Subchronic Stress Research Articles

Chronic escitalopram treatment attenuated the accelerated rapid eye movement sleep transitions after selective rapid eye movement sleep deprivation: a model-based analysis using Markov chains.

BackgroundShortened rapid eye movement (REM) sleep latency and increased REM sleep amount are presumed biological markers of depression. These sleep alterations are also observable in several animal models of depression as well as during the rebound sleep after selective REM sleep deprivation (RD). Furthermore, REM sleep fragmentation is typically associated with stress procedures and anxiety. The selective serotonin reuptake inhibitor (SSRI) antidepressants reduce REM sleep time and increase REM latency after acute dosing in normal condition and even during REM rebound following RD. However, their therapeutic outcome evolves only after weeks of treatment, and the effects of chronic treatment in REM-deprived animals have not been studied yet.ResultsChronic escitalopram- (10 mg/kg/day, osmotic minipump for 24 days) or vehicle-treated rats were subjected to a 3-day-long RD on day 21 using the flower pot procedure or kept in home cage. On day 24, fronto-parietal electroencephalogram, electromyogram and motility were recorded in the first 2 h of the passive phase. The observed sleep patterns were characterized applying standard sleep metrics, by modelling the transitions between sleep phases using Markov chains and by spectral analysis.Based on Markov chain analysis, chronic escitalopram treatment attenuated the REM sleep fragmentation [accelerated transition rates between REM and non-REM (NREM) stages, decreased REM sleep residence time between two transitions] during the rebound sleep. Additionally, the antidepressant avoided the frequent awakenings during the first 30 min of recovery period. The spectral analysis showed that the SSRI prevented the RD-caused elevation in theta (5–9 Hz) power during slow-wave sleep. Conversely, based on the aggregate sleep metrics, escitalopram had only moderate effects and it did not significantly attenuate the REM rebound after RD.ConclusionIn conclusion, chronic SSRI treatment is capable of reducing several effects on sleep which might be the consequence of the sub-chronic stress caused by the flower pot method. These data might support the antidepressant activity of SSRIs, and may allude that investigating the rebound period following the flower pot protocol could be useful to detect antidepressant drug response. Markov analysis is a suitable method to study the sleep pattern.

P.4.e.001 Sub-chronic stress not only induces pro-inflammatory cytokines but also activates NRLP3 inflammasome in rats

P.4.e.001 Sub-chronic stress not only induces pro-inflammatory cytokines but also activates NRLP3 inflammasome in rats

Effect of physical stress on the alteration of mesolimbic system apoptotic factors in conditioned place preference paradigm

Mesocorticolimbic (MCL) dopaminergic system has an essential role in the rewarding action of opiates and is proved to be influenced by stress. Additionally, both morphine and stress can induce apoptosis. In this study, we investigated the effects of morphine-induced conditioned place preference (CPP) in the presence and absence of stress on the changes of apoptotic factors (Bax/Bcl-2 ratio, caspase-3 activation and PARP degradation) in the MCL system. Male Wistar rats were divided into two saline- and morphine-treated supergroups, each of which consisted of control, acute stress (AS) and subchronic stress (SS) subgroups. In all groups, the CPP paradigm was performed; thereinafter alternations of apoptotic factors in the nucleus accumbens, amygdala, striatum and prefrontal cortex were measured. The results indicated that in the saline-treated animals, AS and SS increased apoptotic factors significantly in the mentioned areas (except for the Bax/Bcl-2 ratio after AS in the Str). In addition, in these animals, conditioning scores decreased after SS but not after AS. In the morphine-treated animals, AS and SS increased apoptotic factors remarkably (except for the Bax/Bcl-2 ratio after AS and SS in the Str and caspase-3 activation after AS in the NAc) and also decreased conditioning scores. Our findings suggest that in the saline- or morphine-treated animals, AS and SS can increase the apoptotic factors in the MCL system and it is more prominent in the morphine-treated animals.

