Inescapable Footshock Research Articles

Hippocampal Glycogen Synthase Kinase 3β is Critical for the Antidepressant Effect of Cyclin-Dependent Kinase 5 Inhibitor in Rats

Cdk5 is a member of cyclin-dependent kinase (Cdk), a proline-directed serine/threonine kinase, and plays a key role in normal neural development and function. Evidence of previous study showed that chronic inhibition of Cdk5 in hippocampal dentate gyrus (DG) blocked the development of depressive-like symptoms, suggesting that Cdk5 plays a role in development of depression. Forced swim test, novelty-suppressed feeding test, and learned helplessness were used to evaluate the cellular and molecular mechanisms underlying the behavioral regulation of Cdk5 inhibitors in rats. Two Cdk5 inhibitors butyrolactone and roscovitine were used to investigate the possible antidepressant-like actions of Cdk5 blockade and the potential mechanisms. Systemic administration of butyrolactone (200 mg/kg, IP) or roscovitine (100 mg/kg, IP) produced effective antidepressant-like actions. Moreover, infusion (5 mM) of GSK3β activator LY294002 into DG abolished the antidepressant-like actions of butyrolactone and roscovitine, suggesting that inhibition of GSK3β might be involved in the antidepressant effect of Cdk5 inhibitors. Moreover, pretreatment of LY294002 (5 mM) blocked the antidepressant-like effect of butyrolactone and roscovitine in learned helplessness. Additionally, inescapable footshock induced a significant increase of GSK3β activity, while butyrolactone and roscovitine decreased GSK3β activity. In contrast, pretreatment of LY294002 prevented the inhibitory effects of butyrolactone and roscovitine on GSK3β activation. Finally, a specific GSK3β inhibitor, SB216763 (1 ng, DG), demonstrated an effective antidepressant-like action. These findings demonstrate that systemic administration of Cdk5 inhibitors produced antidepressant-like actions and that inhibition of GSK3β is involved in behavioral response of Cdk5 inhibitors.

Fear-potentiated behaviour is modulated by central amygdala angiotensin II AT1 receptors stimulation.

Central nucleus of the amygdala (CeA) is one of the most important regulatory centres for the emotional processes. Among the different neurotransmitter systems present in this nucleus, AT1 receptors have been also found, but their role in the generation and modulation of emotions is not fully understood. The present work evaluated the effect of intra-amygdalar injection of losartan (AT1 receptor antagonist) and angiotensin II (Ang II) in the anxiety state induced by fear-potentiated plus maze in male Wistar rats. Fear in the elevated plus maze can be potentiated by prior inescapable footshock stress. The decrease in the time spent in the open arms induced by the inescapable footshock was totally prevented by losartan (4 pmol) administration in CeA. It was also found that Ang II (48 fmol) administration decreased the time spent in the open arms in animals with or without previous footshock exposure. The locomotor activity and grooming behaviour were also evaluated. The results obtained from the different parameters analyzed allowed us to conclude that the Ang II AT1 receptors in CeA are involved in the anxiety state induced by stress in the fear-potentiated plus-maze behaviour.

Amnesia for Early Life Stress Does Not Preclude the Adult Development of Posttraumatic Stress Disorder Symptoms in Rats

Traumatic experience can result in life-long changes in the ability to cope with future stressors and emotionally salient events. These experiences, particularly during early development, are a significant risk factor for later life anxiety disorders such as posttraumatic stress disorder (PTSD). However, because traumatic experience typically results in strong episodic memories, it is not known whether such long-term memories are necessary for particular features of PTSD, such as enhanced fear and anxiety. Here, we used a fear conditioning procedure in juvenile rats before maturation of the neural systems supporting declarative memory to assess the necessity of early memory to the later life development of PTSD-related symptoms. Nineteen-day old rats were exposed to unpredictable and inescapable footshocks, and fear memory for the shock context was assessed during adulthood. Thereafter, adult animals were either exposed to single-trial fear conditioning or elevated plus maze or sacrificed for basal diurnal corticosterone and quantification of neuronal glucocorticoid and neuropeptide Y receptors. Early trauma exposed rats displayed stereotypic footshock reactivity, yet by adulthood, hippocampus-dependent contextual fear-related memory was absent. However, adult rats showed sensitized fear learning, aberrant basal circadian fluctuations of corticosterone, increased amygdalar glucocorticoid receptors, decreased time spent in the open arm of an elevated plus maze, and an odor aversion associated with early-life footshocks. These results suggest that traumatic experience during developmental periods of hippocampal immaturity can promote lifelong changes in symptoms and neuropathology associated with human PTSD, even if there is no explicit memory of the early trauma.

