Influence of various acute stressors on the activity of adult male rats in a holeboard and in the forced swim test

The effects of various acute stressors on the activity of adult male rats in a holeboard and in the forced swim test were studied. When tested immediately or 24 h after 1 h exposure to noise, restraint in tubes or tail shock, no changes in either defecation rate or activity in the holeboard were observed. In contrast, immediately after 1 h immobilization in wood-boards, a reduction of the number of areas crossed and the number of head-dips was found. The inhibitory effect of immobilization on head-dips persisted 24 h later. The behavior of the rats in the forced swim test was classified into three categories: struggling, mild swim and immobility. The changes in behavior were critically dependent on the type of stressor, and more specifically on its intensity, that was evaluated with three different physiological parameters (serum prolactin, corticosterone and glucose levels). Thus, if tested immediately after stress, noise did not alter the response of the rats, restraint in tubes and tail shock-reduced immobility, and the latter stressor increased mild swim. In the second experiment, immobilization in wood-boards reduced struggling. Twenty-four hours after stress, noise, restraint in tubes or tail shock were without effect, but immobilized rats showed increased immobility and reduced mild swim activity. The present data clearly indicate that behavior of rats in a holeboard and in a forced swim situation are not related, and that acute stress could have a differential effect on the various categories of behavior in a forced swim situation.     

Behavioral and neurochemical changes in response to acute stressors: influence of previous chronic exposure to immobilization.

The effect of daily (2 h) exposure to immobilization (IMO) for 15 days on the behavioral and neurochemical responses of adult male rats to acute stress caused by 2-h IMO or 2-h tail-shock was studied. The brain areas studied were frontal cortex, hippocampus, hypothalamus, midbrain, and pons plus medulla. Chronic exposure to IMO did not alter noradrenaline (NA), 3-methoxy,4-hydroxyphenyletileneglycol-SO4 (MHPG-SO4), serotonin, or 5-hydroxindoleacetic acid (5-HIAA) concentrations in any brain area as measured approximately 20 h after the last exposure to IMO. Exposure to behavioral tests did not modify neurochemical variables except NA levels in the hypothalamus of nonchronically stressed (control) rats. Both exposure to 2-h IMO or 2-h shock significantly decreased NA levels in hypothalamus and midbrain of nonchronically stressed rats. These decreases in response to the two acute stressors were not observed in chronically stressed rats. However, MHPG-SO4 levels increased to the same extent in control and chronically stressed rats after exposure to the acute stressors. Likewise, increased 5-HIAA concentrations observed in response to acute stressors were similar in control and chronically stressed rats. The inhibition of activity (areas crossed and rearing) in the holeboard caused by acute IMO was less marked in rats previously exposed to the same stressor than in control rats, but the response to shock was similar. In the forced swim test, acute IMO decreased struggling in control rats but tended to increase it in chronically stressed rats. The response to shock followed the same pattern as that to IMO, although it was slight.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of Aspirin and Dexamethasone against Experimentally Induced Depression in Rats

A large number of current studies indicate that inflammatory mediators may contribute to depression in experimental models as well as in human beings. Nevertheless, the subject, whether anti‐inflammatory treatments can prevent depression still remains controversial. In the present study, a chronic mild stress (CMS) model of male Sprague Dawley rats was used to investigate the role of anti‐inflammatory drugs in the treatment of depression. All the animals in different groups, except the normal control group, were exposed to CMS procedure for 28 days and concurrently treated with aspirin (10 mg/kg, p.o.), dexamethasone (1 mg/kg p.o.) and amitriptyline (10 mg/kg p.o., reference standard), respectively. Amitriptyline was also used in combination with aspirin and dexamethasone to inspect any synergistic effects. Tests performed towards the end of the study included sucrose preference test, behavioural tests like forced swim test, elevated plus‐maze, light/dark box, locomotor activity and biochemical estimations like serum cortisol and brain neurotransmitters. Disease control group (CMS‐treated) produced significant depressive behaviour in rats. The animals treated with aspirin showed increased sucrose preference, decreased immobility time in forced swim test, decreased serum cortisol and increased brain serotonin levels signifying antidepressant action. In contrast, there was aggravation of depressive behaviour in rats treated with dexamethasone. Together, these findings suggest that aspirin can serve as a potential antidepressant both individually and as adjunctive agent in the treatment of depression. Inhibition of the inflammatory mediators during stress procedures or any other potential physiological and biochemical mechanisms may be involved in its antidepressant effect.     

