Inescapable Swim Stress Research Articles

Kappa opioid regulation of depressive-like behavior during acute withdrawal and protracted abstinence from ethanol.

The dynorphin/kappa opioid receptor (DYN/KOR) system appears to be a key mediator of the behavioral effects of chronic exposure to alcohol. Although KOR opioid receptor antagonists have been shown to decrease stress-related behaviors in animal models during acute ethanol withdrawal, the role of the DYN/KOR system in regulating long-term behavioral changes following protracted abstinence from ethanol is not well understood. The objective of the current study was to further explore the role of the DYN/KOR system in regulating stress-related behavioral changes associated with acute withdrawal and protracted abstinence from ethanol. More specifically, the present experiments sought to examine the ability of the KOR antagonist norbinaltorphimine (nor-BNI) to reverse depressive-like behavior in the forced swim test in rats exposed to chronic ethanol. In the first experiment, rats were fed an ethanol or control liquid diet for 28–30 days, and then 24 hours after removal of the diet, were exposed to inescapable swim stress. Immediately following this procedure, rats were injected with nor-BNI (20 mg/kg) or saline and then tested 24 hours later in the forced swim test. A second experiment used a similar procedure to examine the effects of nor-BNI on behavioral changes during protracted abstinence in rats tested in the forced swim test 3 weeks after exposure to the ethanol liquid diet procedure. Ethanol-dependent rats showed increased immobility, which is thought to indicate a depressive-like state, when examined during acute withdrawal and protracted abstinence compared to controls, an effect attenuated by nor-BNI. These results suggest that the DYN/KOR system plays role in mediating both short- and long-term behavioral changes associated with depression following chronic alcohol exposure.

Prior stress exposure increases pain behaviors in a rat model of full thickness thermal injury

Thermal burns among individuals working in highly stressful environments, such as firefighters and military Service Members, are common. Evidence suggests that pre-injury stress may exaggerate pain following thermal injury; however current animal models of burn have not evaluated the potential influence of pre-burn stress. This sham-controlled study evaluated the influence of prior stress exposure on post-burn thermal and mechanical sensitivity in male Sprague-Dawley rats. Rats were exposed to 20min of inescapable swim stress or sham stress once per day for three days. Exposure to inescapable swim stress (1) increased the intensity and duration of thermal hyperalgesia after subsequent burn and (2) accelerated the onset of thermal hyperalgesia and mechanical allodynia after subsequent burn. This stress-induced exacerbation of pain sensitivity was reversed by pretreatment and concurrent treatment with the serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine. These data suggest a better understanding of mechanisms by which prior stress augments pain after thermal burn may lead to improved pain treatments for burn survivors.

(362) Combined serotonin and norepinephrine reuptake inhibition reduces the effects of stress on post-injury pain behaviors in a rat model of burn injury