Acute psychological stress results in the rapid development of insulin resistance

In recent years, the roles of chronic stress and depression as independent risk factors for decreased insulin sensitivity and the development of diabetes have been increasingly recognized. However, an understanding of the mechanisms linking insulin resistance and acute psychological stress are very limited. We hypothesized that acute psychological stress may cause the development of insulin resistance, which may be a risk factor in developing type 2 diabetes. We tested the hypothesis in a well-established mouse model using 180 episodes of inescapable foot shock (IES) followed by a behavioral escape test. In this study, mice that received IES treatment were tested for acute insulin resistance by measuring glucose metabolism and insulin signaling. When compared with normal and sham mice, mice that were exposed to IES resulting in escape failure (defined as IES with behavioral escape failure) displayed elevated blood glucose levels in both glucose tolerance and insulin tolerance tests. Furthermore, mice with IES exposure and behavioral escape failure exhibited impaired hepatic insulin signaling via the insulin-induced insulin receptor/insulin receptor substrate 1/Akt pathway, without affecting similar pathways in skeletal muscle, adipose tissue, and brain. Additionally, a rise in the murine growth-related oncogene KC/GRO was associated with impaired glucose metabolism in IES mice, suggesting a mechanism by which psychological stress by IES may influence glucose metabolism. The present results indicate that psychological stress induced by IES can acutely alter hepatic responsiveness to insulin and affect whole-body glucose metabolism.

Low-frequency stimulation of the ventral hippocampus facilitates extinction of contextual fear

Difficulties to treat fear-associated disorders, including posttraumatic stress disorder, are thought to result from dysfunction in fear extinction learning and/or memory. Animal studies on extinction modulation are therefore promising for the development of new treatments. Recent rat studies, including ones using low-frequency stimulation (LFS), have demonstrated that the ventral hippocampus (VH) modulates extinction memory. The present study explores whether the VH also modulates extinction learning. For this, rats were implanted with stimulating electrodes in the VH and experienced contextual fear conditioning, followed 6 or 24h later by VH LFS and three sessions of extinction training. We found that, whatever the delay used (6 or 24h), animals that received VH LFS displayed persistent low levels of freezing from the second extinction session, whereas control rats showed low levels of freezing only during the third session. In animals submitted to a stress condition (provoked by a single inescapable foot-shock followed by three sessions of situational reminders) prior to fear conditioning, VH LFS also reduced freezing levels, which, in contrast, remained high in control rats during the course of extinction training. These data suggest that LFS, targeting the VH, may be useful in reducing fear responses during extinction learning.

Effect of Five-Consecutive-Day Exposure to an Anxiogenic Stressor on Sleep-Wake Activity in Rats