Chronic variable stress or chronic morphine facilitates immobility in a forced swim test: reversal by naloxone

The behaviors displayed in a forced swim test were investigated in rats previously exposed to a chronic variable stress treatment or chronic administration of morphine. In addition, to further explore the participation of an endogenous opiate mechanism in these behavioral effects, naloxone was either administered during the chronic treatment (prior to each stress or morphine exposure) or immediately prior to the forced swim test. Animals were submitted daily to a different stressor for 1 week or injected with morphine (10 mg/kg, IP) for 6 days, whereas controls were unmanipulated except for the injection process. On the day following the last stressor, control and stressed animals were administered saline or naloxone (2 mg/kg, IP) 15 min prior to the forced swim test. Morphine treated animals were similarly tested on the third day following the last morphine injection. In a separate group of rats, naloxone (2 mg/kg, IP) was administered daily 10 min prior to each stressor of the chronic stress regime or each daily morphine injection. A significant increase in the time spent in immobility was observed in stressed animals as well as in rats chronically treated with morphine. In both groups, this potentiated immobility was attenuated by naloxone pretreatment prior to the forced swim test or when given before each daily stressor or morphine injection. In addition, the concurrent exposure to stress or morphine along with naloxone administration enhanced struggling in the first 5 min of the forced swim test. Taken together, the results of these experiments support the conclusion that the increase in immobility seen following chronic variable stress or repeated morphine exposure is modulated by the activation of an endogenous opiate mechanism, given that this effect is attenuated by naloxone administration.     

Chronic fluoxetine treatment partly attenuates the long-term anxiety and depressive symptoms induced by MDMA ('Ecstasy') in rats.

Use of the drug 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') can have long-term adverse effects on emotion in both humans and laboratory animals. The present study examined whether chronic treatment with the antidepressant drug fluoxetine could reverse such effects. Male Wistar rats were briefly exposed to MDMA (4 x 5 mg/kg over 4 h) or vehicle on 2 consecutive days. Approximately 9-12 weeks later, half of the rats received a dose of approximately 6 mg/kg/day fluoxetine in their drinking water for a 5-week period. Fluoxetine administration reduced fluid intake and body weight in MDMA and vehicle pretreated rats. After several weeks of fluoxetine treatment, rats were assessed on the social interaction test, the emergence test of anxiety and the forced swim model of depression. MDMA pretreated rats showed reduced social interaction, increased anxiety on the emergence test, and increased immobility and decreased active responses in the forced swim test. Fluoxetine treatment reversed MDMA-induced anxiety in the emergence test and depressive-like effects in the forced swim test, yet exhibited no effects on the social interaction test. MDMA pretreated rats had decreased 5-HT and 5-HIAA levels in limbic and cortical regions, and decreased density of serotonin transporter sites in the cortex. Fluoxetine treatment did not greatly affect 5-HT levels in MDMA pretreated rats, but significantly decreased 5-HIAA levels in all brain sites examined. Postmortem blood serum levels of fluoxetine and norfluoxetine did not differ in MDMA and vehicle pretreated rats. These results indicate that fluoxetine may provide a treatment option for some of the deleterious long-term effects resulting from MDMA exposure.     

