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Perinatal hypoxia causes long-term neurobiological consequences, including alterations in mechanisms of activity-dependent synaptic plasticity and cognitive dysfunction. Changes in neurotransmitter receptors have been associated with these alterations, but little is known on how early hypoxia influences the expression and function of metabotropic glutamate (mGlu) receptors in adult life. This is an important issue because mGlu receptors are implicated in mechanisms of synaptic plasticity. Here, we examined the expression of mGlu1, mGlu5, and mGlu2/3 receptor subtypes in the hippocampus, nucleus accumbens, prefrontal cortex, and dorsal striatum in 6-month old Wistar rats (a) born by vaginal delivery; (b) born by caesarean section; and (c) born by caesarean section followed by 20 min of asphyxia. Unexpectedly, we found a large reduction of mGlu1α protein levels in the hippocampus of rats born by caesarean section regardless of the presence of asphyxia. No changes in mGlu1α receptor protein levels were found in the other brain regions. Levels of mGlu5 and mGlu2/3 receptors and levels of GluA2/3 and GluN1 subunits of AMPA and NMDA receptors did not differ among the three groups of rats in any brain region. These results are consistent with previous findings showing that changes in mGlu1 receptors occur within the epigenetic programming caused by early-life events. more...

Knowledge of animals’ hormonal status is important for conservation studies in wild or semi-free-ranging conditions as well as for behavioural and clinical experiments conducted in laboratory research, mostly performed on rats and mice. Faecal sampling is a useful non-invasive method to obtain steroid hormone assessments. Nevertheless, in laboratory studies, unlike other contexts, faecal sampling is less utilised. One of the issues raised is the necessity to collect samples belonging to different animals, separately. Usually, researchers using faecal sampling solve this problem through the isolation of animals or taking the cage rather than single animal as unit of study. These solutions though, could lead to unreliable measurements, and cannot be applied in many studies. Our aim was to show the biological reliability of individual faecal corticosterone metabolite (FCM) assessments in socially housed male and female Wistar rats. We analytically validated the enzyme immunoassay kit used for FCM assessments. Then, we exposed the animals to two different stress stimuli that are known to activate the hypothalamus–pituitary–adrenal axis and the following release of corticosterone to biologically validate the EIA kit: environmental enrichment and predator odour. Individual faecal sampling from social animals was collected through short-time handling. The results demonstrated that both the stimuli increased FCM levels in male and female rats showing the reliability of EIA kit assessment and the applicability of our sampling method. We also found a diurnal rhythm in FCM levels. These results could help to increase the use of faecal hormone metabolite determinations in studies conducted on rats. more...

Alzheimer’s disease is the most common neurodegenerative disorder characterized by the presence of β-amyloid aggregates deposited as senile plaques and by the presence of neurofibrillary tangles of tau protein. To date, there is a broad consensus on the idea that neuroinflammation is one of the most important component in Alzheimer’s disease pathogenesis. Chemokines and their receptors, beside the well-known role in the immune system, are widely expressed in the nervous system, where they play a significant role in the neuroinflammatory processes. Prokineticins are a new family of chemokine-like molecules involved in numerous physiological and pathological processes including immunity, pain, inflammation, and neuroinflammation. Prokineticin 2 (PROK2) and its receptors PKR1 and PKR2 are widely expressed in the central nervous system in both neuronal and glial cells. In Alzheimer’s disease, PROK2 sustains the neuroinflammatory condition and contributes to neurotoxicity, since its expression is strongly upregulated by amyloid-β peptide and reversed by the PKR antagonist PC1. This review aims to summarize the current knowledge on the neurotoxic and/or neuroprotective function of chemokines in Alzheimer’s disease, focusing on the prokineticin system: it represents a new field of investigation that can stimulate the research of innovative pharmacotherapeutic strategies. more...

Vortioxetine is a multimodal antidepressant that potently antagonizes 5-HT3 serotonin receptors, inhibits the high-affinity serotonin transporter, activates 5-HT1A and 5-HT1B receptors, and antagonizes 5-HT1D and 5-HT7 receptors. 5-HT3 receptors largely mediate the hyperalgesic activity of serotonin that occurs in response to nerve injury. Activation of 5-HT3 receptors contributes to explain why selective serotonin reuptake inhibitors, such as fluoxetine, are not indicated in the treatment of neuropathic pain. Here, we studied the analgesic action of vortioxetine in the chronic constriction injury model of neuropathic pain in mice. Vortioxetine was injected once a day for 27 days at doses (10 mg/kg, intraperitoneally) that determine >90% 5-HT3 receptor occupancy in the central nervous system. The action of vortioxetine was compared to the action of equal doses of the serotonin-noradrenaline reuptake inhibitor, venlafaxine (one of the gold standard drugs in the treatment of neuropathic pain), and fluoxetine. Vortioxetine caused a robust analgesia in chronic constriction injury mice, and its effect was identical to that produced by venlafaxine. In contrast, fluoxetine was inactive in chronic constriction injury mice. Vortioxetine enhanced mechanical pain thresholds in chronic constriction injury mice without changing motor activity, as assessed by the open-field and horizontal bar tests. None of the three antidepressants caused analgesia in the complete Freund's adjuvant model of chronic inflammatory pain. These findings raise the attractive possibility that vortioxetine can be effective in the treatment of neuropathic pain, particularly in patients with comorbid depression and cognitive dysfunction. more...