Repeated exposure to an anxiogenic stressor (AS) is a known environmental factor for the development of depression, yet the progression of sleep-wake (S-W) changes associated with the onset of AS-induced depression (ASID) is not completely understood. Thus, the aim of this study was to identify these progressive S-W changes by developing ASID in rats, via repeated exposure to an AS, and compare this ASID-associated sleep phenotype with the sleep phenotype of human depression. To achieve this aim, rats were first recorded for a 6 h period of baseline S-W activity without AS. Then, rats were subjected to 5 days of AS [Day 1: inescapable foot-shock; 5 trials of 3 s foot-shocks (1.0 mA) at 3 min intervals; Days 3–5: 15 trials of 5 s foot-shocks at 45 s intervals]. S-W activity was recorded for 6 h immediately after each AS treatment session. Two days later rats were again recorded for 6 h of S-W activity, but with no exposure to the AS (NASD). Compared to the baseline day: Day 1 of AS (ASD-1) increased wakefulness, slow-wave sleep (SWS) latency, and rapid-eye movement (REM) sleep latency, but decreased the total amount of REM sleep; ASD-2 animals remained awake throughout the 6 h S-W recording period; ASD-3, ASD-4, and ASD-5 (ASDs-3–5) decreased wakefulness, SWS latency, and REM sleep latency, but increased the total amount of REM sleep. Interestingly, these results reveal that initial exposure to the AS versus later, repeated exposure to the AS produced opposing S-W changes. On NASD, animals exhibited baseline-like S-W activity, except slightly less REM sleep. These results suggest that repeated AS produces a sleep phenotype that resembles the sleep phenotype of depression in humans, but consistent re-exposure to the AS is required. These results are promising because the methodological simplicity and reversibility of the ASID-associated S-W phenotype could be more advantageous than other animal models for studying the pathophysiological mechanisms that underlie the expression of ASID.

Behavioral Consequences of Chronic Stress and Effects of Antidepressant Treatment on Animal Models of Depression

Major depression has a high prevalence and a high mortality. In order to understand the molecular changes underlying major depression animal models are needed. The different animal models of depression simulate the etiology and replicates symptoms, course and treatment of human depression properly. In this study, we investigated stress-induced depressogenic induction among the rats using Shuttle Box Escape Test, Open Field Test (OFT) and Elevated Plus Maze (EPM) Test. Fluoxetine hydrochloride (FLX), an antidepressant was administered chronically to determine antidepressant mediated recovery of their behavioral homeostasis. In addition, all the behavioral tests demonstrated a variety of specific symptoms like changes in locomotor activity, impaired learning ability and cognition deficit etc. From these findings, we can conclude that chronic inescapable foot-shocks at 0.8mA intensity for 15 sec duration are the most effective stressor to produce animal model of depression. After exposure to chronic foot-shocks, FLX mediated recovery strengthen our findings. In addition, the rats were screened through shuttle box escape test that mimic depressive-like behavior properly in animals. Our observation clearly corroborates well with the learned helplessness (LH) paradigm. So, the animal models of depression using electric foot-shock to induce depressive like behavior, have excellent face validity and replicate anhedonia and anergia in analogy to loss of interest and pleasure.

Novelty, but not operant aversive learning, enhances Fos and Egr-1 expression in the medial prefrontal cortex and hippocampal areas of rats.

Immediate early genes (IEG) are presumed to be activated in response to stress, novelty, and learning. Evidence supports the involvement of prefrontal and hippocampal areas in stress and learning, but also in the detection of novel events. This study examined whether a previous experience with shocks changes the pattern of Fos and Egr-1 expression in the medial prefrontal cortex (mPFC), the hippocampal cornus ammonis 1 (CA1), and dentate gyrus (DG) of adult male Wistar rats that learned to escape in an operant aversive test. Subjects previously exposed to inescapable footshocks that learned to escape from shocks were assigned to the treated group (EXP). Subjects from Group Novelty (NOV) rested undisturbed during treatment and also learned to escape in the test. The nonshock group (NSH) rested undisturbed in both sessions. Standard immunohistochemistry procedures were used to detect the proteins in brain sections. The results show that a previous experience with shocks changed the pattern of IEG expression, then demonstrating c-fos and egr-1 induction as experience-dependent events. Compared with NSH and EXP an enhanced Fos expression was detected in the mPFC and CA1 subfield of Group NOV, which also exhibited increased Egr-1 expression in the mPFC and DG in comparison to NSH. No differences were found in the DG for Fos, or in the CA1 for Egr-1. Novelty, and not the operant aversive escape learning, seems to have generated IEG induction. The results suggest novel stimuli as a possible confounding factor in studies on Fos and/or Egr-1 expression in aversive conditions.