Single and combined effects of prenatal immune activation and peripubertal stress on parvalbumin and reelin expression in the hippocampal formation.

Exposure to prenatal infection and traumatizing experiences in peripubertal life are two environmental risk factors for developmental neuropsychiatric disorders. Modeling the cumulative neuronal impact of these factors in a translational animal model has led to the recent identification of pathological interactions between these environmental adversities in the development of adult brain dysfunctions. The present study explored the consequences of combined prenatal immune challenge and peripubertal stress on discrete cellular abnormalities in the γ-aminobutyric acid (GABA) system of the hippocampus. Pregnant mice were treated with the viral mimetic poly(I:C) (=polyriboinosinic-polyribocytidilic acid) or control solution, and offspring born to poly(I:C)-exposed or control mothers were then left undisturbed or subjected to unpredictable sub-chronic stress during peripubertal development. Stereological estimations of parvalbumin-expressing cells revealed a significant reduction of these GABAergic interneurons in the ventral dentate gyrus of adult offspring exposed to combined immune activation and stress. Single exposure to either environmental factor was insufficient to cause similar neuropathology. We further found that peripubertal stress exerted opposite effects on reelin-immunoreactive cells in the dorsal cornu ammonis (CA) region of the hippocampus, with stress increasing and decreasing reelin expression in control offspring and prenatally immune challenged animals, respectively. The present data suggest that the combination of two environmental risk factors, which have each been implicated in the etiology of major neuropsychiatric disease, induces significant but restricted neuropathological effects on hippocampal GABAergic cell populations known to be affected in brain disorders with neurodevelopmental components.

Changes in apoptotic factors in hypothalamus and hippocampus after acute and subchronic stress induction during conditioned place preference paradigm.

The hypothalamus (HYP) and hippocampus (HIP) are important regions involved in stress responses. These areas are also associated with reward processing. In this study, the effects of acute and subchronic stress on the changes in apoptotic factors (Bax/Bcl-2 ratio, caspase-3 activation and PARP degradation) in the HYP and HIP during conditioned place preference (CPP) paradigm were evaluated. Male Wistar rats were divided into two saline- and morphine-treated supergroups. Each supergroup contained control, acute stress (AS) and subchronic stress (SS) groups. In all groups, CPP paradigm was done and thereinafter alterations of apoptotic factors were measured by western blot. The results revealed that in the HYP, all mentioned factors increased significantly in saline- or morphine-treated animals during AS and SS. On the other hand, in the HIP, Bax/Bcl-2 ratio in saline-treated animals increased significantly during AS and SS, while in morphine-treated animals this ratio did not have any significant alteration during AS and was decreased during SS compared with morphine-control group. Caspase-3 and PARP increased during AS and SS in saline- or morphine-treated animals. For example, caspase-3 increased during AS and SS in morphine-treated animals by 2.4 folds and PARP (89 KDa) increased by 3.1 and 3.5 folds, respectively. Interestingly, the increase of apoptotic factors in morphine-treated animals was more considerable than that of saline-treated animals. These results strongly implied that AS and SS trigger apoptotic events in the HYP and HIP of saline- and/or morphine-treated animals as well as morphine reinforces the effect of stress on the induction of apoptosis.

Changes in the levels of p-ERK, p-CREB, and c-fos in rat mesocorticolimbic dopaminergic system after morphine-induced conditioned place preference: the role of acute and subchronic stress.

