Footshock Stress Research Articles

Neurotoxic lesion of the rostral perirhinal cortex blocks stress-induced exploratory behavioral changes in male rats

Exposure to stress leads to adaptive responses including both behavioral and physiological changes. This process is induced by the activation of multiple brain regions. The present study examined the role of the rostral perirhinal cortex (rPRh) in behavioral changes following electrical foot shock-induced stress. The rPRh of rats was lesioned bilaterally by local microinjections of 10 μg N-methyl-d-aspartic acid (NMDA) before foot shocks (0.7 mA, 1 s). The effects of these lesions on foot shock-induced changes in exploratory behaviors were tested in the open field (4 h, 48 h, 72 h, and 14 days after foot shocks) and the light–dark box (7 days after foot shocks). Foot-shocked and sham-lesioned rats showed several well known behavioral changes in the open field (e.g., immobility, reduction of exploratory activity) most marked at 48 h after foot shocks, and the light–dark box (e.g., reduction of time spent and activity in the lit compartment). All these stress-induced behavioral changes were blocked by neurotoxic lesions of the rPRh. Furthermore, rPRh lesions did not affect behavior in the open field and the light–dark box in unstressed rats. Taken together, these data indicate that the rPRh is involved in neurophysiological mechanisms that mediate changes induced by foot-shock stress in exploratory behaviors which indicate unconditioned fear or anxiety.

Immunoglobulin Secretions in the Mesenteric Lymph Node in Stressed Rats

To study the effects of different types of stressors on intestinal immune function, the lymphocyte subsets and associated immunoglobulin production in stressed rats were observed. Physical (electric foot shock) or psychological (non foot-shock) stress respectively were induced using a communication box. Rats were exposed to stress for 2 h per day, and the treatment was maintained for 14 consecutive days. Lymphocytes were isolated from the mesenteric lymph node (MLN) and spleen using Lympholyte-Rat. There was no change the lymphocyte subsets in MLN or spleen in either group. Foot-shock stress increased immunoglobulin secretions in MLN lymphocytes. These results demonstrated that intestinal immune functions were adaptively regulated under conditions of moderate stress.

Decreased postnatal neurogenesis in the hippocampus combined with stress experience during adolescence is accompanied by an enhanced incidence of behavioral pathologies in adult mice

BackgroundAdolescence is a vulnerable period in that stress experienced during this time can affect the incidence of psychiatric disorders later, during adulthood. Neurogenesis is known to be involved in the postnatal development of the brain, but its role in determining an individual's biological vulnerability to the onset of psychiatric disorders has not been addressed.ResultsWe examined the role of postnatal neurogenesis during adolescence, a period between 3 to 8 weeks of age in rodents. Mice were X-irradiated at 4 weeks of age, to inhibit postnatal neurogenesis in the sub-granule cell layer of the hippocampus. Electrical footshock stress (FSS) was administered at 8 weeks old, the time at which neurons being recruited to granule cell layer were those that had begun their differentiation at 4 weeks of age, during X-irradiation. X-irradiated mice subjected to FSS during adolescence exhibited decreased locomotor activity in the novel open field, and showed prepulse inhibition deficits in adulthood. X-irradiation or FSS alone exerted no effects on these behaviors.ConclusionThese results suggest that mice with decreased postnatal neurogenesis during adolescence exhibit vulnerability to stress, and that persistence of this condition may result in decreased activity, and cognitive deficits in adulthood.