Interaction between chronic stress and clomipramine treatment in rats. Effects on exploratory activity,behavioral despair,and pituitary-adrenal function

The interaction between the effects of chronic electrical tail shock and clomipramine (CMI) on exploratory activity, behavioral despair and pituitary-adrenal function was studied in adult male rats. Both CMI and shock administered alone significantly reduced exploratory activity in a novel environment (holeboard). Neither interaction nor additive effects were observed when the two treatments were combined. In contrast, chronic shock increased the immobility in the forced swimming test (behavioral despair) and this effect was completely prevented by concomitant CMI administration. Pituitary-adrenal function was not significantly influenced by any of the treatments. The results indicate that: (a) chronic CMI treatment prevented some but not all behavioral changes caused by chronic shock, and (b) no interaction with basal and stress levels of pituitary-adrenal hormones was observed.     

Delayed effects of antidepressant drugs in rats

The present study has addressed the question of what is more important for the occurrence of adaptive changes observed in the organism treated with antidepressant drugs: a daily dosing of the drug or the period of time necessary for the plastic events to develop. Here, we report on the effects of desipramine given to rats acutely (and tested following 2 drug-free weeks) as when the drug was administered repeatedly, on behavior in the forced swim test (i.e. significant shortening of immobility time by ca. 60%) and on the binding of [3H]CGP12177 to beta-adrenergic receptors in the rat brain cortex (significant decrease of the binding by ca. 15%). Additionally, using the procedure of the repeated forced swim test (six times over 21 days), we show that the shortening of immobility time induced by a single dose of imipramine persisted throughout the whole experimental period and was similar to that seen in a group of animals treated repeatedly with the drug. Also, the effects of citalopram on immobility and climbing were similar after acute treatment and delayed testing to those seen after repeated drug exposure. The results obtained in the present study may question some conclusions that are usually drawn from the behavioral and, especially, biochemical studies concerning the need for repeated treatment with antidepressant drugs to induce various adaptive changes in the brain, which are thought to be responsible for the therapeutic efficacy of these drugs.     

An estrogenic effect of 5alpha-androstane-3beta, 17beta-diol on the behavioral response to stress and on CRH regulation

The gender difference in behavioral and hormonal response to stress is well known, but the underlying mechanism remains elusive. Arginine-vasopressin (AVP) and corticotrophin-releasing hormone (CRH) are two major regulatory peptides in the brain involved in stress regulation. Their response to stress has been shown to be modulated by sex hormones. The androgen metabolite, 5alpha-androstane-3beta, 17beta-diol (3beta-diol), has been identified as an estrogenic hormone. It binds to estrogen receptors (ERs) and modulates estrogen response element mediated promoter activities via the ER pathway. The present study involved in vitro transfection assays to examine whether 3beta-diol can directly modulate CRH and AVP promoter activity. Our results demonstrate that in CHO-K1 cell lines, when ERs were over-expressed, 3beta-diol could significantly stimulate CRH and AVP promoter activity through an ER pathway. The effect of 3beta-diol on the behavioral, the CRH and the AVP response to stress in the rat was also investigated. We found that chronic, but not acute administration of 3beta-diol significantly decreased the immobile duration in the forced swim test. In rats exposed to the forced swim test, CRH mRNA expression in the hypothalamus was enhanced by chronic 3beta-diol administration, while the AVP mRNA expression was not affected. These results suggest that 3beta-diol may play an anti-depressive role in affective behavior and may have a direct effect on CRH expression.     