ERK pathway plays a critical role in the cellular adaptive responses to environmental changes. Stressful conditions can induce the activation of activate ERK, and its downstream targets, CREB and c-fos, in neural cells. Exposure to opioids has the same effect. In this study, we investigated the effects of morphine-induced conditioned place preference (CPP) on p-ERK/ERK ratio, p-CREB/CREB ratio and c-fos level in the mesocorticolimbic dopaminergic system including the nucleus accumbens (NAc), amygdala (AMY), striatum (Str), and prefrontal cortex (PFC).Our aim was to determine if acute and subchronic stress would affect these alterations. Male Wistar rats were divided into two saline- and morphine-treated groups. Each group contained of control, acute stress, and subchronic stress subgroups. The CPP procedure was performed for all of the rats. We dissected out the NAc, AMY, Str, and PFC regions and measured the mentioned ratios and c-fos level by Western blot analysis. The results revealed that in saline-treated animals, all factors enhanced significantly after performing acute and subchronic stress while there was an exception in p-ERK/ERK ratio in the Str and PFC; the changes were not significant during acute stress. Conditioning score decreased after applying the subchronic but not acute stress. In morphine-treated animals, all factors were increased after application of acute and subchronic stress, and conditioning scores also decreased after stress. Our findings suggest that in saline- or morphine-treated animals, acute and subchronic stress increases p-ERK, p-CREB, and c-fos levels in the mesocorticolimbic system. It has been shown that morphine induces the enhancement of the mentioned factors; on the other hand, our result demonstrates that stress can amplify these changes.

The interplay of conditional NCAM-knockout and chronic unpredictable stress leads to increased aggression in mice

The neural cell adhesion molecule (NCAM) is a key regulator of brain plasticity. Substantial evidence indicates that NCAM is down-regulated by exposure to sustained stress and chronic stress seems to lead to increased aggression. In addition, constitutional NCAM deletion in mice has been shown to lead to increased intermale aggression and altered emotionality Forebrain-specific postnatal NCAM knockout was previously shown to impair cognitive function, particularly when animals were exposed to subchronic stress, but the effects on emotional and social behavior remain unclear. In this study, we investigated the potential interplay of a forebrain-specific postnatal NCAM deletion and exposure to different lengths of repeated stress (i.e. subchronic: 14 days; chronic: 29 days) on aggressive and emotional behavior. Our results show that postnatal deletion of NCAM in the forebrain leads to increased aggression and altered emotionality depending on the duration of stress, whereas conditional NCAM knockout has no basal impact on these behaviors. These findings support the involvement of NCAM in the regulation of emotional and aggressive behaviors, suggesting that diminished NCAM expression might be a critical vulnerability factor for the development of these behavioral alterations under repeated exposure to stress.

Protective Effect of Edible Marine Algae, Laminaria japonica and Porphyra haitanensis, on Subchronic Toxicity in Rats Induced by Inorganic Arsenic

Arsenic, a potent environmental toxic agent, causes various hazardous effects on human health. This study was performed to evaluate the protective effects of edible marine algae, Laminaria japonica and Porphyra haitanensis, on subchronic stress of rats induced by arsenic trioxide (As2O3). The co-treatment of marine algae could slightly increase the growth rates of body weights compared to the As2O3-treated group. The marine algae application restored liver and renal function by preventing the increment in the activities of alanine transaminase and alkaline phosphatase, and the levels of total protein, blood urea nitrogen, and creatinine. The increase in the contents of total cholesterol, triglyceride, and low density lipoprotein cholesterol, and decrease in the contents of high density lipoprotein cholesterol were observed in algae co-treated groups which indicated that marine algae could reverse the abnormal lipid metabolisms induced by arsenic. Moreover, these algae could protect the rats from lipid peroxidation by restoring the depletion of superoxide dismutase and glutathione peroxidase activities and sulfhydryl group contents, and lowering the enhanced malondialdehyde contents. Therefore, evidences indicate that L. japonica and P. haitanensis can serve as an effective regimen for treating arsenic poisoning.