Stress Increases Voluntary Alcohol Intake, but Does not Alter Established Drinking Habits in a Rat Model of Posttraumatic Stress Disorder

Life-altering anxiety disorders, such as posttraumatic stress disorder (PTSD), can co-occur at high rates with substance use disorders. Alcoholism, compared with other substance use disorders, is particularly common. Rodent studies of acute stress effects on alcohol consumption show that stress can alter ethanol (EtOH) consumption. This study examined voluntary EtOH consumption in male Long-Evans rats that had undergone a stress-enhanced fear learning (SEFL) procedure. Adult Long-Evans rats were exposed to a stress that consisted of 15 inescapable foot-shocks (1mA, 1second) known to cause a long-lasting nonassociative enhancement of subsequent fear learning. Control animals received no shock. One day later, animals were placed in a novel and very different context and received a single foot-shock. On day 3, animals were returned to the single shock context and freezing was used as a measure of learned fear. The intermittent access 2-bottle choice (2BC) regimen consisted of 1 bottle of water and 1 bottle of experimental solution, either 19% EtOH or 28.4% sucrose-0.08% quinine, for a 24-hour period, 3days a week, and all other times 2 water bottles. This regimen lasted until stable levels of experimental solution drinking were reached, at which point the experimental solution was removed for 40days and then returned to measure the resumption of consumption. Rats that received stress prior to EtOH consumed significantly more EtOH than control rats before and after reinstatement. Rats that received stress after drinking was established did not consume significantly more EtOH when the drug was returned. Stress had no significant effect on sucrose-quinine drinking, our calorie and taste control for EtOH. A single traumatic event sufficient to produce long-lasting enhancement of fear learning increases voluntary EtOH consumption, but does not alter previously acquired EtOH drinking habits or alter the consumption of a calorically equivalent sweet-bitter-tasting solution.

Subsecond Dopamine Release in the Nucleus Accumbens Predicts Conditioned Punishment and Its Successful Avoidance

The mesolimbic dopamine system is believed to be a pathway that processes rewarding information. While previous studies have also implicated a general role for dopamine in punishment and its avoidance, the precise nature of subsecond dopamine release during these phenomena remains unknown. Here, we used fast-scan cyclic voltammetry to investigate whether subsecond dopamine release events in the nucleus accumbens encode cues predicting the avoidance of punishment during behavior maintained in a signaled footshock avoidance procedure. In this task, rats could initiate an avoidance response by pressing a lever within a warning period, preventing footshock. Alternatively, once footshocks commenced, animals could initiate an escape response by pressing the lever, terminating footshock. This design allowed us to assess subsecond dopamine release events during the presentation of a warning signal, safety periods, and two distinct behavioral responses. We found that release consistently increased upon presentation of the warning signal in a manner that reliably predicted successful punishment avoidance. We also observed subsecond dopamine release during the safety period, as occurs following the receipt of reward. Conversely, we observed a decrease in release at the warning signal during escape responses. Because of this finding, we next assessed dopamine release in a conditioned fear model. As seen during escape responses, we observed a time-locked decrease in dopamine release upon presentation of a cue conditioned to inescapable footshock. Together, these data show that subsecond fluctuations in mesolimbic dopamine release predict when rats will successfully avoid punishment and differentially encode cues related to aversive outcomes.

Impact of the time in an animal model of mood disorder

The objective of the study is to evaluate whether intervening and testing in different rest-activity periods of the day would produce different measurements in animal behavior studies. Methodology: Thirty-five, 60-day-old male Wistar rats were submitted to an inescapable foot shock (IFS) stress model and behavioral tests (Light–Dark Box test). The animals received intervention and were tested in both light and dark phases, resulting in the following groups: control L (tested in the light), control D (tested in the dark), LL (IFS and tested in the light), LD (IFS in the light and tested in the dark), DL (IFS in the dark and tested in the light), and DD (IFS and tested in the dark). Results: The Light–Dark Box test showed that control L was not significantly different from other groups in any of the parameters. However, when comparing control D with the intervention groups, we observed a difference in the mean length of time spent in the light compartment (t=2.56; p=0.045). A significant difference in the number of crossings into the light compartment was only observed between the control D and the LL and LD groups (t=−2.608; p=0.028; t=−2.571; p=0.030, respectively). The latency time for the control D group was significantly lower than that of the DD group (t=−2.556; p=0.043). Conclusions: These results show that behavior testing during the animal's period of highest activity (dark period) revealed differences caused by the intervention, whereas no differences were apparent when the control group was observed during the day.

