Persistent stress-induced elevations of urinary corticosterone in rats

Exposure of rats to inescapable stressors (IS) results in persistent elevations in plasma corticosterone (CORT), which are selective to the trough of the circadian rhythm. Although affective disorders (depression, anxiety) in humans are also characterized by persistent hypothalamic-pituitary-adrenal axis (HPAA) activation, the predominant measure of HPAA activation in clinical studies is 24-h urinary cortisol. To facilitate interspecies comparisons regarding the persistent effects of stress on HPAA activity, we compared the effects of IS on plasma and urinary CORT in rats. Male Sprague-Dawley rats were exposed to three 2-h sessions of IS (40, 2.0 mA tailshocks) or remained in their home cages. The 24-h urine samples were collected daily from 2 days prior to stress to 5 days after stressor cessation, then weekly for 3 weeks. In addition, plasma samples were obtained at 08:00 (trough) and 20:00 hours (peak) for the first 3 days after stressor cessation and weekly for 3 weeks thereafter. Consistent with our earlier work, plasma CORT elevations were apparent in the trough, but not the peak samples for 3 days after stressor cessation. The 24-h urinary CORT levels were elevated during stressor exposure, and remained elevated for 3 days after stressor cessation. Persistent stress-induced urinary CORT elevations in rats are reminiscent of the clinical HPAA abnormalities described for major depression and affective disorders.     

Conditioned neuroendocrine and cardiovascular stress responsiveness accompanying behavioral passivity and activity in aged and in young rats.

Mean arterial pressure (MAP), heart rate (HR), plasma epinephrine (E), plasma norepinephrine (NE), and plasma corticosterone (CORT) were measured in 3-month- and 24-month-old male Wistar rats exposed to a conditioned emotional stress response (CER) paradigm and a conditioned defensive burying (CDB) paradigm. In the CER situation blood samples were taken during reexposure to the training environment one day after a single inescapable footshock (0.6 mA, AC for 3 s) had been administered. In the CER paradigm the young rats displayed passive behavior (immobility) accompanied by an increase in plasma levels of CORT and E, whereas both the control and conditioned animals showed increased NE responses. Previously shocked aged rats exhibited an attenuated plasma NE response, whereas levels of E remained elevated to a greater extent. Aged animals showed elevated basal levels of CORT one day after footshock administration. Stress-induced immobility was preserved in the aged rats. These animals had an increase in basal MAP values and a decrease in basal HR values compared to young ones. In the CDB paradigm, rats were exposed to a nonelectrified probe 1 day after the repeated shock (2 mA/contact) procedure. Young rats displayed defensive burying accompanied by increments in MAP, HR, CORT, and NE. The aged animals showed similar hormonal, autonomic, and behavioral stress responses. Thus, the age-related alterations in neuroendocrine and autonomic response patterns are apparent in stressed animals during behavioral passivity in absence of control (CER) rather than during active control (defensive burying).     

Behavior and body temperature in rats following chronic foot shock or psychological stress exposure

In an attempt to examine stress-induced behavioral disorders, including circadian rhythm disturbances, we measured motor activity, feeding, drinking, and body temperature over a 14-day period following a long-term stress exposure in rats. Male Wistar rats were exposed to foot shock (physical) or non-foot shock stress (psychological) induced by the communication box for 1 h daily over 12 weeks. Two to three months after the termination of the stress sessions, motor activity, food intake, water intake, and body temperature were measured by means of an automatic behavioral measurement system under a 12:12-h light:dark cycle. Motor activity, feeding, and drinking patterns were not influenced by either of the previous stress exposures. Daily rhythm of body temperature was also unchanged in either stress group, however, a significant elevation in body temperature (by 0.20 degrees C, p<0.05) was observed only in non-foot-shocked rats. The present study suggests that only psychological stress induces an elevation of body temperature following the stress exposures; however, long-term stress exposures in the present experiment do not disturb behavioral activities and daily rhythms of behaviors.     

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.     