Early postnatal interference with the expression of multiple Sp1 regulated genes leads to disparate behavioral response to sub-chronic and chronic stress in rats

It is currently accepted that complex behavior and mental disorder results from a combination of biological susceptibility and exposure to environmental stimuli. Most of the gene-environment interaction models focus on the interaction between the stimuli and a single candidate gene. We suggest that an alternative approach is interference with the expression of multiple genes followed by exposure to environmental insults. Early interference with gene transcription was performed by treatment of 7 days old Wistar male rats for 4 days with the Sp1/DNA binding inhibitor, mithramycin. Environmental insult was mimicked by exposing these rats during adulthood (34 days) to sub-chronic (12 days, n=30) or chronic stress (28 days, n=48). The effects of mithramycin and stress treatment on the behavioral response and serum corticosterone concentration were assessed. Exposure of mithramycin treated rats to sub-chronic stress led to anxious behavior in the open field test, high startle response, low sucrose preference, indifference to novel objects and high serum corticosterone concentration. However, exposure to chronic stress resulted in normal sucrose preference, startle response and serum corticosterone, novelty seeking behavior and reduced anxiety. In saline treated rats the extension of stress duration led to behavioral and hormonal adaptation to stress. Our study suggests that postnatal temporal interference with multiple gene expression can lead to hyper-responsiveness to environmental stimuli, the features of which affects the phenotypic outcomes. Such a paradigm may be used to model gene-environmental interaction in the etiology of behavioral disorders.

Animal models as tools to study the pathophysiology of depression

The incidence of depressive illness is high worldwide, and the inadequacy of currently available drug treatments contributes to the significant health burden associated with depression. A basic understanding of the underlying disease processes in depression is lacking; therefore, recreating the disease in animal models is not possible. Popular current models of depression creatively merge ethologically valid behavioral assays with the latest technological advances in molecular biology. Within this context, this study aims to evaluate animal models of depression and determine which has the best face, construct, and predictive validity. These models differ in the degree to which they produce features that resemble a depressive-like state, and models that include stress exposure are widely used. Paradigms that employ acute or sub-chronic stress exposure include learned helplessness, the forced swimming test, the tail suspension test, maternal deprivation, chronic mild stress, and sleep deprivation, to name but a few, all of which employ relatively short-term exposure to inescapable or uncontrollable stress and can reliably detect antidepressant drug response.

Involvement of oxidative stress in liver injury after subchronic intoxication with low doses of chlorpyrifos — study on rats

Abstract Organophosphate compounds are nowadays the most frequently used pesticides. For these insecticides, the primary target is acetylcholinesterase and for this reason the main clinical effect of acute intoxication with organophosphate insecticides involves an irreversible inhibition of the activity of this enzyme. However, in the chronic or subchronic exposition oxidative stress has been reported as the main mechanism of its toxicity. The present study investigated the effect of three low doses (0.2, 2, 5 mg/kg bw) of chlorpyrifos for 14 or 28 days on serum liver enzymes and on oxidative stress parameters in the liver of rats. Chlorpyrifos treatment resulted in aminotransferases and alkaline phosphatase increase after 14 days (higher doses) and 28 days (all doses) treatment together with changes of antioxidative enzymes activities and reduced glutathione and malonyldialdehyde level in the liver. The enhancement of lipid peroxidation is temporary, reaching a peak after 14 days and decreasing after 28 days of treatment. Based on the experimental findings of this study the temporary liver injury caused by oxidative stress has been shown. The disturbances in the liver antioxidative status and increased liver membrane permeability may appear in case of doses near to the accepted human daily intake.

Fluoxetine prevents development of an early stress-related molecular signature in the rat infralimbic medial prefrontal cortex. Implications for depression?