The behavioral and physiological traits of an individual are strongly influenced by early life events. One of the major systems implicated in the responses to environmental manipulations and stress is the hypothalamus-pituitary-adrenal (HPA) axis. Glucocorticoid hormones (cortisol in humans and corticosterone in rodents) represent the final step in the activation of the HPA system and play an important role in the effects induced by the perinatal environment. We demonstrated, in rats with some differences between males and females, that mothers whose drinking water was supplemented with moderate doses of corticosterone throughout the lactation period, give birth to offspring better able to meet the demands of the environment. The progeny of these mothers, as adults, show improved learning capabilities, reduced fearfulness in anxiogenic situations, lower metabotropic glutamate receptors and higher glucocorticoid receptors in the hippocampus with a persistent hyporeactivity of the HPA axis leading to a resistance to ischemic neuronal damage. Other studies performed in mice showed that low doses of corticosterone in the maternal drinking water, which, as in our rat model, may reflect a form of mild environmental stimulation, enhanced the offspring's ability to cope with different situations, while elevated doses, comparable to those elicited by strong stressors, caused developmental disruption. Significantly, adult rats and mice that had been nursed by mothers with a mild hypercorticosteronemia provide an example of how a moderate corticosterone increase mediates the salutary effects of some events occurring early in life. Both maternal and infantile plasma levels of the hormone may play a role in these effects, the first influencing maternal behavior, the second acting directly on the central nervous system of the developing rat. more...

Anoxia in the first week of life can induce neuronal death in vulnerable brain regions usually associated with an impairment of cognitive function that can be detected later in life. We set-up a model of subneurotoxic anoxia based on repeated exposures to 100% nitrogen during the first 7 days of post-natal life. This mild post-natal exposure to anoxia specifically modified the behaviour of the male adult rats, which showed an attention deficit and an increase in anxiety, without any impairment in spatial learning and any detectable brain damage (magnetic resonance imaging and histological analysis). Post-anoxic rats showed a reduction in the expression of group-I metabotropic glutamate receptors (i.e. mGlu1 and mGlu5 receptors) in the hippocampus and cerebral cortex, whereas expression of the mGlu 2/3 receptors, the NR1 subunit of NMDA receptors, and the GluR1 subunit of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors was unchanged. mGlu1 and mGlu5 receptor signalling was also impaired in postanoxic rats, as revealed by a reduced efficacy of the agonist (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) to stimulate polyphosphoinositide hydrolysis in hippocampal slices. We conclude that rats subjected to subneurotoxic doses of anoxia during the early post-natal life develop behavioural symptoms that are frequently encountered in the inattentive subtype of the attention deficit hyperactivity disorder, and that group-I mGlu receptors may be involved in the pathophysiology of these symptoms. more...

Following the hypothesis of the “signal-to-noise” ratio (Riedel, 1996) we examined whether changes in the activity of group-I metabotropic glutamate (mGlu) receptors in the hippocampus are associated with a condition that specifically enhances the learning capacity in rats. As a model, we used rats that had been nursed by mothers drinking a solution of corticosterone (13.5 mg of daily intake of corticosterone hemisuccinate) during the lactation period. These rats were prone to learn, as indicated by a better performance in a passive avoidance test. Stimulation of polyphosphoinositide (PI) hydrolysis by the mGlu receptor agonist, 1S,3R-1-amino-cyclopentan-1,3-dicarboxylic acid (1S,3R-ACPD), was attenuated in hippocampal slices prepared from corticosterone-nursed male and female rats at 30 or 60 days of postnatal life, an age at which an increased learning capacity could be demonstrated. This effect was specific because the PI response to carbamylcholine was unchanged. A reduced PI hydrolysis in corticosterone-nursed rats was also observed when group-I mGlu receptors (i.e. mGlu1 and -5 receptors) were selectively activated using 3,5-dihydroxyphenylglycine or 1S,3R-APCD combined with the selective group-II mGlu receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)propionate. Western blot analysis showed a selective reduction in the expression of mGlu1a receptor protein in the hippocampus of corticosterone-nursed rats, whereas expression of mGlu5 and mGlu2/3 receptors was unchanged. The reduction in mGlu-receptor mediated PI hydrolysis in the hippocampus may contribute to the greater learning capacity of corticosterone-nursed rats by reducing the background noise over which a specific signal must be superimposed during learning. This hypothesis was supported by the evidence that mGlu-receptor stimulated PI hydrolysis was amplified in hippocampal slices from rats subjected to a passive avoidance learning paradigm, and that this amplification was greater in slices from corticosterone-nursed rats of both sexes. more...