Effects of chronic stress on plasma corticosterone, ACTH and prolactin

Rats were placed in a stressful environment for 24 hr per day and levels of plasma hormones were measured after varying numbers of days in the environment. Rats were habituated to operant chambers placed in sound-attenuated enclosures. Food pellets were available by lever press on a FR1 schedule. After 3 days of habituation, rats in the “stressed” group were trained to pull a ceiling chain to avoid or escape shock. Following training, stress trials, consisting of a consecutive sequence of 5 sec each of a warning light, warning tone and 0.16, 0.32, 0.65, 1.3 and 2.6 mA of footshock, occurred approximately once per 5 min around-the-clock. For the first day, the sequence was terminated when the ceiling chain was pulled. On subsequent days, 90% of all shock presentations could be avoided or escaped by chain pull; the remaining 10% of trials were inescapable and the entire sequence was presented. Control rats lived in identical chambers without presentation of shock. Rats were sacrificed after 1, 2, 3, 4, 7 or 14 days in this environment and levels of plasma corticosterone, ACTH and prolactin were determined. Levels of plasma corticosterone were elevated during the first 7 days in the stressful environment, but returned to control values by day 14. Levels of plasma ACTH and prolactin were similar in stressed and control rats at all time points measured. These data suggest that stress-induced changes in glucocorticoids but not in ACTH or prolactin might mediate some of the physiological changes that occur as the result of chronic stress.     

Stress vulnerabilities in an animal model of post-traumatic stress disorder

We have studied the effects of inescapable electric foot shocks (ISs) on rats by using a subsequent avoidance/escape task performed in a shuttle box as an animal model of post-traumatic stress disorder (PTSD). In this study, the behavioral differences and the effects of chronic stress exposure prior to IS were examined among male rats of the Wistar, Fischer 344, and Lewis strains. In concordance with our previous report on the Wistar rats, we observed the characteristic features of PTSD in all three rat strains tested, that is, the hyperactive and hypoactive bidirectional behavioral changes that are associated with hypervigilant and hyperarousal behavior, and the numbing and avoidant behavior, respectively. The induction of hypoactive behaviors after IS was most exaggerated in the Fischer and Lewis strains. Although the count of hyperactive behaviors was maximal in the Fischer strain both at basal levels without IS and after IS, the increase in the rate of hyperactive behaviors by IS was the most prominent in the Lewis strain. In addition, preloaded chronic variable stress (CVS) enhanced the degree of hyperactive behavioral changes in the Wistar strain. Thus, we consider that the present study further validates the use of shuttle box paradigm as an animal model of PTSD by demonstrating the vulnerability due to genetic background and environmental preloaded stress.     

Circadian rhythmicity and behavioral depression: I. Effects of stress

Rats were exposed to repeated sessions of inescapable footshock, and behavioral depression was subsequently assessed by measuring escape performance during exposure to escapable shock in a different testing environment. Free-running circadian activity rhythms were assessed using running wheels for approximately three weeks before and after administration of inescapable shock. Several animals showed lengthening of free-running period and decreases in activity level following shock. Similar effects were also seen in rats that were removed from their running wheels, placed within the shock apparatus, and not given shock, but not in nonhandled control animals. Furthermore, period lengthening in shocked and handled rats was positively correlated with escape performance, suggesting that circadian rhythm alterations occurred in those animals that were best able to cope with shock or handling-related stressors. In contrast, individual differences in circadian period and activity level during baseline conditions were not predictive of either escape performance or circadian rhythm alterations. These results suggest that successful behavioral adaptation to stress may be associated with alterations of circadian rhythmicity.     

GSK650394对慢性应激抑郁症模型大鼠行为及海马神经营养的调节作用

目的探讨血清和糖皮质激素调节蛋白激酶1(SGK1)抑制剂GSK650394对抑郁症模型大鼠抑郁样行为及海马神经营养的调节作用。方法将SD大鼠随机分为对照组、抑郁模型(慢性温和不可预见性应激加孤养)组、GSK650394(2.8 g/L,按1 mL/kg腹腔注射)干预组;采用强迫游泳、糖水消耗、Morris水迷宫实验观察模型动物的情绪行为变化;用ELISA检测大鼠海马血浆和血清中皮质酮(CORT)、5-羟色胺(5-HT)、去甲肾上腺素(NE)含量;用Western blot检测海马中脑源性神经营养因子(BDNF)、神经营养素3(NT-3)、神经生长因子(NGF)的表达。结果与对照组比较,模型组大鼠蔗糖水偏食度显著降低、游泳不动时间增加(P<0.01)、逃避潜伏期(EL)、目标象限的潜伏时间(Lat.T)均显著延长(P<0.05或P<0.01);血浆CORT显著升高(P<0.01)、血清5-HT、NE和海马NT-3、BDNF、NGF表达显著降低(P<0.05或P<0.01)。与模型组比较,GSK650394可显著增加蔗糖水偏食度、降低游泳不动时间(P&l...     