Even with currently available medications, moderate or severe pain after burn injuries is typical and remains a major clinical challenge. There is an urgent need for improvement in the understanding of mechanisms that mediate pain after thermal burn injury in order to reduce patient suffering and enhance recovery. Previous studies suggest that stress may exaggerate pain processing, reduce sensitivity to pain therapeutics, and increase the probability of developing chronic post-burn pain. However, the potential influence of stress has not been incorporated into animal models of thermal burn injury. This sham-controlled study evaluated the influence of prior stress exposure on post-burn thermal and mechanical sensitivity in male Sprague-Dawley rats. Rats were exposed to twenty minutes of inescapable swim stress or sham stress once per day for three days. Prior to the first session, and 24 hours following the third session, mechanical and thermal hindpaw sensitivity was recorded. Pain behaviors were determined as the force required to elicit voluntary withdrawal of the hindpaw from a non-noxious mechanical stimulus and the latency to remove the hindpaw from a noxious thermal stimulus. Rats then received a standardized full thickness thermal injury to the right hindpaw and subsequent pain behaviors were recorded at 24 hours, 96 hours, 1 week, 2 weeks, and 3 weeks following thermal injury. Exposure to inescapable swim stress (1) increased the intensity and duration of thermal hyperalgesia after subsequent burn injury and (2) accelerated the onset of both thermal hyperalgesia and mechanical allodynia after subsequent burn injury. This stress-induced exacerbation of pain sensitivity was reversed by seven days of pretreatment with the SNRI, duloxetine. These data suggest a better understanding of mechanisms by which prior stress augments pain after thermal burn injury may lead to improved pain treatments for burn injury survivors. Even with currently available medications, moderate or severe pain after burn injuries is typical and remains a major clinical challenge. There is an urgent need for improvement in the understanding of mechanisms that mediate pain after thermal burn injury in order to reduce patient suffering and enhance recovery. Previous studies suggest that stress may exaggerate pain processing, reduce sensitivity to pain therapeutics, and increase the probability of developing chronic post-burn pain. However, the potential influence of stress has not been incorporated into animal models of thermal burn injury. This sham-controlled study evaluated the influence of prior stress exposure on post-burn thermal and mechanical sensitivity in male Sprague-Dawley rats. Rats were exposed to twenty minutes of inescapable swim stress or sham stress once per day for three days. Prior to the first session, and 24 hours following the third session, mechanical and thermal hindpaw sensitivity was recorded. Pain behaviors were determined as the force required to elicit voluntary withdrawal of the hindpaw from a non-noxious mechanical stimulus and the latency to remove the hindpaw from a noxious thermal stimulus. Rats then received a standardized full thickness thermal injury to the right hindpaw and subsequent pain behaviors were recorded at 24 hours, 96 hours, 1 week, 2 weeks, and 3 weeks following thermal injury. Exposure to inescapable swim stress (1) increased the intensity and duration of thermal hyperalgesia after subsequent burn injury and (2) accelerated the onset of both thermal hyperalgesia and mechanical allodynia after subsequent burn injury. This stress-induced exacerbation of pain sensitivity was reversed by seven days of pretreatment with the SNRI, duloxetine. These data suggest a better understanding of mechanisms by which prior stress augments pain after thermal burn injury may lead to improved pain treatments for burn injury survivors.

The stressed female brain: neuronal activity in the prelimbic but not infralimbic region of the medial prefrontal cortex suppresses learning after acute stress

Women are nearly twice as likely as men to suffer from anxiety and post-traumatic stress disorder (PTSD), indicating that many females are especially vulnerable to stressful life experience. A profound sex difference in the response to stress is also observed in laboratory animals. Acute exposure to an uncontrollable stressful event disrupts associative learning during classical eyeblink conditioning in female rats but enhances this same type of learning process in males. These sex differences in response to stress are dependent on neuronal activity in similar but also different brain regions. Neuronal activity in the basolateral nucleus of the amygdala (BLA) is necessary in both males and females. However, neuronal activity in the medial prefrontal cortex (mPFC) during the stressor is necessary to modify learning in females but not in males. The mPFC is often divided into its prelimbic (PL) and infralimbic (IL) subregions, which differ both in structure and function. Through its connections to the BLA, we hypothesized that neuronal activity within the PL, but not IL, during the stressor is necessary to suppress learning in females. To test this hypothesis, either the PL or IL of adult female rats was bilaterally inactivated with GABAA agonist muscimol during acute inescapable swim stress. About 24 h later, all subjects were trained with classical eyeblink conditioning. Though stressed, females without neuronal activity in the PL learned well. In contrast, females with IL inactivation during the stressor did not learn well, behaving similarly to stressed vehicle-treated females. These data suggest that exposure to a stressful event critically engages the PL, but not IL, to disrupt associative learning in females. Together with previous studies, these data indicate that the PL communicates with the BLA to suppress learning after a stressful experience in females. This circuit may be similarly engaged in women who become cognitively impaired after stressful life events.

Effects of Swim Stress on Ne ophobia and Re conditioning Using a Conditioned Taste Aversion Procedure

Previous research has found that swim stress during a classical conditioning trial attenuates conditioned taste aversion (CTA). In the current study, rats were used to examine the effects of inescapable swim stress on the habituation of neophobia to a flavored solution and reacquisition of an extinguished conditioned taste aversion. In Experiment 1, subjects were initially exposed to a taste, with some subjects receiving a swim experience to assess the level of neophobia on a subsequent taste-exposure test. Rats in Experiment 2 were given a taste-LiCl trial followed by extensive CS-alone extinction trials. Subjects then received the taste-LiCl pairing again, followed for some by a swim experience to examine its effect on subsequent reconditioning. Swim stress influenced CS processing on the final extinction trial. Thus, reacquisition was attenuated by swim, but there was no effect of swim stress on the attenuation of neophobia. These results are discussed in terms of the effects of stress on CS processing.