The beneficial effects of Environmental Enrichment (EE) applied immediately after weaning or even in adulthood have been widely demonstrated. Less is known about the possible changes in behaviour and brain development of the progeny following the exposure of dams to EE. In order to further investigate this matter, female rats were reared in EE for 12 weeks, from weaning until delivery. After having confirmed the presence of relevant behavioural effects of EE, both control and EE females underwent mating. Maternal behaviour was observed and male and female offspring were then administered a battery of behavioural test at different ages. EE mothers showed a decreased frequency of total nursing and, during the first 2 days of lactation, an increase in licking/grooming behaviour. Maternal exposure to EE affected offspring behaviour in a sex-specific manner: social play behaviour and anxiety-like behaviour were increased in males but not in females and learning ability was improved only in females. As a general trend, maternal EE had a marked influence on motility in male and female offspring in both locomotor activity and swimming speed. Overall, this study highlights the importance of environmental stimulation, not only in the animals directly experiencing EE, but for their progeny too, opening the way to new hypothesis on the heritability mechanisms of behavioural traits. more...

In infancy, glucocorticoids have been shown to affect hypothalamus–pituitary–adrenal (HPA) axis activity and behavior. Both the activity of the HPA axis and many aspects of behavior exhibit important gender-dependent differences physiologically. In our previous studies, male offspring of hypercorticosteronemic mothers show long-lasting changes of learning as well as adrenocortical activity. In the light of these findings, this study aims to determine the long-term effects of glucocorticoids in the early stages of life in female rats. Corticosterone (200 μg/ml) was added to the drinking water of the dams. Female offspring exhibited lower adrenocortical secretory response to stress, improvement in learning (water maze at 21, 30 and 90 days; active avoidance at 15 months) and reduced fearfulness in anxiogenic situations (dark–light test at 1 and 15 months; conditioned suppression of drinking at 3 months; plus maze at 15 months) after weaning, from 21 days up to 15 months of age, but not before. No difference in hippocampal adrenocorticoid receptors was observed. These results, together with previous data on male offspring, show that the outcomes of maternal hypercorticosteronemia on hormonal stress response and behavior are similar in males and females, but the effects on some aspects of the HPA axis activity are gender-dependent. Possible explanations for these differences are discussed. more...

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. more...

The long-term consequences of a physiological-range increase of maternal corticosterone during lactation were investigated on the 15-month-old progeny. The offspring of rats drinking water supplemented with corticosterone (200 μg/ml of corticosterone hemisuccinate) from day 1 postpartum to weaning exhibited: (i) better performance in a conditioned learning test; (ii) reduction of fearfulness in two conflict situations; (iii) lower stress-induced corticosterone secretion and (iv) higher number of corticosteroid receptors in the hippocampus. The results of this study show that the effects of maternal physiological-range hypercorticosteronemia during lactation are lifelong. Moreover, these data suggest that corticosteroids, secreted during neonatal life, may constitute a factor directing the neurobiological development of the infant. In line with this hypothesis, glucocorticoid-induced early events have consequences on the behavioral and physiological status of adulthood. These consequences may be either “beneficial” or “detrimental” depending on the plasma levels of corticosterone induced by the early life occurrences, as well as on the kind of the stimulus and the developmental stage at which the neonate experiences the event. The present study demonstrates that, when the increase of corticosterone in infancy is moderate, the adult rats show reduced anxiety, improved learning and a better coping strategy to deal with stressful situations. more...

International audience; Opposing emotional events (negative/trauma or positive/maternal care) during the postnatal period may differentially influence vulnerability to the effects of stress later in life. The development and course of intestinal disorders such as inflammatory bowel disease are negatively affected by persistent stress, but to date the role of positive life events on these pathologies has been entirely unknown. In the present study, the effect of early life beneficial experiences in the development of intestinal dysfunctions, where inflammation and stress stimuli play a primary role, was investigated. As a "positive'' experimental model we used adult male rat progeny nursed by mothers whose drinking water was supplemented with moderate doses of corticosterone (CORT) (0.2 mg/ml) during the lactation period. Such animals have been generally shown to cope better with different environmental situations during life. The susceptibility to inflammatory experimental colitis induced by intracolonic infusion of TNBS (2,4,6-trinitrobenzenesulphonic acid) was investigated in CORT-nursed rats in comparison with control rats. This mild increase in maternal corticosterone during lactation induced, in CORT-nursed rats, a long lasting protective effect on TNBS-colitis, characterized by improvements in some indices of the disease (increased colonic myeloperoxidase activity, loss of body weight and food intake) and by the involvement of endogenous peripheral pathways known to participate in intestinal disorder development (lower plasma corticosterone levels and colonic mast cell degranulation, alterations in the colonic expression of both corticotrophin releasing factor/CRF and its receptor/CRH-1R). All these findings contribute to suggesting that the reduced vulnerability to TNBS-colitis in CORT-nursed rats is due to recovery from the colonic mucosal barrier dysfunction. Such long lasting changes induced by mild hormonal manipulation during lactation, making the adult also better adapted to colonic inflammatory stress, constitute a useful experimental model to investigate the etiopathogenetic mechanisms and therapeutic treatments of some gastrointestinal diseases. more...