Modification of behavioral response to intra-hippocampal injections of noradrenaline and adrenoceptor agonists by chronic treatment with desipramine and citalopram: functional aspects of adaptive receptor changes

The present study investigated the effects of acute and of chronic treatment with desipramine (DI) and citalopram (CT) on the alterations in rat behavior in the open field and in the forced swim tests produced by intra-hippocampal microinjections of noradrenaline (NA) and adrenoceptor agonists. Chronic but not acute treatment with DI potentiated the stimulatory effects of NA on the rats' behavior in the open field test and in the forced swim test as well as revealed the excitatory effect of microinjections of phenylephrine at a dose producing insignificant changes when given alone. The depressive effects of clonidine in the open field test were antagonized by acute DI administration and reversed by chronic DI. No characteristic changes in the isoproterenol-induced increase in rat locomotion were observed following chronic DI since the antagonistic interaction was found after both acute and chronic DI pretreatment. Chronic though not acute administration of CT produced effects in the forced swim test similar to those of DI, i.e. excitatory effects of phenylephrine and clonidine on behavior. The data indicate a potentiation of excitatory processes in the brain limbic structure, probably mediated via alpha 1-adrenoceptors.     

Pharmacological validation of a chronic social stress model of depression in rats: effects of reboxetine, haloperidol and diazepam

Chronic social stress is one of the most important factors responsible for precipitation of depressive disorder in humans. In recent years, the impact of social stress on the development of psychopathologies has been thoroughly investigated in preclinical animal studies. We have shown recently that behavioural effects of chronic social stress in rats can be reversed by citalopram and fluoxetine. This study has been designed for further pharmacological validation of the chronic social stress paradigm as a model of depressive symptoms in rats. For this, rats were subjected to 5 weeks of daily social defeat and were in parallel treatment for a clinically relevant period of 4 weeks with the antidepressant drug reboxetine (40 mg/kg/day) and the neuroleptic drug haloperidol (2 mg/kg/day). The anxiolytic diazepam (1 mg/kg) was administered acutely at the end of the stress period. Stress caused decreased locomotor and exploratory behaviours, decreased sucrose preference and increased immobility in the forced swim test, but did not affect behaviour in the elevated plus maze. Four weeks of oral treatment with reboxetine ameliorated the adverse effects of social stress and normalized behaviours related to motivation and reward sensitivity. The treatment with haloperidol worsened the adverse effects of chronic social stress having effects similar to stress on reward and motivation-related behaviours. Diazepam reduced anxiety-related behaviours as measured in elevated plus maze in control animals having no effects on socially stressed individuals. Neither sucrose preference nor performance in forced swim test was affected by diazepam. The effectiveness and selectivity of the treatment with the antidepressant reboxetine in ameliorating socially induced behavioural disturbances supports the validity of the chronic social stress as a model of depressive-like symptoms in rats.     

Bright light blocks the capacity of inescapable swim stress to supersensitize a central muscarinic mechanism

Clinical and basic researchers have proposed that muscarinic cholinergic mechanisms mediate some effects of chronic stress. Chronic inescapable (forced) swim stress depletes brain biogenic amines and is used to produce learned helplessness in rats. Behavioral and biochemical characteristics of animals in the state of learned helplessness lead some investigators to believe this condition provides a useful animal model of depression. Inescapable swim stress also produces supersensitivity to the hypothermic effect of the muscarinic agonist oxotremorine in the rat. The authors previously demonstrated that bright light potently induces subsensitivity of a central muscarinic mechanism involved in the regulation of core temperature under a variety of circumstances. They now report using a repeated measures design that inescapable swim stress of five days duration produces supersensitivity to oxotremorine (increase in thermic response of 405%). This supersensitivity is reversed within five days by treatment with bright light, despite continuation of daily swim stress. Daily inescapable swim stress was continued beyond cessation of treatment with bright light. Five days later, supersensitivity to the hypothermic effect of oxotremorine was once again evident.     