Influence of Permethrin and Cypermethrin on Behavior in the Mouse

Permethrin and Cypermethrin are synthetic pyrethroids, belonging to a group of insecticides with low mammalian toxicity and high insecticidal activity. The present study evaluated sub-acute toxicity of dermally administrated permethrin and cypermethrin in mice. Behavioral examination included assessments of lethality, weight gain, grooming, analgesymetry, anxiety, grasping, motor activity, and despair in response to inescapable swim stress. The study was conducted on 70 adult male mice, which were exposed dermally via the whole tail zone for 10 s once daily for 28 consecutive days at concentrations of 0%, 0.1%, 1% and 10% of each compound. No significant changes were observed in body weight gain, grooming behavior or pain sensation among the treated and control groups. However, the following effects were observed in the experimental groups: a tendency towards increased motor activity compared to controls (47% in P0.1% group, P = 0.025), a tendency to lose grasping faster than controls (48% and 40% decreased in P10% and C1% groups, respectively, (P < 0.05), shorter stay in the long arms and longer stay in the short arms on the elevated plus maze task compared to controls (up to 84% difference , P < 0.05), and failure in terms of floating on the inescapable swim stress task (500% and 900% increase in interruption times in the P10% and C10% groups, respectively, P < 0.05). In conclusion, upon long-term dermal exposure, synthetic pyrethroids may lead to increased motor activity, decreased grasping tendency and/or ability, increased apathy, and increased despair in the mouse animal model.

Effects of swim stress on latent inhibition using a conditioned taste aversion procedure

Rats were used to examine the effects of inescapable swim stress on latent inhibition using a conditioned taste aversion procedure. Subjects were subjected to inescapable swim after each of three saccharin taste preexposures and saccharin was later paired with LiCl. The ability of swim to influence latent inhibition was assessed on subsequent saccharin test trials. Swim stress significantly attenuated latent inhibition. The implications of these results regarding the effects of swim stress on conditioned taste aversion are discussed.

Acute Stress Rapidly and Persistently Enhances Memory Formation in the Male Rat

Previous studies, as well as the present one, report that acute exposure to intermittent tailshocks enhances classical eyeblink conditioning in male rats when trained 24 h after stressor cessation. In Experiment 1, it was determined that the facilitating effect of stress on conditioning could also be obtained in response to a stressor of acute inescapable swim stress but not inescapable noise or the unconditioned stimulus of periorbital eyelid stimulation. These selective responses arose despite comparable enhancements of the stress-related hormone corticosterone in response to tailshocks, periorbital eyelid stimulation, noise stress, and supraelevation in response to swim stress. Although corticosterone is necessary for the enhanced learning in response to stress (Beylin & Shors, 1999), these results suggest that it is not sufficient. In addition, the results suggest that the enhancement is not dependent on common characteristics between the stressor and the conditioning stimuli (stimulus generalization). In Experiment 2, it was determined that the facilitating effect of the stressor on conditioning occurs within 30 min of stressor cessation. Thus, the mechanism responsible for facilitating memory formation is rapidly induced as well as persistently expressed. In Experiment 3, it was determined that exposure to the stressor does not enhance performance of the conditioned response after the response has been acquired. Thus, exposure to the stressor enhances the formation of new associations rather than affecting retention or performance of the motor response. These studies extend the circumstances under which stress is known to enhance associative learning and implicate neural mechanisms of memory enhancement that are rapidly induced and persistently expressed.

Behavioural analysis of four mouse strains in an anxiety test battery

Differences in locomotor activity, exploratory activity and anxiety-like behaviour of C57BL/6ChR,C57BL/6J, Swiss Webster/J and A/J strain were investigated in an anxiety battery. The battery consisted of paradigms studying spontaneous behaviour after a mild stressor, tasks of innate anxiety (light–dark box, elevated plus maze, novel object exploration), response to a conflict situation (Vogel conflict), conditioned fear and response to inescapable swim stress. Locomotor activity was studied in an open field and compared with locomotion in the other tests. Exploratory behaviour was studied in a 16-hole board task. The data confirm previous studies suggesting that A/J mice are a relatively anxious strain. Also, the data indicated that locomotor activity was independent of the paradigm employed, while the rank order of strain-dependent effects on anxiety-related behaviour changed as a function of the task under study. Our data provide further support for the notion that choice of strain is essential in studies of anxiety-related behaviour. Influence of strain should be considered in pharmacological and lesion studies, as well as in studies with mutant mice. In addition, the data indicate that different anxiety paradigms tax different aspects of anxiety, suggesting that a battery of different tests should be used in studies of anxiety-related behaviour.