Maternal-fetal HIV-1 transmission can be prevented by administration of AZT, alone or in combination with other antiretroviral drugs to pregnant HIV-1-infected women and their newborns. In spite of the benefits deriving from this life-saving prophylactic therapy, there is still considerable uncertainty on the potential long-term adverse effects of antiretroviral drugs on exposed children. Clinical and experimental studies have consistently shown the occurrence of mitochondrial dysfunction and increased oxidative stress following prenatal treatment with antiretroviral drugs, and clinical evidence suggests that the developing brain is one of the targets of the toxic action of these compounds possibly resulting in behavioral problems. We intended to verify the effects on brain and behavior of mice exposed during gestation to AZT, the backbone of antiretroviral therapy during human pregnancy. We hypothesized that glutamate, a neurotransmitter involved in excitotoxicity and behavioral plasticity, could be one of the major actors in AZT-induced neurochemical and behavioral alterations. We also assessed the antioxidant and neuroprotective effect of L-acetylcarnitine, a compound that improves mitochondrial function and is successfully used to treat antiretroviral-induced polyneuropathy in HIV-1 patients. We found that transplacental exposure to AZT given per os to pregnant mice from day 10 of pregnancy to delivery impaired in the adult offspring spatial learning and memory, enhanced corticosterone release in response to acute stress, increased brain oxidative stress also at birth and markedly reduced expression of mGluR1 and mGluR5 subtypes and GluR1 subunit of AMPA receptors in the hippocampus. Notably, administration during the entire pregnancy of L-acetylcarnitine was effective in preventing/ameliorating the neurochemical, neuroendocrine and behavioral adverse effects induced by AZT in the offspring. The present preclinical findings provide a mechanistic hypothesis for the neurobehavioral effects of AZT and strongly suggest that preventive administration of L-acetylcarnitine might be effective in reducing the neurological side-effects of antiretroviral therapy in fetus/newborn. more...

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. more...

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. more...

U87MG human glioma cells in cultures expressed metabotropic glutamate (mGlu) receptors mGlu2 and mGlu3. Addition of the mGlu2/3 receptor antagonist LY341495 to the cultures reduced cell growth, expression of cyclin D1/2, and activation of the MAP kinase and phosphatidylinositol-3-kinase pathways. This is in line with the evidence that activation of mGlu2/3 receptors sustains glioma cell proliferation. U87MG cells were either implanted under the skin (1x10(6) cells/0.5 ml) or infused into the caudate nucleus (0.5x10(6) cells/5 microl) of nude mice. Animals were treated for 28 days with mGlu receptor antagonists by means of subcutaneous osmotic minipumps. Treatments with LY341495 or (2S)-alpha-ethylglutamate (both infused at a rate of 1 mg/kg per day) reduced the size of tumors growing under the skin. Infusion of LY341495 (10 mg/kg per day) also reduced the growth of brain tumors, as assessed by magnetic resonance imaging analysis carried out every seven days. The effect of drug treatment was particularly evident during the exponential phase of tumor growth, that is, between the third and the fourth week following cell implantation. Immunohistochemical analysis showed that U87MG cells retained the expression of mGlu2/3 receptors when implanted into the brain of nude mice. These data suggest that mGlu2/3 receptor antagonists are of potential use in the experimental treatment of malignant gliomas. more...

Prenatal stress in the rat induces enhanced reactivity of the hypothalamus-pituitary-adrenal (HPA) axis, disturbances in a variety of circadian rhythms and increased anxiety-like behaviour. Such abnormalities parallel those found in human depressed patients. Prenatally stressed (PS) rats could represent, therefore, an interesting animal model for the evaluation of the efficacy of pharmacotherapeutic intervention in psychiatric disorders that has often been addressed using control animals. In the present study, PS and non-stressed rats were chronically treated with the tricyclic antidepressant imipramine (10 mg/kg i.p. for 21 days) and assessed in the forced swim test. Glucocorticoid receptor binding sites in the hippocampus were measured and 5-HT(1A) receptor mRNA levels in the frontal cortex were also assessed. PS rats were characterised by increased immobility in the forced swim test, reduced hippocampal corticosteroid receptor binding and increased levels of cortical 5-HT(1A) mRNA. All these parameters were significantly reversed by chronic imipramine treatment. Conversely, no significant effects were observed for non-stressed rats. All these effects are consistent with the expected pharmacotherapy of depression-like abnormalities in PS rats. These results further indicate that PS rats are a relevant animal model of depression. more...

International audience; Prenatally-stressed (PS) rats are characterized by a general impairment of the hypothalamo-pituitary-adrenal (HPA) axis and sleep disturbances indicating that this model has face validity with some clinical features observed in a subpopulation of depressed patients. The prolonged corticosterone secretion shown by PS rats in response to stress was positively correlated with an increased immobility behavior in the forced swim test. To investigate the predictive validity of this model, a separate group of animals was chronically treated with the antidepressant tianeptine (10 mg/kg i.p. for 21 days). Such chronic treatment reduced in PS rats immobility time in the forced swim test. These findings suggest that the PS rat is an interesting animal model for the evaluation of antidepressant treatment. more...