皮质酮与慢性不可预见性应激诱导的两种抑郁症模型比较

目的从行为学及分子水平比较皮质酮(CORT)与慢性不可预见性应激(CUMS)诱导的抑郁症模型的异同,为抑郁症发病机制研究及抗抑郁药物的筛选与评价模型提供一定的参考。方法将30只雄性C57BL/6小鼠随机分成对照组(Ctrl)、慢性不可预见应激组(CUMS)和皮质酮注射应激组(CORT)组,制作应激模型21d,期间每3d对小鼠进行称重。21d模型制作结束后,对小鼠进行行为学测试,并于第22天,通过眼眶取血收集动物血清,并用ELISA法测定血清皮质酮含量。眼眶取血后脱颈椎处死动物,取出动物的胸腺和脾脏进行称重,计算脏器指数;取出脑组织,置于液氮罐保存,尼氏(Nissl)染色法观察小鼠大脑海马区神经元损伤情况;采用Western blotting、RT-PCR方法测定抑郁症相关蛋白及基因的表达。结果与对照组相比,两种抑郁症模型组开场实验中的行为学指标均改变,强迫游泳和悬尾实验的累积不动时间显著升高。两个模型组的胸腺指数无明显变化,而CORT组的脾脏指数较对照组下降。CUMS和CORT组小鼠血清皮质酮含量高于对照组,CORT组与CUMS组相比有升高趋势,但差异无显著性。CUMS和CORT两种模型均使海马CA1、CA3和DG区神经元密度降低,CORT模型变化更明显。两模型组的促肾上腺素释放激素(CRH)的mRNA和蛋白的表达量均显著性增加,脑源性神经营养因子(BDNF)、磷酸化转录因子环磷腺苷反应元件结合蛋白(p-CREB)和磷酸化细胞外信号调节激酶(p-ERK)的蛋白表达水平均呈现明显地抑制,但CUMS和CORT两组之间差异无显著性。结论 CORT模型和CUMS模型均能成功构建抑郁症模型,且与下丘脑-垂体-肾上腺(HPA)轴紊乱有关,两种模型在小鼠海马结构改变及大脑BDNF-pCREB和ERK信号通路激活等方面差异无显著性。提示,CORT模型可用于抑郁症机制的研究及抗抑郁药的筛选与评价,尤其可用于以HPA轴功能紊乱所引起的抑郁症分子机制探讨。     

Effects of controllable vs. uncontrollable chronic stress on stress-responsive plasma hormones.

We have previously reported effects of chronic stress on circadian rhythms of temperature, eating, and locomotor activity. These studies were conducted using an around-the-clock signalled intermittent footshock paradigm in which some rats have control over shock termination while other rats are yoked to the rats with control. Although this paradigm is stressful, as suggested by decreases in food intake and disrupted circadian rhythms, rats tolerate the paradigm well, continuing to eat, drink, gain weight, and groom. In the present studies, rats were sacrificed following 3 or 14 days of stress, and plasma was collected for hormonal assays. After 3 days of stress, plasma corticosterone and prolactin levels were elevated in both stress groups compared to controls; yoked rats had higher levels of corticosterone than rats in the group with control over shock termination, while prolactin levels in both stressed groups were similar. ACTH levels were similar in stressed and control rats. After 14 days of stress, ACTH and corticosterone levels in both stress groups were similar to control levels. Prolactin levels were elevated in the yoked experimental group compared to levels in control or controllable stress groups. These data support previous studies suggesting that control over stressors attenuates the effects of stress on physiology and demonstrate that two hormones with diverse biological effects are elevated by chronic stress.     

Adrenocortical response to stress in fasted and unfasted artificially reared 12-day-old rat pups

Recent studies have compared artificially reared (AR) rats with dam-reared rats on behavioral outcomes but, despite the fact that they are deprived of their mothers during the stress hyporesponsive period (SHRP), little is known about the effects of AR on the development of the stress response. In this study, the corticosterone (CORT) response to a stressor (saline injection ip) on postnatal Day 12 was assessed in rat pups that had been either dam-reared (DR) or artificially reared since Day 5. In the preceding 24 hr, half the pups in the DR group were maternally deprived (DEP). To control for the food deprivation consequent to maternal deprivation in these groups, half the pups in the AR groups also underwent 24-hr food deprivation (DEP). In the nondeprived condition AR pups did not differ from DR pups on untreated CORT levels or on levels at 1-hr poststress (i.e., all rats demonstrated low levels of CORT characteristic of the SHRP). In contrast, both maternally deprived DR pups and food-deprived AR pups exhibited increased untreated CORT levels as well as a significant increase at 30-min poststress, but CORT elevations were lower in the AR groups than in the DR groups. Thus, long-term maternal deprivation through artificial rearing in rats does not affect the reduced CORT levels and reduced CORT responsiveness associated with the SHRP; however, if animals are food deprived, then all show increased basal CORT levels and a greater CORT response to stress, although this response is lower in AR groups than in DR groups. These results suggest that rat pups artificially reared with adequate nutrition will still exhibit the SHRP.     

Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior

The hippocampus and amygdala are important components of the neural circuitry mediating stress responses. While structural plasticity in the hippocampus may mediate cognitive aspects of behavioral impairments caused by severe stress, changes in the amygdala are more likely to contribute to the affective aspects of stress disorders. Recent reports have identified cellular and molecular correlates of stress-induced amygdaloid plasticity that may underlie anxiety. Hence, we examined the impact of chronic stress, in terms of its duration, at the cellular and behavioral levels in rats. We found that, even after 21 days of stress-free recovery, animals exposed to chronic immobilization stress (CIS) continue to exhibit enhanced anxiety, as manifested by a significant reduction in open-arm exploration and risk-assessment behavior in the elevated plus-maze. At the cellular level, we tested if CIS-induced dendritic remodeling in the amygdala is also as long-lasting as enhanced anxiety after 21 days of recovery. Indeed, long-lasting facilitation of CIS-induced anxiety is accompanied by a persistent increase in dendritic arborization of basolateral amygdala (BLA) spiny neurons. Moreover, CIS-induced BLA hypertrophy is distinct from hippocampal CA3 atrophy, which is reversible within the same period of stress-free recovery. These findings on persistent dendritic remodeling in the amygdala, in addition to highlighting important differences with hippocampal structural plasticity, may provide a cellular basis for examining anxiety and mood disorders triggered by chronic stress.     

Stressors in the learned helplessness paradigm: effects on body weight and conditioned taste aversion in rats

Changes in body weight and taste aversion in the learned helplessness paradigm were examined. In Experiment 1, adult male Sprague-Dawley rats drank saccharin or a control solution, followed by either 100 inescapable shocks or simple restraint. Rats were weighted daily and were tested for saccharin aversion two days after the stress session. Shocked rats gained less weight in the days after stress than restrained controls. Saccharin aversion was apparent only among rats that had consumed saccharin before the stress session. Experiment 2 examined whether control over shock affected body weight or taste aversion. Home-cage controls were included to assess the effects of restraint alone. In addition, the combined effects of shock and a toxin on aversion were studied. Rats drank saccharin solution, followed by escapable or inescapable shock, restraint, or no treatment. Then half of each group was injected with saline; the other half was injected with lithium chloride. As in Experiment 1, shock reduced body weight relative to restraint or no treatment, and shock produced a taste aversion among saline-treated rats. However, shock attenuated the aversion produced by lithium chloride, as did simple restraint. There were no differences in body weight or taste aversion between escapably and inescapably shocked rats. These results suggest a role for stress in the anorexia and weight loss associated with clinical depression and may have implications for theories of learning and learned helplessness.     

The role of IL-1beta in stress-induced sensitization of proinflammatory cytokine and corticosterone responses

Proinflammatory cytokines often sensitize neuronal, hormonal, and behavioral responses to subsequent challenge. Recently, it was observed that exposure to inescapable tailshock enhances peripheral and central proinflammatory cytokine and corticosterone (CORT) responses to subsequent immune challenge up to 4 days later. Thus, we examined the role of central interleukin-1beta (IL-1beta) in stress-induced sensitization of proinflammatory cytokine and CORT responses to a subsequent immune challenge. Rats were administered IL-1 receptor antagonist (IL-1ra) or vehicle into the intra-cisterna magna 1 h prior to tailshock (100, 1.6 mA 5 s shocks) exposure. Twenty-four hours later, rats were challenged i.p. with 10 microg/kg lipopolysaccharide (LPS) and killed 1 h later. IL-1ra had no effect on basal proinflammatory cytokines, but completely blocked the stress-induced enhancement in central and pituitary IL-1beta and plasma IL-6 release following LPS challenge. IL-1ra had no effect on stress-induced enhancement in CORT responses following LPS challenge. Additional rats were administered i.c.v. hrIL-1beta or vehicle and returned to their home cage. Twenty-four hours later, rats were challenged i.p. with either saline or 10 microg/kg LPS and killed 1 h later. Central hrIL-1beta administration significantly elevated central IL-1beta levels and plasma CORT following LPS challenge compared with vehicle-injected controls. These data demonstrate that elevations in central IL-1beta, whether stress-induced or exogenously administered, are sufficient for sensitizing central IL-1beta and CORT responses to subsequent immune challenge. However, during times of stress, exogenous central IL-1ra administration only blocked sensitization of subsequent central IL-1beta responses, not CORT responses, suggesting other factors during the stress response can sensitize CORT responses.     