BackgroundPsychological stress, particularly in chronic form, can lead to mood and cognitive dysfunction and is a major risk factor in the development of depressive states. How stress affects the brain to cause psychopathologies is incompletely understood. We sought to characterise potential depression related mechanisms by analysing gene expression and molecular pathways in the infralimbic medial prefrontal cortex (ILmPFC), following a repeated psychological stress paradigm. The ILmPFC is thought to be involved in the processing of emotionally contextual information and in orchestrating the related autonomic responses, and it is one of the brain regions implicated in both stress responses and depression.ResultsGenome-wide microarray analysis of gene expression showed sub-chronic restraint stress resulted predominantly in a reduction in transcripts 24 hours after the last stress episode, with 239 genes significantly decreased, while just 24 genes had increased transcript abundance. Molecular pathway analysis using DAVID identified 8 pathways that were significantly enriched in the differentially expressed gene list, with genes belonging to the brain-derived neurotrophic factor – neurotrophin receptor tyrosine kinase 2 (BDNF-Ntrk2) pathway most enriched. Of the three intracellular signalling pathways that are downstream of Ntrk2, real-time quantitative PCR confirmed that only the PI3K-AKT-GSK3B and MAPK/ERK pathways were affected by sub-chronic stress, with the PLCγ pathway unaffected. Interestingly, chronic antidepressant treatment with the selective serotonin reuptake inhibitor, fluoxetine, prevented the stress-induced Ntrk2 and PI3K pathway changes, but it had no effect on the MAPK/ERK pathway.ConclusionsThese findings indicate that abnormal BDNF-Ntrk2 signalling may manifest at a relatively early time point, and is consistent with a molecular signature of depression developing well before depression-like behaviours occur. Targeting this pathway prophylactically, particularly in depression-susceptible individuals, may be of therapeutic benefit.

Effects of diphenyl diselenide on depressive-like behavior in ovariectomized mice submitted to subchronic stress: involvement of the serotonergic system

The transition to menopause is associated with an increased risk of depressed mood. This study was conducted to investigate whether diphenyl diselenide [(PhSe)₂] treatment could reduce the effects of postmenopausal depression-like behavior in ovariectomized female mice submitted to subchronic stress exposure. Mice were divided into four groups: sham, (PhSe)₂, ovariectomy (OVX), and OVX + (PhSe)₂. Animals were ovariectomized/sham-operated and subjected to stress session once a day for 7 days from the fifth to the 11th day after OVX. The behavioral tests (open field, tail suspension (TST), and forced swimming (FST)) were performed on the 14th day after OVX. Mice were treated orally once a day with vehicle (canola oil, 10 ml/kg) or (PhSe)₂ (10 mg/kg; 10 ml/kg) 30 min before being exposed to subchronic stress, or from the 11th to the 14th day. Paroxetine (8 mg/kg i.p.) and pargyline (30 mg/kg i.p.) were used as positive controls. The involvement of serotonergic receptor subtypes in the antidepressant-like effect of (PhSe)₂ was assessed in the FST using WAY 100635 (0.1 mg/kg s.c.), ritanserin (1 mg/kg i.p.), and ondansetron (1 mg/kg i.p.) as serotonergic antagonists. Monoamine oxidase (MAO) A and B activities were also determined. The prolongation of immobility time in TST and FST in OVX mice submitted to subchronic stress was prevented by (PhSe)₂ treatment. Ritanserin and ondansetron blocked the antidepressive-like effect of (PhSe)₂, suggesting the involvement of 5-HT(2A/2C) and 5-HT₃ receptor subtypes. Both paroxetine and pargyline were effective in reducing the immobility time of stressed OVX mice in the FST. No alterations in locomotor activity were observed. Although (PhSe)₂ had inhibited in vitro MAO-A and MAO-B activities, none of the groups presented alterations neither in ex vivo MAO-A nor in MAO-B activity. (PhSe)₂ treatment could influence mood and behavior, indicating a promising role of this organoselenium compound in the management of postmenopausal depressive symptoms.