We have studied the immediate and long-term effects of high doses of corticosterone (CORT) on mRNA expression and binding properties of mineralocorticoid receptor and glucocorticoid receptor in the hippocampus and spinal cord of rats. Animals were treated with corticosterone (10 mg/d subcutaneously) for 21 consecutive days, and mineralocorticoid and glucocorticoid receptors were studied either 24 h or 2 wk after the last injection. Major results show that corticosterone treatment reduces mineralocorticoid and glucocorticoid receptor maximum binding capacity (Bmax) in both the hippocampus and spinal cord and that this reduction is partially reversed after cessation of treatment. With respect to mRNA expression, in the hippocampus recovery after cessation of treatment is complete. By contrast, in the spinal cord, mineralocorticoid receptor mRNA expression is irreversibly increased after treatment, but the glucocorticoid receptor mRNA level remains unaffected during and after treatment. Thus, these data suggest the presence of distinct regulatory mechanisms for adrenocorticoid receptors in rat brain and spinal cord, in response to long-term exposure to high levels of circulating corticosterone and after recovery from treatment. more...

The influence of maternal corticosterone during lactation on the development of the hippocampal corticosteroid receptor system, hypothalamus-pituitary-adrenal axis activity and spatial learning/retention performance was investigated in the rat during postnatal days 11 to 30. We increased the plasma levels of corticosterone by adding the hormone (200 μ g/ml) to the drinking water of the dams. When compared to controls corticosterone-nursed offspring displayed: i) higher number of hippocampal type I and type II corticosteroid receptors at 30 days of life, but no changes at 11 and 16 days; ii) higher plasma levels of corticosterone in the basal condition and after 15 min of maternal separation at 11 but not at 16 days; iii) lower adrenal weights at 11 and 16 days, but which were no longer present at the age of 30 days; iv) no difference in performance in the place learning version of the Morris water task and T aquatic maze at 16 days. The present results, together with our previous findings showing that 90-day-old corticosterone-nursed rats have lower basal and restraint stress corticosterone levels and improved learning performance, indicate that the effects of maternal treatment appears only after weaning, thereby suggesting that increased corticosteroid receptors may be responsible, at least partially, for the endocrine and learning modifications induced by pre-weaning corticosterone exposure. The role played by maternal circulating corticosterone during the period of lactation in shaping the characteristics of the hypothalamus-pituitary-adrenal axis and brain of the offspring is outlined. more...

A moderate increase in plasma level of corticosterone was induced in dams by adding the hormone (200 micrograms/ml) to the drinking water from the day after delivery to weaning. This procedure produces a parallel increase in plasma levels of the hormone in the pups (from 0.7 +/- 0.1 to 1.2 +/- 0.2 micrograms/100 ml) at 10 days of lactation. A significant (P < 0.01) reduction in the magnitude of the long-term potentiation (LTP) of the CA1 population spike occurred in hippocampal slices obtained from 30-45 day old male corticosterone-nursed rats with respect to controls, while no significant difference occurred in the magnitude of the basal CA1 evoked extracellular somatic field potentials with respect to controls. The results demonstrate that a moderate increase in plasma corticosterone during neonatal life, obtained through maternal milk, has long-lasting effects on the hippocampal CA1 synaptic plasticity. In addition, these results together with our previous findings [Catalani, A. et al., Brain Res., 624 (1993) 209-215], demonstrating that 30 day old corticosterone-nursed offsprings perform better than controls in the place learning version of the Morris water maze, show no relationships between in vitro CA1 LTP induction and spatial learning in agreement with literature data. more...

Type I and type II brain corticosteroid receptors are regulated by adrenal hormones as well as being under neural control. Recent studies have indicated that neurotransmitters such as serotonin and noradrenaline are also involved in the regulation of corticosteroid receptors. In a previous study, we showed that dopamine also modulates activity of the corticosteroid receptor system. In the present study, we examined the roles of the dopamine D1 and D2 receptor subtypes in the regulation of corticosteroid receptors. Adrenalectomized rats whose corticosterone levels were maintained within normal limits by corticosterone replacement implants, were injected intraperitoneally with the D1 agonist SKF 38393 or the D2 agonist LY 171555. Corticosteroid receptors were assayed in the ventral striatum and hippocampus. We have shown that the D1 agonist SKF 38393 decreased type II receptor affinity in both regions, whereas the D2 agonist LY 171555 had no effects. The results show that the influence of the dopaminergic system on corticosteroid receptors appears to be mediated by D1 receptors. more...