Juvenile stress impairs body temperature regulation and augments anticipatory stress-induced hyperthermia responses in rats

Clinical studies have implicated adolescence as an important and vulnerable period during which traumatic experiences can predispose individuals to anxiety and mood disorders. As such, a stress model in juvenile rats (age 27-29 d) was previously developed to investigate the long-term effects of stress exposure during adolescence on behavior and physiology. This paradigm involves exposing rats to different stressors on consecutive days over a 3-day period. Here, we studied the effects of juvenile stress on long-term core body temperature regulation and acute stress-induced hyperthermia (SIH) responses using telemetry. We found no differences between control and juvenile stress rats in anxiety-related behavior on the elevated plus maze, which we attribute to stress associated with surgical implantation of telemetry devices. This highlights the severe impact of surgical stress on the results of subsequent behavioral measurements. Nonetheless, juvenile stress disrupted the circadian rhythmicity of body temperature and decreased circadian amplitude. It also induced chronic hypothermia during the dark phase of the day, when rats are most active. When subjected to acute social defeat stress as adults, juvenile stress had no impact on the SIH response relative to controls. However, 24 h later, juvenile stress rats displayed an elevated SIH response in anticipation of social defeat when re-exposed to the social defeat environment. Taken together, our findings indicate that juvenile stress can induce long-term alterations in body temperature regulation and heighten the increase in temperature associated with anticipation of social defeat. The outcomes of behavioral measurements in these experiments, however, are severely affected by surgical stress.     

Stress during adolescence alters behavioral sensitization to amphetamine

In humans, chronic intermittent and uncontrollable stress during adolescence is viewed as a key factor for vulnerability to drug abuse and development of psychopathologies later in life. Less is known about the long-term effects of chronic stress in animals during the juvenile period. Although there is evidence of cross sensitization during prenatal period and adulthood between chronic stress and amphetamine-induced behavioral sensitization in the rat, no studies have been conducted on cross sensitization between chronic variable stress in adolescence and behavioral sensitization to amphetamine. To address this question, at the onset of adolescence (28 days) male rats were subjected to 28 days of intermittent non-habituating social stress (isolation, novel environment, crowding, litter-shifting, subordination), or physical stress (restraint, swim, cold, ether, noise), or were handled as controls. Twenty-four hours after the last stressor or handling, all groups were exposed to a novel environment for 1 h, after which they underwent a regimen of behavioral sensitization to amphetamine. Our results showed that socially stressed rats have low locomotor activity in the novel environment, when compared to the control and physical groups who were identical in the same test. Even though socially stressed rats had lower locomotor activity in response to amphetamine injections, there were no significant differences during the training phase between the three groups at this dose of amphetamine. However, when tested for behavioral sensitization to amphetamine control and physically stressed rats showed a robust sensitization, socially stressed rats were significantly inhibited. We conclude that our chronic variable social stress protocol during adolescence inhibits behavioral sensitization to amphetamine during adulthood.     

Habituation of sympathetic-adrenal medullary responses following exposure to chronic intermittent stress

Two experiments examined sympathetic-adrenal medullary responses of laboratory rats after exposure to a brief period of stressful stimulation daily for 26 consecutive days. In the first experiment, rats were exposed to restraint stress for 30 minutes per day and in the second experiment, rats were exposed to inescapable footshock for 10 minutes per day. For each experiment, handled controls were stressed acutely to provide a basis for comparison with chronically stressed animals. In both experiments, chronically stressed rats gained less weight than controls. Basal plasma levels of norepinephrine (NE) and epinephrine (EPI) were similar in control and chronically stressed rats. However, there was a substantial attenuation of the plasma catecholamine response to the 27th episode of restraint or footshock compared to acutely stressed controls. These findings indicate that sympathetic-adrenal medullary responses are dampened considerably in animals exposed to a highly predictable regimen of chronic intermittent stress.     