Impact of water temperature and stressor controllability on swim stress-induced changes in body temperature, serum corticosterone, and immobility in rats

The present study compared the effects of three different water temperatures (20, 25, and 30 degrees C) and stressor controllability on several physiological and behavioral endpoints in an intermittent swim stress paradigm. The escape latency of rats in the 20 and 25 degrees C water was less than that observed for the 30 degrees C group. Both escape and yoked groups at 20 and 25 degrees C exhibited moderate to severe hypothermia following the swim stress session that returned to prestress levels 30-40 min post-stress. At 30 degrees C core body temperature (Tb) only decreased by 1 degree C for either swim group. Following swim, serum corticosterone (CORT) levels were significantly elevated in both escape and yoked groups in comparison to confined and home cage controls. The confined control group showed a significant elevation that was approximately halfway between the home cage control and the swim stress groups. At 30 degrees C, there was still a significant elevation of serum CORT in both swim groups in comparison to confined and home cage controls. Therefore, 30 degrees C appears to be the optimal water temperature to evaluate stress controllability effects in the current paradigm. In a final experiment, swim stressor controllability effects were examined in a 5 min forced swim test (FST) 24 h following the initial stress exposure. Rats exposed to yoked-inescapable swim stress at 30 degrees C exhibited more immobility than their escapable swim stress and confined counterparts, while the escape and confined controls did not differ. These results demonstrate that the behavioral deficits observed in the FST are attributable to the stress of inescapable swim and not swim stress per se.     

Effects of neonatal alcohol and/or cocaine exposure on stress in juvenile and adult female rats

The effects of neonatal exposure to alcohol and/or cocaine on two measures of stress were studied in juvenile and young adult female rats. After implantation with an intragastric cannula, subjects were artificially reared from postnatal days 4-10. This "brain growth spurt" period is roughly equivalent to CNS development during the third trimester of human pregnancy. There were five treatment groups: alcohol (6 g/kg/day), cocaine (60 mg/kg/day), alcohol/cocaine (6 g/kg/day alcohol and 60 mg/kg/day cocaine), stock (an artificially reared control), and sham (a suckled control). Subjects were tested in open field and forced swim tests beginning at 21 or 60-70 days of age, respectively. Compared to controls, alcohol-exposed females displayed longer latencies to become immobile in the forced swim test as juveniles and cocaine-exposed females showed increased immobility as adults. Increased immobility can be interpreted as hyporesponsiveness to stress. In contrast, very few differences were observed in the open field. Furthermore, the group exposed to alcohol and cocaine in combination did not differ from controls in either paradigm. These findings suggest that the forced swim test may be more sensitive to neonatal drug effects than open field, although these effects may not be consistent across age.     

Increased anxiety and "depressive" symptoms months after MDMA ("ecstasy") in rats: drug-induced hyperthermia does not predict long-term outcomes

Rationale There is some uncertainty whether the acute hyperthermia caused by MDMA (ecstasy) plays a significant role in determining the long-term neurotoxic effects on brain 5-HT systems and associated changes in mood and behaviour. Objective The present study assessed whether long-term behavioural and cognitive changes seen in MDMA-treated rats are affected by hyperthermia at the time of drug administration. Method Male Wistar rats were treated with MDMA (4×5 mg/kg i.p. over 4 h on 2 consecutive days) or vehicle at either a high ambient temperature (28°C) or a low ambient temperature (16°C). Eight to 18 weeks later, rats were tested in behavioural measures of anxiety (social interaction and emergence tests), a test of cognition (object recognition test) and the forced swim test of depression. At the conclusion of behavioural testing the rats were killed and their brains analysed using HPLC. Results MDMA treatment caused a clear and consistent hyperthermia at 28°C and hypothermia at 16°C. Months later, rats pre-treated with MDMA at either 16 or 28°C displayed increased anxiety in the social interaction and emergence tests and reduced escape attempts and increased immobility in the forced swim test. MDMA pre-treatment was also associated with poorer memory on the object recognition test, but only in rats given the drug at 28°C. Rats pre-treated with MDMA showed loss of 5-HT in the hippocampus, striatum, amygdala and cortex, regardless of body temperature at the time of dosing. However, 5-HIAA loss in the amygdala and hippocampus was greater in rats pre-treated at 28°C. Dopamine in the striatum was also depleted in rats given MDMA. Conclusions These results indicate that hyperthermia at the time of dosing with MDMA is not necessary to produce subsequent 5-HT depletion and anxiety in rats. They also extend previous findings of long-term effects of brief exposure to MDMA in rats to include apparent "depressive" symptoms in the forced swim model.     