Central type I and type II corticosteroid receptors play a principle role in the regulation of corticosterone secretion. Although the binding capacity of these receptors is thought to be regulated essentially hormonally, there is also evidence for a direct neural control. For example, experimental manipulation of central serotoninergic and noradrenergic activities modifies the binding capacity of type I and type II corticosteroid receptors via a corticosterone-independent mechanism. In this study, we tested the effect of lesions of dopaminergic neurons in the ventral tegmental area on corticosteroid receptor binding capacity. The study was performed in adrenalectomized rats whose corticosterone levels were maintained within normal limits by corticosterone pellets and corticosterone in their drinking water during the dark period to generate the circadian rhythm. Binding properties of corticosteroid receptors were analysed in target regions of the lesioned neurons, including the ventral and dorsal striatum. Corticosteroid receptors in the hippocampus were also studied as a control as these lesions do not significantly affect dopamine content in this structure. Three weeks after the lesion, type II corticosteroid receptor affinity was increased in the ventral striatum. There was no effect on receptors in the dorsal striatum or hippocampus. Our results, together with other reports showing that dopamine inhibits the expression of corticosteroid receptors in the anterior pituitary, suggest that dopamine transmission exerts a negative control on central corticosteroid receptors. more...

Food restriction has been shown to enhance the behavioral sensitivity to addictive drugs. The biological factors involved in this effect are largely unknown. Since food restriction, among other factors, increases corticosterone secretion, the role of this hormone in the effects of food restriction on the response to psychostimulants and opioids was investigated. The effects of food restriction on amphetamine- and morphine-induced locomotor activity were compared in: (i) animals with an intact hypothalamo-pituitary-adrenal axis; (ii) animals in which food restriction-induced corticosterone secretion was suppressed by adrenalectomy, but which received exogenous corticosterone from a subcutaneous implant, which slowly releases corticosterone, producing a stable plasma level within the normal physiological range over a period of 20 days. It was found that food restriction enhanced sensitivity to the psychomotor effects of amphetamine (1 mg/kg i.p.) and morphine (1 mg/kg i.p.) in animals with an intact hypothalamo-pituitary-adrenal axis, but not in animals in which endogenous corticosterone secretion was eliminated. These results suggest that corticosterone secretion may be one of the mechanisms by which food restriction amplifies the behavioral responses to amphetamine and morphine. Since an enhanced locomotor reactivity to addictive drugs has been found to be frequently associated with an enhanced vulnerability to drug self-administration, these findings point to a role for glucocorticoids in the susceptibility to drug abuse. more...

We examined whether a different maternal genotype might differentially affect the brain adrenocorticoid receptor in homozygous diabetes insipidus Brattleboro rats. Two distinct homozygous diabetic offsprings were studied in comparison with Long Evans (LE) rats: one born of a homozygous mother (DI/HOM MOTHER), and the other born of a heterozygous mother (DI/HET MOTHER). The number of type I adrenocorticoid receptors of DI/HET MOTHER rats was significantly lower than that of LE rats in the hippocampus and hypothalamus, while in the amygdala both type I and type II receptors decreased. Surprisingly, the binding capacity of DI/HOM MOTHER rats, notwithstanding the absence of vasopressin (VP), as in the DI/HET MOTHER, did not differ from that of LE. Superimposable results were obtained in all the brain regions examined. No differences in binding affinity values (Kd) were detected. It was hypothesized that an 'unknown factor' linked to the genotype of the homozygous diabetic mother might counterbalance the receptor deficit otherwise induced by the lack of VP. The existence of two subpopulations of diabetic Brattleboro rats, as used in this study, should prompt to reexamine the origins of some behavioral and endocrine discrepancies appearing in studies on the homozygous diabetes insipidus Brattleboro strain. more...

There is evidence that certain psychopathological conditions are accompanied by a dysfunction in both the hypothalamo-pituitary-adrenal axis and dopaminergic systems, although the relationship between these two systems is as yet unclear. In the present study we investigated the effect of a specific lesion of dopamine mesencephalic neurons (Ventral Tegmental Area) on basal and stress-induced corticosterone secretion. Three weeks after injection of 6-OHDA, there was a depletion in dopamine in the frontal cortex and in the ventral and dorsal striatum, whereas norepinephrine and serotonin levels were unchanged. The dopamine-lesioned rats exhibited a lower basal and stress-induced corticosterone secretion than the sham-lesioned animals. The results indicate that the dopaminergic system may have a stimulatory influence on the hypothalamo-pituitary-adrenal axis. more...