Inhibition of in vivo neutrophil accumulation by stress

Psychological stress results in neural and endocrine changes which can alter various aspects of the immune system. However, the effects of stress on inflammation has not received much attention despite the fact that stress hormones, such as the corticosteroids, are known to reduce inflammation. The present study extends a previous finding that stress itself can reduce inflammation. In the first experiment, zymosan was injected into an air pouch on the dorsum of F344 rats. Half of these rats then received three hours of inescapable, intermittent, electric foot shock as a Stressor, The other half of the injected rats served as nonstressed controls. A third group were given air pouches but no zymosan. Fewer neutrophils accumulated at the inflammatory site of stressed rats as compared to nonstressed control rats. However, phagocytosis of zymosan by air pouch neutrophiis was higher in stressed rats. Peripheral perfusion was not altered significantly by shock, but vascular permeability was reduced in stressed rats. The effects of stress on peripheral blood leukocytes of rats not injected with zymosan was investigated. It was found that while peripheral blood monocytes and lymphocyte numbers were decreased by stress, neutrophils were not decreased. Increased neutrophil adherence was found in stressed rats. Additionally, in the presence of endotoxin, neutrophils from stressed rats did not increase their adherence as much as those of control rats. The increased adhesiveness of neutrophils in stressed animals may account for the diminished inflammatory response in the shocked rats.     

Chronic stress augments the long-term and acute effects of methamphetamine

There is growing evidence that exposure to stress alters the acute effects of abused drugs on the CNS. However, it is not known whether stress augments the longer-term neurotoxic effects of psychostimulant drugs, such as methamphetamine. Methamphetamine at high doses decreases forebrain dopamine concentrations. The current study tested the hypothesis that 10 days of unpredictable stress augmented striatal dopamine depletions 7 days following four injections of either 7.5 or 10 mg/kg methamphetamine (1 injection every 2 h). Furthermore, to assess the effects of chronic stress on immediate responses to methamphetamine, extracellular striatal dopamine and methamphetamine concentrations, and rectal temperature were monitored during the methamphetamine injection regimen. Seven days following either a 7.5 mg/kg or 10 mg/kg methamphetamine injection regimen, male rats exposed to unpredictable stress showed greater depletions in striatal dopamine tissue content compared with non-stressed controls injected with methamphetamine. Stressed rats had increased hyperthermic responses and dopamine efflux in the striatum during the methamphetamine injections when compared with non-stressed control rats. Moreover, stressed rats had an increased mortality rate (33%) compared with non-stressed controls (16.7%) following four injections of 10 mg/kg methamphetamine. The enhanced acute and longer-term effects of methamphetamine in stressed rats was not due to a greater concentrations of methamphetamine in the striatum, as extracellular levels of methamphetamine during the injection regimen did not differ between the two groups. In summary, exposure to 10 days of chronic unpredictable stress augments longer-term depletions of dopamine in the striatum, as well as acute methamphetamine-induced hyperthermia and extracellular dopamine levels. These findings suggest that chronic stress increases the responsiveness of the brain to the acute pharmacological effects of methamphetamine and enhances the vulnerability of the brain to the neurotoxic effects of psychostimulants.     

A modified single-prolonged stress model for post-traumatic stress disorder

In the rat, single-prolonged stress (SPS) model produces a core symptom of post-traumatic stress disorder (PTSD), the enhanced fear response to the traumatic cue (conditioned fear response). This investigative tool is typically used for PTSD studies. However, whether SPS can produce another core symptom of PTSD, hyperarousal (the sensitized fear response in animal models), has not been evaluated. It is also not clear whether SPS can enhance both conditioned and sensitized fear responses after different incubation times. In this study, a single inescapable electric foot shock was given to rats immediately after SPS procedures (SPS&S). After different incubation times (1, 7 or 14 days), the conditioned or sensitized fear response was measured by re-exposing the stressed rats to the shock context or a neutral tone in a novel environment. Additionally, paroxetine, a selective serotonin reuptake inhibitor (SSRI) was administered after SPS&S for 14 days to test its potential preventive effect on PTSD-like symptoms. We observed that conditioned fear persisted and sensitized fear increased with ongoing incubation times after SPS&S. Early rapid intervention with paroxetine after SPS&S ameliorated PTSD-like symptoms in both fear responses and anxiety behaviors. Our data suggests that this modified SPS&S model may be both novel and predictably mimic the clinical characteristics of PTSD better than other investigative paradigms.