Personality traits in rats predict vulnerability and resilience to developing stress-induced depression-like behaviors, HPA axis hyper-reactivity and brain changes in pERK1/2 activity

Emerging evidence indicates that certain behavioral traits, such as anxiety, are associated with the development of depression-like behaviors after exposure to chronic stress. However, single traits do not explain the wide variability in vulnerability to stress observed in outbred populations. We hypothesized that a combination of behavioral traits might provide a better characterization of an individual's vulnerability to prolonged stress. Here, we sought to determine whether the characterization of relevant behavioral traits in rats could aid in identifying individuals with different vulnerabilities to developing stress-induced depression-like behavioral alterations. We also investigated whether behavioral traits would be related to the development of alterations in the hypothalamic-pituitary-adrenal axis and in brain activity - as measured through phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2)--in response to an acute stressor following either sub-chronic (2 weeks) or chronic (4 weeks) unpredictable stress (CUS). Sprague-Dawley rats were characterized using a battery of behavioral tasks, and three principal traits were identified: anxiety, exploration and activity. When combined, the first two traits were found to explain the variability in the stress responses. Our findings confirm the increased risk of animals with high anxiety developing certain depression-like behaviors (e.g., increased floating time in the forced swim test) when progressively exposed to stress. In contrast, the behavioral profile based on combined low anxiety and low exploration was resistant to alterations related to social behaviors, while the high anxiety and low exploration profile displayed a particularly vulnerable pattern of physiological and neurobiological responses after sub-chronic stress exposure. Our findings indicate important differences in animals' vulnerability and/or resilience to the effects of repeated stress, particularly during initial or intermediate levels of stress exposure, and they highlight that the behavioral inhibition profile of an animal provides a particular susceptibility to responding in a deleterious manner to stress.

Vulnerability of conditional NCAM-deficient mice to develop stress-induced behavioral alterations

Previous studies in rodents showed that chronic stress induces structural and functional alterations in several brain regions, including shrinkage of the hippocampus and the prefrontal cortex, which are accompanied by cognitive and emotional disturbances. Reduced expression of the neural cell adhesion molecule (NCAM) following chronic stress has been proposed to be crucially involved in neuronal retraction and behavioral alterations. Since NCAM gene polymorphisms and altered expression of alternatively spliced NCAM isoforms have been associated with bipolar depression and schizophrenia in humans, we hypothesized that reduced expression of NCAM renders individuals more vulnerable to the deleterious effects of stress on behavior. Here, we specifically questioned whether mice in which the NCAM gene is inactivated in the forebrain by cre-recombinase under the control of the calcium–calmodulin-dependent kinase II promoter (conditional NCAM-deficient mice), display increased vulnerability to stress. We assessed the evolving of depressive-like behaviors and spatial learning and memory impairments following a subchronic stress protocol (2 weeks) that does not result in behavioral dysfunction, nor in altered NCAM expression, in wild-type mice. Indeed, while no behavioral alterations were detected in wild-type littermates after subchronic stress, conditional NCAM-deficient mice showed increased immobility in the tail suspension test and deficits in reversal spatial learning in the water maze. These findings indicate that diminished NCAM expression might be a critical vulnerability factor for the development of behavioral alterations by stress and further support a functional involvement of NCAM in stress-induced cognitive and emotional disturbances.

Metyrapone and fluoxetine suppress enduring behavioral but not cardiac effects of subchronic stress in rats

In humans, chronic stressors have long been recognized as potential causes for cardiac dysregulation. Despite this, the underlying mechanistic links responsible for this association are still poorly understood. The purpose of this study was to determine whether exposure to a paradigm of subchronic stress can provoke enduring changes on the heart rate of experimental rats and, if so, to reveal the autonomic and neural mechanisms that mediate these effects. The study was conducted on adult male Sprague-Dawley rats instrumented for telemetric recording of heart rate and locomotor activity. Animals were submitted to a subchronic stress protocol, consisting of a 1-h foot shock session on five consecutive days. Heart rate and locomotor activity were recorded continuously for 3 days before and for 6 days after the subchronic stress period. Subchronic foot shock produced significant and enduring reduction in heart rate both during the dark/active [Δ= -23 ± 3 beats per minute (bpm)] and light/inactive (Δ= -20 ± 3 bpm) phases of the circadian cycle, and a reduction in locomotor activity during the dark/active phase [Δ= -54 ± 6 counts per hour (cph)]. The bradycardic effect of subchronic stress was not related to a reduced locomotion. Selective sympathetic (atenolol) and vagal (methyl-scopolamine) blockades were performed to reveal which autonomic component was responsible for this effect. We found that the fall in heart rate persisted after subchronic stress in animals treated with atenolol (active phase Δ= -16 ± 3 bpm, inactive phase Δ= -19 ± 2 bpm), whereas vagal blockade with scopolamine transiently prevented this effect, suggesting that the bradycardia following subchronic stress was predominantly vagally mediated. Fluoxetine (selective serotonin reuptake inhibitor) and metyrapone (inhibitor of corticosterone synthesis) treatments did not affect heart rate changes but prevented the reduction in locomotion. We conclude that subchronic stress exposure in rats reduces heart rate via a rebound in vagal activation and that this effect is serotonin- and corticosterone-independent.

