Chronic agomelatine treatment corrects the abnormalities in the circadian rhythm of motor activity and sleep/wake cycle induced by prenatal restraint stress in adult rats.

Agomelatine is a novel antidepressant acting as an MT1/MT2 melatonin receptor agonist/5-HT2C serotonin receptor antagonist. Because of its peculiar pharmacological profile, this drug caters the potential to correct the abnormalities of circadian rhythms associated with mood disorders, including abnormalities of the sleep/wake cycle. Here, we examined the effect of chronic agomelatine treatment on sleep architecture and circadian rhythms of motor activity using the rat model of prenatal restraint stress (PRS) as a putative 'aetiological' model of depression. PRS was delivered to the mothers during the last 10 d of pregnancy. The adult progeny ('PRS rats') showed a reduced duration of slow wave sleep, an increased duration of rapid eye movement (REM) sleep, an increased number of REM sleep events and an increase in motor activity before the beginning of the dark phase of the light/dark cycle. In addition, adult PRS rats showed an increased expression of the transcript of the primary response gene, c-Fos, in the hippocampus just prior to the beginning of the dark phase. All these changes were reversed by a chronic oral treatment with agomelatine (2000 ppm in the diet). The effect of agomelatine on sleep was largely attenuated by treatment with the MT1/MT2 melatonin receptor antagonist, S22153, which caused PRS-like sleep disturbances on its own. These data provide the first evidence that agomelatine corrects sleep architecture and restores circadian homeostasis in a preclinical model of depression and supports the value of agomelatine as a novel antidepressant that resynchronizes circadian rhythms under pathological conditions.

Prenatal restraint stress generates two distinct behavioral and neurochemical profiles in male and female rats.

Prenatal Restraint Stress (PRS) in rats is a validated model of early stress resulting in permanent behavioral and neurobiological outcomes. Although sexual dimorphism in the effects of PRS has been hypothesized for more than 30 years, few studies in this long period have directly addressed the issue. Our group has uncovered a pronounced gender difference in the effects of PRS (stress delivered to the mothers 3 times per day during the last 10 days of pregnancy) on anxiety, spatial learning, and a series of neurobiological parameters classically associated with hippocampus-dependent behaviors. Adult male rats subjected to PRS ("PRS rats") showed increased anxiety-like behavior in the elevated plus maze (EPM), a reduction in the survival of newborn cells in the dentate gyrus, a reduction in the activity of mGlu1/5 metabotropic glutamate receptors in the ventral hippocampus, and an increase in the levels of brain-derived neurotrophic factor (BDNF) and pro-BDNF in the hippocampus. In contrast, female PRS rats displayed reduced anxiety in the EPM, improved learning in the Morris water maze, an increase in the activity of mGlu1/5 receptors in the ventral and dorsal hippocampus, and no changes in hippocampal neurogenesis or BDNF levels. The direction of the changes in neurogenesis, BDNF levels and mGlu receptor function in PRS animals was not consistent with the behavioral changes, suggesting that PRS perturbs the interdependency of these particular parameters and their relation to hippocampus-dependent behavior. Our data suggest that the epigenetic changes in hippocampal neuroplasticity induced by early environmental challenges are critically sex-dependent and that the behavioral outcome may diverge in males and females.

Prenatal stress alters the negative correlation between neuronal activation in limbic regions and behavioral responses in rats exposed to high and low anxiogenic environments.

Behavioral adaptation to an anxiogenic environment involves the activity of various interconnected limbic regions, such as the amygdala, hippocampus and prefrontal cortex. Prenatal stress (PS) in rats affects the ability to cope with environmental challenges and alters brain plasticity, leading to long-lasting behavioral and neurobiological alterations. We examined in PS and control animals whether behavioral reactivity was correlated to neuronal activation by assessing Fos protein expression in limbic regions of rats exposed to a low or high anxiogenic environment (the closed and open arms of an elevated plus maze, respectively). A negative correlation was found between behavioral and neuronal activation, with a lower behavioral reactivity and a higher neuronal response observed in rats exposed to the more anxiogenic environment (the open arm) with respect to the less anxiogenic environment (the closed arm). Interestingly, the variation in the neurobehavioral response between the two arms of the maze was less pronounced in rats that had been subjected to PS. This study provides a remarkable example of how long-lasting changes in brain plasticity induced by PS affect the ability of limbic neurons to cope with anxiogenic stimuli of different strength.

Prenatal stress alters Fos protein expression in hippocampus and locus coeruleus stress-related brain structures.

Prenatal stress (PS) durably influences responses of rats from birth throughout life by inducing deficits of the hypothalamo-pituitary-adrenal (HPA) axis feedback. The neuronal mechanisms sustaining such alterations are still unknown. The purpose of the present study was to determine whether in PS and control rats, the exposure to a mild stressor differentially induces Fos protein in hippocampus and locus coeruleus, brain areas involved in the feedback control of the HPA axis. Moreover, Fos protein expression was also evaluated in the hypothalamic paraventricular nucleus (PVN) that reflect the magnitude of the hormonal response to stress. Basal plasma corticosterone levels were not different between the groups, while, PS rats exhibited higher number of Fos-immunoreactive neurons than controls, in the hippocampus and locus coeruleus in basal condition. A higher basal expression of a marker of GABAergic synapses, the vGAT, was also observed in the hypothalamus of PS rats. Fifteen minutes after the end of the exposure to the open arm of the elevated plus-maze (mild stress) a similar increased plasma corticosterone levels was observed in both groups in parallel with an increased number of Fos-immunoreactive neurons in the PVN. Return to basal plasma corticosterone values was delayed only in the PS rats. On the contrary, after stress, no changes in Fos-immunoreactivity were observed in the hippocampus and locus coeruleus of PS rats compared to basal condition. After stress, only PS rats presented an elevation of the number of activated catecholaminergic neurons in the locus coeruleus. In conclusion, these results suggest for the first time that PS alters the neuronal activation of hippocampus and locus coeruleus implicated in the feedback mechanism of the HPA axis. These data give anatomical substrates to sustain the HPA axis hyperactivity classically described in PS rats after stress exposure.

Inhibition of COX-2 reduces the age-dependent increase of hippocampal inflammatory markers, corticosterone secretion, and behavioral impairments in the rat.

Brain aging as well as brain degenerative processes with accompanying cognitive impairments are generally associated with hyperactivity of the hypothalamus-pituitary-adrenal axis, the end product of which, the glucocorticoid hormone, has been warranted the role of cell damage primum movens ("cascade hypothesis"). However, chronic inflammatory activity occurs in the hippocampus of aged rats as well as in the brain of Alzheimer's disease patients. The concomitant increase in the secretion of the glucocorticoid hormone, the endogenous anti-inflammatory and pro-inflammatory markers, has prompted us to investigate the two phenomena in the aging rat, and to work out its meaning. This study shows that: (I) interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and prostaglandin E(2) (PGE(2)) increase with age in the rats hippocampus, and (II) chronic oral treatment with celecoxib, a selective cycloxygenase-2 (COX-2) inhibitor, is able to contrast the age-dependent increase in hippocampal levels of pro-inflammatory markers and circulating anti-inflammatory corticosterone, provided that it is started at an early stage of aging. Under these conditions, age-related impairments in cognitive ability may be ameliorated. Taken together, these results indicate that there is a natural tendency to offset the age-dependent increase in brain inflammatory processes via the homeostatic increase of the circulating glucocorticoid hormone.