Injection of vehicle is not a stressor in Porsolt's swim test.

A single injection or chronic injections with vehicle are reported to induce physical changes in the brain, suggesting this treatment may be stressful. Furthermore, preliminary observations indicate that vehicle injections may interact with the behavioral effects of psychoactive compounds. We investigated the behavioral response to an injection in two tests sensitive to stress: Porsolt's swim test of depressive behavior and the resident-intruder test of aggression. Acute or repeated injections of vehicle did not alter immobility in the swim test in "normal" male NIH Swiss mice, isolated mice, or mice previously exposed to continuous fight stress. Behavior in the resident-intruder test was similar in injected and noninjected mice. The present data suggest that in male NIH Swiss mice a vehicle injection does not induced behavioral changes in tests sensitive to stress, although it is shown to alter various physiological parameters indicative of stress.     

Stressors affect the response of male and female rats to clomipramine in a model of behavioral despair (forced swim test)

Aim of the present study was to evaluate the effects of physical stressors (electric foot-shocks) on effect of the antidepressant drug, clomipramine and plasma corticosterone levels in male and female rats tested in a model of behavioral despair (forced swim test,). Male and female rats of the Wistar strain were injected with clomipramine (50 mg/kg, i.p.) or saline. A group of animals also received electric shocks of different intensity and duration of 24, 5 and 1 h before being subjected to forced swim test. At the end of behavioral procedures, vaginal smears were assessed in all female animals and data on immobility time were plotted according to the ovarian cycle phase. After decapitation, corticosterone plasma levels were measured by radioimmunoassay in both male and female rats. Application of mild shocks (5 ms, 0.1 mA) significantly reduced immobility time in forced swim test of untreated male rats and augmented clomipramine effect on this parameter. Moderate shocks of higher intensity or duration (5 ms, 1.0 mA) also resulted in decreased immobility time of untreated male rats, but in reduced effect of clomipramine treatment. Furthermore, application of severe shocks (10 ms, 1.0 mA) increased the immobility time in untreated animals and totally abolished clomipramine effect in forced swim test. Untreated non-shocked female rats in proestrous and estrous phases exhibited a longer immobility time as compared to diestrous animals. Immobility time appeared to be generally higher when mild, moderate or severe shocks were applied prior to behavioral testing in proestrous and estrous animals, while the behavioral response of diestrous and metestrous animals did not differ from that of controls. Clomipramine effect on immobility time was generally reduced by application of shocks of every strengths. Stress-induced plasma corticosterone levels surge correlated with intensity and duration of shocks in both male and female rats, but clomipramine treatment generally blunted the hormonal response. However, severe shocks were followed by a surge of plasma corticosterone levels in both male and female clomipramine-treated rats.

These results demonstrate that duration and intensity of stressful stimuli may deeply affect the behavioral response of rats in forced swim test and influence clomipramine effect in this behavioral model depending on gender-based variables, probably of the hormonal type. Plasma corticosterone levels correlate with the behavioral response to clomipramine treatment suggesting that reactivity of hypothalamus–pituitary–adrenal axis to stress may be involved in the antidepressant effect of this drug.     