Stages of estrous mediate the stress-induced impairment of associative learning in the female rat.

Exposure to a stressful event facilitates classical eyeblink conditioning in male rats and impairs conditioning in females. The contribution of stages of estrous to the stress-induced impairment of eyeblink conditioning was evaluated. Females in proestrus, estrus and diestrus were either exposed to an acute stressor of intermittent tailshocks or swim stress and compared to unstressed females in the three stages. Females in proestrus, when estrogen levels are high, acquired the conditioned response at a facilitated rate relative to females in other stages. However, exposure to a stressor of either intermittent tailshocks or inescapable swim stress severely impaired acquisition in females during proestrus. These results suggest that the enhancing effect of estrogen on procedural memory formation is disrupted by previous exposure to a stressful event.

Experimental hypothyroidism increases immobility in rats in the forced swim paradigm

Effects of severe and mild hypothyroidism on the immobile response to inescapable stress were examined in male Wistar rats using the forced swim paradigm. Rats were exposed to two sessions of inescapable swim stress: pretest (for 15 min) followed by test (for 5 min) 24 h later. Surgically thyroidectomized rats showed a significant increase (by 90%) in immobility during test compared to sham rats. Chronic administration of high (200 μg/kg per day) but not low (15 μg/kg per day) dose of T4 prevented the increase in immobility in thyroidectomized rats. Normal rats submitted to iodine-free diet for 2 weeks in order to produce a mild hypothyroidism showed a significant increase (by 60%) in immobility time during test compared to control rats. The results indicate that hypothyroid rats are more vulnerable to inescapable stress than normothyroid rats.

Chronic swim stress enhances the motoric inhibiting effects of a muscarinic agonist

The authors previously demonstrated that chronic inescapable swim stress and footshock increase the capacity of a fixed dose of a muscarinic agonist to produce hypothermia in the rat. This project was designed to determine whether chronic inescapable swim stress in cold water would render a low dose of a muscarinic agonist, devoid of an effect on motor behavior in the naive rat (i.e., prior to subjection to the course of swim stress), an inhibitor of mobility. The study involved two groups of rats, an experimental group which received arecoline and a control group which received saline five minutes prior to being placed in an open field. Number of crossings, the dependent variable, was measured in both groups before and after a 14-day course of twice daily inescapable swim stress of 10 minutes duration at 12°C. The arecoline-treated group, as hypothesized, exhibited a significantly greater reduction in number of crossings than the saline-treated groups following the course of swim stress.

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.

Chronic stress supersensitizes rats to the inhibition of locomotion produced by arecoline

Chronic inescapable footshock and swim stress supersensitize a hypothalamic muscarinic mechanism which regulates core body temperature. We studied the inhibitory effects of arecoline, a muscarinic agonist, on locomotion in rats before and after chronic swim stress in order to examine the effects of stress on an extra-hypothalamic muscarinic mechanism. We counted crossings in an open field during the days before and after six days of twice-daily swim stress (8 minutes/session at 12C). We first examined the effects of eight doses of ip arecoline (0.01 to 2.0 mg/kg) and normal saline (N = 6 to 8 rats/group) on crossings before and after chronic stress. Doses greater than 0.25 mg/kg inhibited pre-stress crossings relative to saline and did not potentiate the inhibition of locomotion post-stress. The 0.125 mg/kg dose reduced crossings post-stress relative to saline. We reexamined the effects of the 0.125 mg/kg dose saline (N = 20 rats/group) on crossings before and after six days of swim stress. Chronic stress potentiated arecoline-induced inhibition of locomotion. Our results suggest that chronic uncontrollable stressors may supersensitize an extra-hypothalamic muscarinic mechanism involved in the stress response and the pathophysiology of stress-related disease such as major depression.