Adrenoceptors and Adaptive Mechanisms in the Heart during Stress

Several cardiovascular disorders have been related to alterations in beta-adrenoceptor (beta-AR) signaling at or beyond the receptor level. During the stress reaction, the sympathetic-adrenal medullary system and the hypothalamus-pituitary-adrenal cortex axis are activated, causing beta-AR overstimulation and remodeling of the beta(1)/beta(2)/beta(3)-AR ratio in cardiomyocytes. In a model of foot-shock stress, we described decreased beta(1)-AR signaling occurring simultaneously with increased beta(2)-AR signaling, whereas the response to the nonconventional agonist, CGP12177, was not altered. These alterations may play an adaptive role to the increased sympathetic drive to the heart, protecting the cardiac tissue from the cardiotoxic effects mediated by beta(1)-ARs overstimulation without altering cardiac output, since this would be sustained by the beta(2)-AR, which would also protect myocytes from apoptosis. Moreover, the selective enhancement of the beta(2)-AR population might help to diminish the risk of overstimulation since this adrenoceptor subtype couples to both, stimulatory G (Gs) and inhibitory G (Gi) proteins. On the other hand, in the model of neurogenic hypertension, the decrease in beta(1)-AR-mediated response is not followed by increase in the beta(2)-AR-mediated response. However, the response to CGP12177, which was desensitized 48 h after the surgery, was normalized 7 days after that, when beta(1)-AR were downregulated. Therefore, both experimental models provided evidence that the classical isoform of beta(1)-AR and the recently described low-affinity isoform of beta(1)-AR show independent behavior and provide the heart with adaptive mechanisms to increased sympathetic stimulation during stress.

Gender differences in corticotropin and corticosterone secretion and corticotropin-releasing factor mRNA expression in the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala in response to footshock stress or psychological stress in rats

Anorexia nervosa is mostly seen in adolescent females, although the gender-differentiation mechanism is unclear. Corticotropin-releasing factor (CRF), a key peptide for stress responses such as inhibition of food intake, increases in arousal and locomotor activity, and gonadal dysfunction, is thought to be involved in the pathophysiology of anorexia nervosa. CRF in the paraventricular nucleus of the hypothalamus (PVN) and CRF in the central nucleus of the amygdala (CeA) are involved in the regulation of stress responses, and gender differences in CRF mRNA expression in these regions in response to various stressors are controversial. We therefore examined CRF gene expression in the PVN and CeA as well as corticotropin (ACTH) and corticosterone secretion in response to a 60-min period of electric footshock (FS) or psychological stress (PS) induced by a communication box in both male and female rats in proestrus or diestrus in an effort to elucidate the mechanism underlying the gender difference in the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the mechanism underlying the remarkable prevalence of anorexia nervosa in females. Female rats in proestrus showed higher basal plasma ACTH and CRF mRNA expression levels in the PVN and CeA than males. Females more rapidly showed higher plasma ACTH and corticosterone levels and a higher CRF mRNA expression level in the PVN in response to FS than males. Although females in both proestrus and diestrus showed significant increases in plasma ACTH and corticosterone and CRF mRNA expression in the PVN in response to PS, no significant responses of the HPA axis to PS were found in males. FS significantly increased CRF mRNA expression in the CeA in both females and males, with significantly higher peaks in females in proestrus than in males, while PS significantly increased CRF mRNA expression in the CeA only in males. These results suggest that gender affects differentially the function of the stress-related regions such as the PVN and CeA. The finding that CRF gene expression in the PVN responds to PS only in females may be a clue to elucidation of the neurobiological mechanism underlying the gender-differential prevalence of anorexia nervosa.

Age‐ and Sex‐Dependent Effects of Footshock Stress on Subsequent Alcohol Drinking and Acoustic Startle Behavior in Mice Selectively Bred for High‐Alcohol Preference

Exposure to stress during adolescence is known to be a risk factor for alcohol-use and anxiety disorders. This study examined the effects of footshock stress during adolescence on subsequent alcohol drinking in male and female mice selectively bred for high-alcohol preference (HAP1 lines). Acoustic startle responses and prepulse inhibition (PPI) were also assessed in the absence of, and immediately following, subsequent footshock stress exposures to determine whether a prior history of footshock stress during adolescence would produce enduring effects on anxiety-related behavior and sensorimotor gating. Alcohol-naïve, adolescent (male, n = 27; female, n = 23) and adult (male, n = 30; female, n = 30) HAP1 mice were randomly assigned to a stress or no stress group. The study consisted of 5 phases: (1) 10 consecutive days of exposure to a 30-minute footshock session, (2) 1 startle test, (3) one 30-minute footshock session immediately followed by 1 startle test, (4) 30 days of free-choice alcohol consumption, and (5) one 30-minute footshock session immediately followed by 1 startle test. Footshock stress exposure during adolescence, but not adulthood, robustly increased alcohol drinking behavior in both male and female HAP1 mice. Before alcohol drinking, females in both the adolescent and adult stress groups showed greater startle in phases 2 and 3; whereas males in the adolescent stress group showed greater startle only in phase 3. After alcohol drinking, in phase 5, enhanced startle was no longer apparent in any stress group. Males in the adult stress group showed reduced startle in phases 2 and 5. PPI was generally unchanged, except that males in the adolescent stress group showed increased PPI in phase 3 and females in the adolescent stress group showed decreased PPI in phase 5. Adolescent HAP1 mice appear to be more vulnerable to the effects of footshock stress than adult mice, as manifested by increased alcohol drinking and anxiety-related behavior in adulthood. These results in mice suggest that stress exposure during adolescence may increase the risk for developing an alcohol-use and/or anxiety disorder in individuals with a genetic predisposition toward high alcohol consumption.