Background Cannabinoids (CBs) evoke their effects by activating the cannabinoid receptor subtypes CB1-r and CB2-r and exert anti-inflammatory effects altering chemokine and cytokine expression. Various cytokines and chemokines are produced and released by rodent pancreatic acini in acute pancreatitis. Although CB1-r and CB2-r expressed in rat exocrine pancreatic acinar cells do not modulate digestive enzyme release, whether they modulate inflammatory mediators remains unclear. We investigated the CB-r system role on exocrine pancreas in unstimulated conditions and during acute pancreatitis. Methods We evaluated in vitro and in vivo changes induced by WIN55,212 on the inflammatory variables amylasemia, pancreatic edema and morphology, and on acinar release and content of the cytokine interleukin-6 (IL-6) and chemokine monocyte chemo-attractant protein-1 (MCP-1) in untreated rats and rats with caerulein (CK)-induced pancreatitis. Key Results In the in vitro experiments, WIN55,212 (10−6 mol L−1) inhibited IL-6 and MCP-1 release from acinar cells of unstimulated rats and after CK-induced pancreatitis. In vivo, when rats were pretreated with WIN55,212 (2 mg kg−1, intraperitoneally) before experimentally-induced pancreatitis, serum amylase, pancreatic edema and IL-6 and MCP-1 acinar content diminished and pancreatic morphology improved. Conversely, when rats with experimentally-induced pancreatitis were post-treated with WIN55,212, pancreatitis worsened. Conclusions & Inferences These findings provide new evidence showing that the pancreatic CB1-r/CB2-r system modulates pro-inflammatory factor levels in rat exocrine pancreatic acinar cells. The dual, time-dependent WIN55,212-induced changes in the development and course of acute pancreatitis support the idea that the role of the endogenous CB receptor system differs according to the local inflammatory status. more...

The rat model of prenatal restraint stress (PRS) is particularly valuable to study the mechanisms involved in the pathophysiology of anxiety/depression since adult PRS rats show endocrine and behavioral abnormalities that are corrected by antidepressant medication. We have previously shown that agomelatine chronic treatment reversed the anxiety behaviour and decreased hippocampal neurogenesis observed in PRS. Here, we investigated the mechanisms that may contribute to the antidepressant activity of agomelatine, by assessing the effects of a chronic treatment with agomelatine on neurobiological markers of neuroplasticity in the rat hippocampus such as BDNF and its receptor, TrkB, the transcription factor pCREB and metabotrophic glutamate receptors (mGluRs). Adult SD control and PRS rats were treated chronically with agomelatine (40mg/kg ip) or vehicle. 16h after last drug administration, animals were sacrificed and hippocampus dissected for biochemical analysis.PRS animals showed reduced levels of pCREB in the hippocampus and increased hippocampal BDNF, and TrkB receptor levels. Agomelatine reversed changes in pCREB and BDNF/TrkB levels in PRS rats, had no effect on pCREB in control rats, and, interestingly, increased BDNF and TrkB receptor levels in control rats. Moreover, agomelatine reversed the reduced expression (for mGluR5 and mGluR2/3 receptors) and function (for mgluR5 receptor) observed in the hippocampus of PRS rats.In conclusion, we have shown that agomelatine treatment reversed all biochemical and cellular changes induced by PRS in rats. These changes, independently of their direction, are the expression of an enduring maladaptive form of neuroplasticity that may contribute to the depressive/anxious phenotype of PRS rats. more...

Repeated exposure to stressful situations has been shown to increase individual reactivity to addictive drugs. However, the biological factors involved in such stress-induced changes are largely unknown. In this study, we investigated the role of corticosterone in the effects of restraint stress on the response to psychostimulants and opioids. The effects of repeated stress on amphetamine- and morphine-induced locomotor activity were compared in: (i) animals with an intact hypothalamo-pituitary-adrenal (HPA) axis; (ii) animals in which stress-induced corticosterone secretion was blocked by adrenalectomy, but who received exogenous corticosterone from a subcutaneous implant. The implanted pellets (50 mg) slowly release corticosterone producing a stable plasma level within the normal physiological range over a period of 20 days. Restraint stress increased the locomotor response to both amphetamine (1.5 mg/kg i.p.) and morphine (2 mg/kg s.c.) in animals with an intact HPA axis, but not in animals in which stress-induced corticosterone secretion was suppressed. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress amplifies behavioral responses to amphetamine and morphine. Since an enhanced locomotor reactivity to addictive drugs has been found to be frequently associated with an enhanced vulnerability to drug self-administration, these findings point to a role for glucocorticoids in the susceptibility to drug abuse. more...

The effects of repeated restraint stress exposures (daily 60 min, for 6 days) on extracellular dopamine in the nucleus accumbens, during and after the stress experience, have been investigated in rats by in vivo microdialysis. On the first day, restraint increased dopamine release during the first 40 min followed by a return to basal levels (50-60 min later). As soon as restraint ceased and the rats were set free, there was another increase in dopamine release lasting 40 min. On the second and third day, restraint produced only a slight increase in dopamine release, while no significant changes were evident from the fourth to the sixth day. By contrast, from the second to the sixth day the increase in dopamine release observed once rats were freed, was unchanged in comparison to the first day. The present results show that the activation of the mesolimbic dopaminergic system induced by aversive stimuli adapts to repeated experiences differently from that produced by pleasurable events, suggesting that aversive and rewarding experiences involve different neural systems. more...