Reactivation of an aversive memory modulates learning strategy preference in male rats

Reminders of an aversive event adversely impact retrieval of hippocampus-dependent memories and exacerbate stress-induced levels of anxiety. Interestingly, stress and anxiety shift control over learning away from the hippocampus and toward the striatum. The aims of the current study were to determine whether spatial memory and learning strategy are impacted by reminders of a stressor. Adult male Long-Evans rats (N = 47) were subjected to an inhibitory avoidance (IA) training trial in which 32 rats were exposed (3 s) to a single inescapable electrical footshock (0.6 mA). Prior to the retention trial of a Y-maze task and the probe trials of two different learning strategy tasks, some of the rats that were exposed to the footshock (n = 17) were reminded of the stressor on an IA retrieval trial. Both groups of rats exposed to the initial stressor exhibited hypoactivity, but no impairment in spatial memory, on the Y-maze task conducted 1 week after exposure to the footshock. One month after exposure to footshock, both groups of rats exposed to the initial stressor tended to prefer a striatum-dependent learning strategy on a water T-maze task. However, 2 months after exposure to footshock, only shocked rats that were reminded of the stressor exhibited a preference for a striatum-dependent learning strategy on a visible-platform water maze task, which corresponded with lower levels of activity in an open field. The results indicate that reminders of a stressor perpetuate the deleterious effects of stress on affective and cognitive processes.

Long-term effects of footshock and social defeat on anxiety-like behaviours in rats: Relationships to pre-stressor plasma corticosterone concentration

We compared the consequences of two stressors, ‘unnatural’ inescapable footshocks (IFSs) and ‘natural’ social defeat (SD), on behaviours typically sensitive to stress [sucrose preference, open field (OF), elevated plus maze (EPM) and acoustic startle responses (ASRs)] and the association with pre-stressor plasma corticosterone concentration. After initial blood sampling, rats (n = 20 per group) were exposed to either 10 IFSs (1 mA intensity, 5 s duration each) or to 1 h SD (defeat by an aggressive resident male rat and further exposure but separated in a small cage) or to control procedures (handling). Rats were tested once for ASR (day 19), while the other behavioural tests were applied once weekly for 3 weeks. Both stress groups showed short-lasting lowered sucrose preference, and in the EPM they showed shorter total distance moved, shorter distance moved on open arms and less time on open arms compared to controls. In the OF test, IFS rats showed shorter total distance moved up to 2 weeks after stress. The SD group showed shorter total distance moved in the OF, which was only significant 2 weeks after stress. Low pre-stressor plasma corticosterone concentration was only associated with defecation (IFS rats) and latency to enter open arms in the EPM (all low corticosterone subgroups, n = 10 per subgroup). SD rats with high initial plasma corticosterone concentration showed enhanced ASR compared to the other subgroups with high initial plasma corticosterone concentration (n = 9 per subgroup). The results indicate that footshock and SD, while generally leading to an increase in anxiety behaviours, represent qualitatively different stressors.

Effects of different adrenergic blockades on the stress resistance of Wistar rats

The coordinated responses of the sympathoadreno-medullary (SAM) system and hypothalamic-pituitary-adrenal (HPA) axis could improve the organism's capacity to cope with stress, but its underlying mechanism is still unclear. In the present study, 32 Wistar rats were employed and divided into four groups: control, CUMS, PROP and PRAZ. After the chronic unpredicted mild stress (CUMS) model was built in the latter three groups, all animals were exposed to inescapable footshock. We found that α1-adrenoceptor antagonist prazosin (PRAZ) administration could improve behavior changes, reduce the cellular impairment in brain and inhibit the hyperfunction of HPA axis induced by CUMS exposure. Moreover, it decreased the heat shock protein 70 and inducible nitric oxide synthase expression in different brain areas as subsequently exposed to acute stress. In conclusion, α1-adrenoceptor may play a major role in regulating the coordinated responses between two physiological axes and improve the stress resistance.