Foot-shock Stress-Induced Regional Iron Accumulation and Altered Iron Homeostatic Mechanisms in Rat Brain

Like in other organs, iron in the brain plays an important role in various biological processes. Previous studies have shown that systemic iron homeostasis in mammalians was changed under specific stress conditions. The present study aimed to investigate effects of stress on brain iron homeostasis in rats using a foot-shock stress model. Young adult male Sprague-Dawley rats were randomly assigned to foot-shock stress group subjected to 30 min of cutaneous foot-shock (0.80 mA, 1 pulse/s, 300 ms duration) daily for 1 week or control group left undisturbed. Then, the rats were sacrificed and iron concentration in serum, liver, and some brain regions were measured using atomic absorption spectrophotometry. Expression of ferritin, Transferrin receptor (TfR), divalent metal transporter 1 (DMT1, with or without iron-responsive element), lactoferrin (Lf), and iron regulatory protein 1 (IRP1) in rat hippocampus were determined using western blot analysis. The results showed that stress induced decreased serum iron concentration, increased liver iron content, and elevated iron contents in specific brain regions including hippocampus, striatum, and frontal cortex. In the hippocampus, stress caused decreased expression of ferritin, increased expression of TfR and IRP1, and no change in expression of DMT1 or Lf. Results of this study demonstrated that foot-shock stress induced region specific iron accumulation and altered iron homeostatic mechanisms in the brain in addition to a changed systemic iron homeostasis characterized by decreased serum iron concentration and increased liver iron content. And, elevated IRP1 expression might be associated with the increased TfR and decreased ferritin expression, leading to subsequent iron accumulation and possible increased vulnerability to oxidative damage in hippocampus.

Chronic stress during paradoxical sleep deprivation increases paradoxical sleep rebound: Association with prolactin plasma levels and brain serotonin content

Previous studies suggest that stress associated to sleep deprivation methods can affect the expression of sleep rebound. In order to examine this association and possible mechanisms, rats were exposed to footshock stress during or immediately after a 96-h period of paradoxical sleep deprivation (PSD) and their sleep and heart rate were recorded. Control rats (maintained in individual home cages) and paradoxical sleep-deprived (PS-deprived) rats were distributed in three conditions (1) no footshock--NF; (2) single footshock--SFS: one single footshock session at the end of the PSD period (6-8 shocks per minute; 100 ms; 2 mA; for 40 min); and (3) multiple footshock--MFS: footshock sessions with the same characteristics as described above, twice a day throughout PSD (at 7:00 h and 19:00 h) and one extra session before the recovery period. After PSD, animals were allowed to sleep freely for 72 h. Additional groups were sacrificed at the end of the sleep deprivation period for blood sampling (ACTH, corticosterone, prolactin and catecholamine levels) and brain harvesting (monoamines and metabolites). Neither SFS nor MFS produced significant alterations in the sleep patterns of control rats. All PS-deprived groups exhibited increased heart rate which could be explained by increased dopaminergic activity in the medulla. As expected, PS deprivation induced rebound of paradoxical sleep in the first day of recovery; however, PSD+MFS group showed the highest rebound (327.3% above the baseline). This group also showed intermediate levels of corticosterone and the highest levels of prolactin, which were positively correlated with the length of PS episodes. Moreover, paradoxical sleep deprivation resulted in elevation of the serotonergic turnover in the hypothalamus, which partly explained the hormonal results, and in the hippocampus, which appears to be related to adaptive responses to stress. The data are discussed in the realm of a prospective importance of paradoxical sleep for processing of traumatic events.