Distinctive effects of unpredictable subchronic stress on memory, serum corticosterone and hippocampal BDNF levels in high and low exploratory mice

Stress affects learning and memory processes and sensitivity to stress greatly varies between individuals. We studied behavioral and neurobiological effects of unpredictable subchronic stress (USCS) in two behavioral extremes of mice from the same strain (CF1) selected by their exploratory behavior of the central arena of an open field. The top and bottom 25% explorers were classified as low exploratory (LE) and high exploratory (HE) mice, respectively. The open field task, the novel object recognition task (NOR), sucrose intake and tail suspension task were evaluated in LE and HE groups exposed to USCS for two weeks or control conditions. Also serum corticosterone and hippocampal BDNF and S100B levels were analyzed. Both stressed groups exhibited less exploratory activity when submitted to USCS, but their difference in exploratory behavior remained. This short stress protocol did not induce changes in sucrose intake or immobility in the tail suspension task. Also, LE mice exhibited impaired NOR performance after USCS, whereas HE mice changed their pattern of exploration towards less exploration of the familiar object. HE had lower corticosterone levels than LE mice, but corticosterone levels increased after stress only in HE mice. Hippocampal BDNF in LE was lower than in HE but decreased after USCS only in HE mice, whereas S100B levels were not different between groups and did not change with USCS. In conclusion, our results suggest that individual differences in exploratory behavior in rodents from the same strain influence cognitive and biochemical response to stress.

A subchronic application period of glucocorticoids leads to rat cognitive dysfunction whereas physostigmine induces a mild neuroprotection

The cholinergic neurotransmitter system and prolonged glucocorticoid-induced stress can affect cognitive functions in opposite ways. While pharmacological enhancement of cholinergic neurotransmission is known to induce neuroprotective effects, chronic glucocorticoids impair cognitive functions. Up to now, there is no consensus as to whether a subchronic stress period of several days would affect cognitive function. The goal of this study was to investigate whether or not repeated applications of physostigmine over 3 days lead to protective effects on rat spatial cognitive abilities in contrast to the deteriorating effect on rat cognitive function after corticosterone treatment. Furthermore, we wanted to investigate in what extent this cognition-modulating effect is associated with rat cerebral acetylcholinergic system. Male adult rats (n = 40) were randomly divided into four groups with n = 10 per group: (I) placebo-, (II) corticosterone- (15 mg/day), (III) physostigmine- (0.014 mg/day), and (IV) physostigmine + corticosterone-treated rats. Body mass and plasma corticosterone concentrations were measured. Psychometric investigations were conducted using a Morris water maze before and after a subchronic treatment. In cerebral tissue, ACh and acetylcholinesterase (AChE) content and ACh receptor density were determined. Tissue corticosterone concentration was measured in cerebral cortex, hippocampus, and adrenal glands. In corticosterone-treated rats, reduced spatial cognitive abilities were associated with a significant increase in plasma (+25%) and cerebral corticosterone levels (+350%) parallelled by a significant reduction in adrenal gland concentrations (-84%) as compared to placebo. Repeated physostigmine injections improved rats' spatial memory and increased cerebral ACh and AChE content (p < 0.05). When physostigmine was administered at the same time as corticosterone (group IV), it was not able to reverse the corticosterone effect. A significant correlation was detected between cerebral AChE and corticosterone concentrations as well as between AChE and psychometric parameters. We conclude that subchronic exogenous corticosterone administration induces memory dysfunction whereas physostigmine exerts cognitive-enhancing effects if given for 3 days. An apparently existing interaction between glucocorticoid excess and ACh metabolism is discussed.