Long-Lasting Effects of Maternal Separation on an Animal Model of Post-Traumatic Stress Disorder: Effects on Memory and Hippocampal Oxidative Stress

Adverse early life events, such as periodic maternal separation, may alter the normal pattern of brain development and subsequently the vulnerability to a variety of mental disorders in adulthood. Patients with a history of early adversities show higher frequency of post-traumatic stress disorder (PTSD). This study was undertaken to verify if repeated long-term separation of pups from dams would affect memory and oxidative stress parameters after exposure to an animal model of PTSD. Nests of Wistar rats were divided into intact and subjected to maternal separation (incubator at 32°C, 3h/day) during post-natal days 1-10. When adults, the animals were subdivided into exposed or not to a PTSD model consisting of exposure to inescapable footshock, followed by situational reminders. One month after exposure to the shock, the animals were exposed to a memory task (Morris water maze) and another month later animals were sacrificed and DNA breaks and antioxidant enzymes activities were measured in the hippocampus. Rats exposed to shock or maternal separation plus shock showed long-lasting effects on spatial memory, spending more time in the opposite quadrant of the water maze. This effect was higher in animals subjected to both maternal separation and shock. Both shock and maternal separation induced a higher score of DNA breaks in the hippocampus. No differences were observed on antioxidant enzymes activities. In conclusion, periodic maternal separation may increase the susceptibility to the effects of a stressor applied in adulthood on performance in the water maze. Increased DNA breaks in hippocampus was induced by both, maternal separation and exposure to shock.

Effects of corticotropin releasing factor (CRF) on sleep and body temperature following controllable footshock stress in mice

Rapid eye movement sleep (REM) is increased after controllable stress (modeled by escapable footshock, ES) and decreased after uncontrollable stress (modeled by inescapable footshock, IS). Decreases in REM after IS are exacerbated by corticotropin releasing factor (CRF) and attenuated by a CRF antagonist. In this study, we trained mice with ES following injections of CRF, astressin (AST), or saline (SAL) to determine whether CRF would alter REM after ES. Male BALB/cJ mice (n=7) were implanted for recording sleep, activity and body temperature via telemetry and with a guide cannula aimed into a lateral ventricle. After recovery from surgery, sleep following exposure to a novel chamber was recorded as a handling control (HC). The mice received one day of training with ES without injection followed by weekly training sessions in which they received counterbalanced intracerebroventricular (ICV) microinjections of either SAL or CRF (days 7 & 14) or SAL or AST (days 21 & 28) prior to ES. On each experimental day, sleep was recorded for 20h. Compared to HC, the mice showed significantly increased REM when receiving either SAL or AST prior to ES whereas CRF prior to ES significantly reduced REM. Stress-induced hyperthermia had longer duration after ES compared to HC, and was not significantly altered by CRF or AST compared to SAL. The current results demonstrate that activity in the central CRF system is an important regulator of stress-induced alterations in REM.

Effects of Intra-accumbens Administration of Dopamine Agonists on Stress-induced Behavioural Deficit

The effect of post-footshock injections of (+)-amphetamine, the selective D2-receptor agonist quinpirole (LY 171555), and the D2-receptor antagonist metoclopramide, into the nucleus accumbens, on the formation of the open field deficit, has been studied in rats. Microinjections of (+)-amphetamine (10 micrograms) stimulated rat locomotor activity tested 5 min later, while quinpirole (10 micrograms) significantly inhibited animal motility in the test. The open field behaviour was not changed 24 h after injection of either drug. Amphetamine applied immediately after inescapable footshock did not modify stress-induced locomotor depression, when the rats' behaviour was examined 24 h later. On the other hand, post-shock injections of quinpirole significantly attenuated the long-term effects of the stressor, in the open field. Metoclopramide (10 micrograms) inhibited rat locomotor activity 5 min, but not 24 h, after local injection. Administration of a solution containing both quinpirole (10 micrograms) and metoclopramide (1 microgram) decreased motor activity of unstressed rats to a smaller degree than did quinpirole (10 micrograms) alone. Post-footshock injection of metoclopramide did not affect stress-induced hypomotility. It is concluded that the present data support the hypothesis that local depletion of brain dopaminergic stores causes some behavioural effects of stressors.