Acute mild footshock alters ethanol drinking and plasma corticosterone levels in C57BL/6J male mice, but not DBA/2J or A/J male mice

Stress is an often-reported cause for alcohol consumption in humans. Acute intermittent footshock is a frequently used paradigm to produce stress in laboratory animals including mice. The effect produced by intermittent footshock stress on ethanol self-administration has been inconsistent: both increases and decreases in ethanol consumption have been reported. The current set of studies further investigates, in three commonly studied mouse strains, the effect of footshock stress on ethanol self-administration. Furthermore, the effect of footshock on plasma corticosterone levels was determined to investigate potential biochemical correlates. Adult male C57BL/6J, DBA/2J, and A/J mice were allowed to self-administer 10% (wt/vol) ethanol for 12 days in a standard 23-h two-bottle paradigm before receiving either 15 min of mild inescapable footshock or no footshock. Shock intensity was equal to the mean intensity at which each strain vocalized as previously determined. Following footshock, animals had the opportunity to self-administer ethanol for an additional 23 h. Separate animals were subjected to either footshock or no shock prior to collection of plasma for corticosterone. Mild footshock stress altered ethanol self-administration and increased plasma corticosterone levels in C57BL/6J mice. Footshock stress did not alter ethanol self-administration or plasma corticosterone levels in DBA/2J or A/J mice. These data demonstrate that mild footshock stress is a suboptimal method of modeling the stress-induced increases in ethanol consumption often reported by humans.

Effects of acute and chronic physical exercise and stress on different types of memory in rats

Here we study the effect of acute and chronic physical exercise in a treadmill and of daily stress (because forced exercise involves a degree of stress) during 2 or 8 weeks on different types of memory in male Wistar rats. The memory tests employed were: habituation in an open field, object recognition and spatial learning in the Morris water maze. Daily foot-shock stress enhanced habituation learning after 2 but not after 8 weeks; it hindered both short- (STM) and long-term memory (LTM) of the recognition task at 2 weeks but only STM after 8 weeks and had no effect on spatial learning after either 2 or 8 weeks. Acute but not chronic exercise also enhanced habituation in the open field and hindered STM and LTM in the recognition task. Chronic exercise enhanced one important measure of spatial learning (latency to escape) but not others. Our findings indicate that some care must be taken when interpreting effects of forced exercise on brain parameters since at least part of them may be due to the stress inherent to the training procedure.

Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat

A major clinical concern with the use of cannabinoid receptor 1 (CB1) direct agonists is that these compounds increase alcohol drinking and drug abuse-related behaviours. As an alternative approach, CB1-receptor-mediated activity can be facilitated by increasing anandamide levels with the use of hydrolase fatty acid amide hydrolase (FAAH) inhibitors. Using the selective FAAH inhibitor URB597, we investigated whether activation of the endogenous cannabinoid tone increases alcohol abuse liability, as what happens with the CB1 receptor direct agonists. URB597 was tested on alcohol self-administration in Wistar rats and on homecage alcohol drinking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. In Wistar rats, URB597 effects on alcohol-induced anxiety and on stress-, yohimbine- and cue-induced reinstatement of alcohol seeking were also evaluated. For comparison, the effect of the CB1 receptor antagonist rimonabant on ethanol self-administration was also tested. Under our experimental condition, intraperitoneal (IP) administration of URB597 (0.0, 0.3 and 1.0 mg/kg) neither increased voluntary homecage alcohol drinking in msP rats nor facilitated fixed ratio 1 and progressive ratio alcohol self-administration in nonselected Wistars. In the reinstatement tests, the compound did not have effects on cue-, footshock stress- and yohimbine-induced relapse. Conversely, URB597 completely abolished the anxiogenic response measured during withdrawal after an acute IP administration of alcohol (3.0 g/kg). Rimonabant (0.0, 0.3, 1.0 and 3.0 mg/kg) significantly reduced ethanol self-administration. Results demonstrate that activation of the endocannabinoid anandamide system by selective inhibition of FAAH does not increase alcohol abuse risks but does reduce anxiety associated to alcohol withdrawal. We thus can speculate that medication based on the use of endocannabinoid system modulators such as URB597 may offer important advantages compared to treatment with direct CB1 receptor activators.