The different involvement of the amygdalar nuclei in the palatability-induced ingestion

1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]-1,2,3,6-tetrahydropyridine-4-carboxamide benzenesulfonate (R278995/CRA0450) is a newly synthesized corticotropin-releasing factor subtype 1 (CRF1) receptor antagonist. In the present study, in vitro and in vivo pharmacological profiles of R278995/CRA0450 were investigated. R278995/CRA0450 showed high affinity for recombinant and native CRF1 receptors without having affinity for the CRF2 receptor. R278995/CRA0450 attenuated CRF-induced cyclic AMP formation in AtT-20 cells and CRF-induced forepaw treading in gerbils, indicating that R278995/CRA0450 is an antagonist of the CRF1 receptor. In addition to CRF1 receptor antagonism, R278995/CRA0450 showed high affinity for the σ1 receptor, and attenuated (+)-SKF10,047-induced head-weaving behavior, suggesting σ1 receptor antagonism. R278995/CRA0450 showed dose-dependent in vivo occupancy when assessed by ex vivo receptor binding, indicating good brain penetration. R278995/CRA0450 did not alter spontaneous anxiety when tested in the rat elevated plus maze (up to 3 mg/kg, p.o.) or lick suppression test (up to 10 mg/kg, i.p.). However, potent anxiolytic-like properties were observed in rats subjected to swim stress prior to testing on the elevated plus-maze, indicating activity primarily in tests taxing stress-induced anxiety. R278995/CRA0450 was inactive in mouse tail suspension, rat forced swim and rat differential-reinforcement-of-low-rate 72-s (DRL72), while it showed dose-dependent antidepressant-like effects in the rat learned helplessness paradigm and the olfactory bulbectomy model, demonstrating activity in a subset of animal models of depression associated with subchronic stress exposure. No or only mild effects were seen in tests of locomotor activity, motor coordination and sedation. These results indicate that R278995/CRA0450 is an orally active CRF1 and σ1 receptor antagonist with potent anxiolytic-like and antidepressant-like activities.

Maternal hyperthyroidism in rats impairs stress coping of adult offspring

Given the evidence that maternal hyperthyroidism (MH) compromises expression of neuronal cytoskeletal proteins in the late fetal brain by accelerated neuronal differentiation, we investigated possible consequences of MH for the emotional and cognitive functions of adult offspring during acute and subchronic stress coping. Experimental groups consisted of male rat offspring from mothers implanted with osmotic minipumps infusing either thyroxine (MH) or vehicle (Ctrl) during pregnancy. Body weight and T4 level were monitored during the first 3 postnatal months, and no differences were found with the controls. We analyzed hippocampal CA3 pyramidal neurons and dentate granular cell morphology during several postnatal stages and found increased dendritic arborization. On postnatal day 90 a modified subchronic mild stress (SCMS) protocol was applied to experimental subjects for 10 days. The Morris water maze was used before, during, and after application of the SCMS protocol to measure spatial learning. The tail suspension test (TST) and forced-swimming test (FST) were used to evaluate behavioral despair. The MH rats displayed normal locomotor activity and spatial memory prior to SCMS, but impaired spatial learning after acute and chronic stress. In both the FST and TST we found that MH rats spent significantly more time immobile than did controls. Serum corticosterone level was found to increase after 30 min of restraint stress, and corticotropin-releasing factor immunoreactivity was found to be increased in the central nucleus of the amygdala. Our results suggest that MH in rats leads to the offspring being more vulnerable to stress in adulthood.