Changes in PPARδ expression in a rat model of stress‐induced depression

Depression is a common mental disorder that has been linked to a decrease in the expression of serotonin and/or the serotonin transporter in the brain. Antidepressants that target the monoaminergic system are widely used in the clinical setting. Peroxisome proliferator‐activated receptor δ (PPAR δ) overexpression or activation is thought to improve depression‐like behaviours in rodents. The present study was designed to characterize the changes in PPARδ expression in the hippocampus in rats with stress‐induced depression. We used an unpredictable chronic mild stress (CMS) model in rats to study the role of PPARδ in the hippocampus. Behaviour was evaluated via a forced swim test (FST), a tail suspension test (TST), and a sucrose preference test (SPT). Then, the changes in PPARδ expression and other signals were determined using Western blots. We found that PPARδ expression in the hippocampus was markedly reduced in rats with depression. Moreover, the expression of the serotonin transporter was also significantly decreased. Treatment with a PPARδ agonist enhanced the expression of PPARδ and the serotonin transporter in the hippocampus of rats with stress‐induced depression. Additionally, treatment with a PPARδ agonist increased the expression of the serotonin transporter in cultured hippocampal (H19‐7) cells, and this action was ablated in the absence of PPARδ, which was attenuated with shRNA. Taken together, we found that PPARδ plays an important role in the regulation of serotonin transporter expression and that chronic stress may lower PPARδ expression in the brain via apoptosis and may attenuate serotonin transporter expression, thus inducing depression in rats.     

Antidepressant-like effects of NMDA-receptor antagonist injected into the dorsal hippocampus of rats

Exposure to uncontrollable stressors causes behavioral changes that have been related to depressive states in humans. Poststress intrahippocampal administration of amino-7-phosphonoheptanoic acid (AP-7), a glutamate NMDA-receptor antagonist, attenuated the restraint-induced decreased exploration of an elevated plus maze 24 h later. The objective of the study was to test if this treatment would also attenuate the increased immobility seem in the forced swim test (FST) due to preexposition to this stressful situation. Male Wistar rats with cannulae aimed at the dorsal hippocampus were submitted to 15 min of forced swimming and tested 24 h later. They received bilateral intrahippocampal injections of AP-7 (10 nmol) either before or after the pretest swimming session or before the test. Poststress treatment increased latency to display the first episode of immobility and tended to reduce total immobility time. The drug was ineffective when given before stress or before test and in nonstressed animals. This suggests that glutamate NMDA receptors located in the dorsal hippocampus are involved in the behavioral changes observed in the FST.     

Chronic treatment with imipramine reverses immobility behaviour, hippocampal corticosteroid receptors and cortical 5-HT(1A) receptor mRNA in prenatally stressed rats

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.     

Chronic forced swim stress inhibits ultra-low dose morphine-induced hyperalgesia in rats

Ultra-low doses of morphine (UL-morphine) induce hyperalgesia, which is assumed to be mediated by stimulatory G proteins (G(alphas)) signaling pathway. G(alphas) pathway inhibition and chronic stress both attenuate development of tolerance to analgesic effect of morphine. This study evaluated the effect of chronic stress on UL-morphine-induced hyperalgesia to find out if chronic stress interacts with the G(alphas) signaling pathway. Repeated daily forced swim stress was applied to induce chronic stress. UL-morphine (1 microg/kg, intraperitoneal)-induced hyperalgesia was assessed using the tail-flick test on day 6, in male rats that during days 1-5 received different treatments of swim stress, dexamethasone, swim stress following adrenalectomy (ADX) or swim stress after sham operation. Chronic stress by itself induced hyperalgesia in control and sham-operated rats but inhibited UL-morphine-induced hyperalgesia. In ADX animals, chronic stress did not produce hyperalgesia and could not inhibit UL-morphine-induced hyperalgesia. Chronic dexamethasone produced hyperalgesia but did not change the UL-morphine-induced hyperalgesia. Inhibition of UL-morphine hyperalgesia by chronic stress suggests that chronic stress interacts with the G(alphas) signaling pathway, which is responsible for UL-morphine-induced hyperalgesia. The absence of this effect in the ADX-rats or after repetitive dexamethasone administration demonstrates that hypothalamic-pituitary-adrenal (HPA) axis activation is necessary for controlling UL-morphine-induced hyperalgesia. Finally, the interaction of stress with the G(alphas) signaling pathway may provide an explanation for the inhibitory effect of stress on development of tolerance to the analgesic effect of morphine.