SSR504734, a glycine transporter-1 inhibitor, attenuates acquisition and expression of contextual conditioned fear in rats

Conditioned stress-induced freezing has been used as an indicator of anxiety in rodents to evaluate the anxiolytic effects of various compounds. However, the role of glycinergic neurotransmission in fear conditioning is not well understood. In this study, we investigated the effects of a selective glycine transporter-1 inhibitor, SSR504734, on contextual fear conditioning. In a fear acquisition experiment, rats were administered SSR504734 (3-30 mg/kg, intraperitoneal) 1 h before fear conditioning (i.e. inescapable footshock). Twenty-four hours after fear conditioning, the rats were placed in the experimental chamber without footshock, and freezing behavior was observed. SSR504734 (30 mg/kg) significantly inhibited contextual conditioned freezing. In a fear expression experiment, rats were administered SSR504734 (3-30 mg/kg, intraperitoneal) 23 h after fear conditioning and were tested 1 h after injection. SSR504734 (30 mg/kg) significantly inhibited contextual conditioned freezing. These findings indicate that SSR504734 attenuates both the acquisition and expression of contextual conditioned fear, and suggest that glycinergic neurotransmission may play an important role in conditioned fear.

Swimming exercise effects on the expression of HSP70 and iNOS in hippocampus and prefrontal cortex in combined stress

Exercise could play a beneficial role in stress, but its underlying mechanism especially about heat shock protein 70 (HSP70) and inducible nitric oxide synthase (iNOS) in brain has not been fully clarified. Moreover, few studies have investigated swimming exercise and its effects on the combined stress of both chronic and acute stress. In this study we tried to investigate the role of swimming exercise in combined stress and whether its biological mechanism was related to the HSP70 and iNOS in hippocampus and prefrontal cortex. 32 Wistar rats were enrolled and divided into four groups: control, CUMS, labetalol and exercise. After the animal model of chronic unpredicted mild stress (CUMS) was built in the latter three groups, all the rats were given the novel acute stress of inescapable footshock. The behavioral changes were measured by open field test. Radioimmunoassay (RIA) was adopted to test the change of serum corticosterone (CORT). The expression of HSP70 and iNOS in hippocampus and prefrontal cortex was analyzed by Western blot. The results demonstrated that swimming exercise could not only improve the behavior changes and protect the function of HPA axis stable in CUMS animals exposed to novel acute stress, but also increase the HSP70 expression and decrease the iNOS expression in hippocampus and prefrontal cortex. In conclusion, swimming exercise could play a beneficial role in combined stress by up-regulating HSP70 level and down-regulating iNOS level in brain.

Disrupted startle modulation in animal models for affective disorders

Affective startle modulation is used to study emotional reactivity in humans, and blunted affective startle modulation has been reported in depressed patients. To determine whether blunted affective startle modulation is also a common feature in animal models for affective disorders, light-enhanced startle was studied in three models: inescapable foot shock (IFS), repeated restraint stress (RRS) and olfactory bulbectomy (OBX). In addition, prepulse inhibition was studied in these models. Light-enhanced startle was blunted following IFS and OBX and RRS decreased overall startle responding. Prepulse inhibition, however, was unaffected. These findings indicate that induction models for affective disorders may be associated with long term effects on affective startle modulation. The lack of changes in sensory motor gating suggests that these changes can be ascribed to alterations in emotional reactivity. In conclusion, our results indicate that the blunted affective startle modulation seen in animal models for affective disorders may be used to examine the mechanisms underlying altered emotional reactivity.