The effects of L-alpha-glycerylphosphorylcholine (alpha-GPC) on scopolamine-induced memory impairment and on brain acetylcholine (ACh) synthesis and release were investigated in rats. Oral administration of alpha-GPC 3 h before the behavioural test prevented the learning impairment induced by scopolamine given 30 min before the acquisition of a passive avoidance response. Similarly, retrograde amnesia induced by scopolamine, given immediately after acquisition training, was also completely reversed by the drug. These effects were dose-dependent with a maximum at 300 mg/kg. The mechanism of action of this compound was investigated by measuring hippocampal ACh synthesis and release both in vivo by means of the microdialysis technique and in vitro in tissue slices. alpha-GPC dose dependently increased ACh release with a maximum at 300 mg/kg. In addition, i.v. injection of [14C]alpha-GPC resulted in [14C]ACh formation. The data suggest that the behavioural effects of alpha-GPC may be related to its property to increase hippocampal ACh synthesis and release. more...

Microdialysis was employed to assess extracellular dopamine from medial prefrontal cortex, nucleus accumbens, nucleus caudatus, and acetylcholine from the hippocampus of conscious rats during and after 120 min restraint stress. Restraint stress rapidly stimulated the release and the metabolism of dopamine in the medial prefrontal cortex and in the nucleus accumbens, and acetylcholine release in the hippocampus. Fifty-sixty min later, although rats were still restrained, dopamine and acetylcholine release gradually returned to basal levels. When the animals were freed a considerable increase in the release of both neurotransmitters was observed. No changes in the striatum were observed throughout the experiments. The time-course of plasma corticosterone did not parallel that of dopamine and acetylcholine release, increasing during the whole stress procedure, and decreasing when the animals were released. Adrenalectomized rats responded to stress and liberation in much the same way as intact rats. The administration of exogenous corticosterone (0.5-1.5 mg/kg s.c.) did not change the release of dopamine from the prefrontal cortex and nucleus accumbens, and of acetylcholine from the hippocampus, while the dose of 3.0 mg/kg which stimulated them, raised plasma corticosterone to very high concentrations which had never been attained during stress. Moreover, RU 38486, an antagonist of brain glucocorticoid receptors, did not antagonize the stress-induced increase of neurotransmitter release.(ABSTRACT TRUNCATED AT 250 WORDS) more...

Systemic administration of the 5-HT3 receptor antagonist ICS 205-930, but not of the benzodiazepine diazepam, was able to prevent the stimulation of dopamine release in the nucleus accumbens and prefrontal cortex induced by restraint stress. These findings suggest that stress is not simply co-extensive with anxiety and that 5-HT3 receptors could regulate the dopaminergic response to stress. more...

A correlation has been demonstrated between binding capacity for [3H]corticosterone in the hippocampus and the performance in passive and active avoidance in the rat, and impaired behavior in adrenalectomized rats by exogenous corticosterone is restored. On this basis we have studied the possible correlation between strain-dependent behavioral differences and the glucocorticoid binding capacity in the hippocampus in mice and rats. In Naples high- (NHE) and low-excitability (NLE) rat strains, genetically selected on the basis of divergent locomotor activity upon forced exposure to a spatial novelty situation, no differences were found in glucocorticoid maximal binding capacity while both strains had a lower capacity than Naples random-breed (NRB) control rats. However, the intra-strain correlative analysis of hippocampal glucocorticoid receptors number and behavioral scores demonstrated that motor and emotional indexes of arousal to novelty were positively correlated in NLE-and negatively in NHE- while no correlation was present in NRB rats. Using two inbred strains of mice, C57BL/6 and Balb/c, extensively investigated for learning abilities, the lower active avoidance score of C57BL/6 was associated with a lower binding capacity for [3H]corticosterone in the hippocampus. Altogether the above results support the involvement of the hippocampal glucocorticoid receptor in the modulation of some adaptive behavioral responses, while do not prove that genetic differences in behavior rest on parallel differences in binding capacity for glucocorticoid hormone. more...

Maximal individual [3H]corticosterone binding capacity in the hippocampus was lower in C57BL/6 mice than in BALB/c mice, and positively correlated with active avoidance learning in the two strains. Moreover, a parallel difference in the activity of hypothalamo-pituitary adrenocortical axis (HPAA) was found, consisting in a level of plasma corticosterone in C57BL/6 higher than in BALB/c mice. These results confirm the genetically determined differences in behavior of C57BL/6 and BALB/c mice, and demonstrate their association with differences in hippocampal corticosterone binding capacity, pointing to a functional relationship between the behavioral and neuroendocrine parameters. more...

Les etudes sur un cerveau dialyse d'un rat conscient soumis a un stress ont montre une augmentation de la liberation de dopamine (DA) et de ses metabolites (acide dihydroxyphenylacetique = le DOPAC, l'acide homovanillique = HVA) ainsi que de la liberation d'acetylcholine, au niveau des aires limbiques. Apres surrenalectomie ces augmentations sont moins importantes; de plus l'administration de corticosterone est capable a elle seule d'augmenter la liberation de DA et d'acetylcholine. Il en resulte donc que l'axe hypophyso-corticosurrenalien joue un role dans l'augmentation induite par le stress de la liberation de DA et d'Ac choline dans les aires limbiques more...