HPA axis hyperactivity (as seen by the increased FOS-ir in the paraventricular hypothalamic nucleus (PVN), plasma corticosterone and adrenal hypertrophy), reduces hippocampal BrdU immunoreactivity and suppresses cortical-limbic CREB phosphorylation in female rats. Long-term citalopram treatment, in contrast, attenuates stress-induced elevation of corticosterone levels and adrenal hypertrophy, although it does not reverse footshock-mediated induction of FOS-ir in the PVN, inhibition of CREB phosphorylation and reduction of hippocampal BrdU-labeling. Moreover, citalopram administration was also associated with significant hypophagic effects and inhibition of CREB phosphorylation. These data suggest that, in female rats, normalization of chronic stress-induced HPA axis abnormalities may represent an initial phase of citalopram-mediated therapeutic actions and despite this SSRI's apparent lack of effects on neuroplasticity, we cannot exclude the possibility that some neurochemical adaptations occur in a later stage which may require more than 3 weeks of treatment to manifest.

Pair-housing of male and female rats during chronic stress exposure results in gender-specific behavioral responses.

UNLABELLED: Social support has a positive influence on the course of a depression and social housing of rats could provide an animal model for studying the neurobiological mechanisms of social support. Male and female rats were subjected to chronic footshock stress for 3 weeks and pair-housing of rats was used to mimic social support. Rats were isolated or housed with a partner of the opposite sex. A plastic tube was placed in each cage and subsequently used as a 'safe' area in an open field test. Time spent in the tube was used as a measurement of anxiety levels. Chronic stress increased adrenal weights in all groups, except for isolated females who showed adrenal hypertrophy in control conditions. In isolated males, chronic stress resulted in an increase in the time the animals spent in the tube. While stress did not affect this parameter in socially housed males, males with a stressed partner showed a similar response as isolated stressed males. Even though adrenal weights showed that isolated females were more affected by stress, after chronic stress exposure, they spent less time in the tube than socially housed females. Socially housed stressed females spent less time in the 'safe' tube compared to control counterparts, indicating that stress has a gender-specific behavioral effect. IN CONCLUSION: pair-housing had a stress-reducing effect on behavior in males. Isolation of females was stressful by itself. Pair housing of females was not able to prevent stress-induced behavioral changes completely, but appeared to reduce the effects of chronic stress.

Gender-specific effects of social housing on chronic stress-induced limbic Fos expression.

Stress plays an important role in the development of affective disorders. Women show a higher prevalence for these disorders then men. The course of a depressive episode is thought to be positively influenced by social support. We have used a chronic mild stress model in which rats received footshocks daily for 3 weeks. Since rats are social animals we hypothesised that social housing, as a possible model for human social support, might reduce the adverse effects of chronic stress. Brain activity after chronic stress was measured in several limbic brain areas with the neuronal activation marker c-fos. High behavioural activity due to housing rats under reversed light-dark conditions could be responsible for the observed high within group variability in some limbic regions. FOS- (ir) in the paraventricular nucleus of the hypothalamus (PVN) was increased in all stress-exposed groups, except for the socially housed females who showed increased FOS-ir in control condition. Individually housed males and socially housed females showed increased FOS-ir in the dorsal raphe (DRN). Amygdala nuclei were differentially affected by stress, gender and housing conditions. Also the mesolimbic dopaminergic system showed gender specific responses to stress and housing conditions. These results indicate that social support can enhance stress coping in female rats, whereas in males rats, group housing appears to increase the adverse effects of chronic stress, although the neurobiological mechanism is not simply a reduction or enhancement of stress-induced brain activation.

Bromodeoxyuridine and methylazoxymethanol exposure during brain development affects behavior in rats: consideration for a role of nerve growth factor and brain derived neurotrophic factor.

Rats prenatally exposed to the neurotoxins methylazoxymethanol (MAM) or 5-Bromo-2'-deoxyuridine (BrdU) are used as animal models of brain maldevelopment. We administered in rats MAM (20 mg/kg), or BrdU (100 mg/kg) or both at gestational day 11. Locomotion was not affected by any prenatal treatment whereas learning was delayed in the Morris maze in MAM animals. BrdU induced decreased NGF and BDNF levels in the hippocampus. In the parietal cortex prenatal BrdU administration induced NGF potentation associated with decreased BDNF. Animals treated with both MAM and BrdU showed also an increased immunopositivity for choline acetyltransferase (ChAT) and low affinity neurotrophins' receptor (p75) in the septum and Meynert's nuclei. These findings suggest that embryonic exposure to MAM and/or BrdU may be useful for studying mechanisms associated with neurodegenerative diseases affecting brain morphology and behavior.

Incidence of arrhythmias and heart rate variability in wild-type rats exposed to social stress.

Psychological stressors of different natures can induce different shifts of autonomic control on cardiac electrical activity, with either a sympathetic or a parasympathetic prevalence. Arrhythmia occurrence, R-R interval variability, and plasma catecholamine elevations were measured in male wild-type rats exposed to either a social stressor (defeat) or a nonsocial challenge (restraint). Electrocardiograms were telemetrically recorded, and blood samples were withdrawn through jugular vein catheters from normal, freely moving animals. Defeat produced a much higher incidence of arrhythmias (mostly ventricular premature beats), which were mainly observed in the 60-s time periods after attacks. The social challenge also induced a much stronger reduction of average R-R interval, a lower R-R interval variability (as estimated by the time-domain parameters standard deviation of mean R-R interval duration, coefficient of variance, and root mean square of successive differences in R-R interval duration), and higher elevations of venous plasma catecholamines compared with restraint. These autonomic and/or neuroendocrine data indicate that a social stressor such as defeat is characterized by both a higher sympathetic activation and a lower parasympathetic antagonism compared with a nonsocial restraint challenge, which results in a higher risk for ventricular arrhythmias.