Nicotine Self-Administration Differentially Regulates Hypothalamic Corticotropin-Releasing Factor and Arginine Vasopressin mRNAs and Facilitates Stress-Induced Neuronal Activation

Acute nicotine is a potent stimulus for activation of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis, while chronic nicotine self-administration (SA) desensitizes the ACTH response to self-administered nicotine but cross-sensitizes to mild footshock stress (mFSS). To identify underlying mechanisms, we investigated (1) the effects of chronic nicotine SA on the coexpression of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) mRNAs, the primary hypothalamic neuropeptides regulating ACTH release, in the parvocellular division of paraventricular nucleus (pcPVN), and (2) mFSS-induced activation of these neurons during nicotine SA. Adult male Sprague Dawley rats were given 23 h/d unlimited access to self-administer nicotine (0.03 mg/kg per injection, i.v.) for 19 d. Brains were double labeled with fluorescence in situ hybridization of CRF and AVP mRNAs and triple labeled after mFSS exposure for CRF and AVP mRNAs and c-Fos protein. Chronic nicotine SA significantly increased AVP mRNA signal and the number of pcPVN AVP-positive (AVP(+)) neurons (twofold to threefold), reduced the number of CRF-positive (CRF(+)) neurons by approximately 60%, but increased pcPVN CRF(+)/AVP(+) neuronal number fivefold. Significantly, although chronic nicotine SA did not affect total c-Fos expression induced by mFSS in pcPVN CRF(+) neurons, the majority of the new CRF(+)/AVP(+) population was activated by this heterotypic stressor. These phenotypic neuronal alterations may provide the pivotal mechanism underlying the capacity of chronically self-administered nicotine to cross-sensitize the HPA response to specific stressors, suggesting that nicotine may augment HPA responsiveness to specific stressors in human smokers.

A dopamine mechanism is implied in the acquisition and expression of amphetamine and stress-induced effects observed in the lymphocyte subpopulations

Drugs of abuse and stress are associated with changes in circulating cell populations and reductions in cell-mediated immune responses. The main goal of this study was to determine the influence of repeated and acute d-amphetamine treatments on the foot-shock stress-induced effects on the peripheral lymphocyte subpopulations, and the involvement of a dopamine mechanism in the development and expression of this phenomenon. Wistar rats received an acute (5 mg/kg/day i.p.) or a repeated (2 mg/kg/day i.p. during 9 days) amphetamine treatment, and were exposed to a foot-shock stress (1 mA, 3 s) 4 days after the last amphetamine injection. Another group was administered with haloperidol (1 mg/kg/day i.p.) 15 min previous to each daily amphetamine injection or previous to the foot-shock stress session. Then, blood cells stained with monoclonal antibodies against CD3-FITC, CD8-PE and CD4-Cy-Chrome, and against CD161a-FITC, CD3-PE, and CD45RA-Cy-Crhome, were analyzed by multiparameter flow cytometry. The exposure to a foot-shock stress induced a decrease in the absolute number of peripheral lymphocytes, as well as in CD4+ and CD8+ T-cells and B-cells in acute and repeatedly amphetamine-treated rats, whereas the NK-cell population remained unchanged. Haloperidol administration previous to each drug administration or the foot-shock stress session reversed these effects. This study provides strong evidence that dopamine can play a more general role in the influence of amphetamine on the stress-induced effects on the lymphocyte subsets.

The Central and Peripheral Production of Pro-inflammatory Cytokine, IL-1b after Immune and Stress Stimulation in Rats

Interleukin-1β (IL-1β), one of the pro-inflammatory cytokines, acts as an endogenous pyrogen and is an important mediator of behavioral and physiological responses to immune stimulation as well as exposure to stressors. The objective of the present study was to examine the pattern of central or peripheral IL-1 β response to lipopolysaccharide (LPS) or exposure to the foot shock stress (FS) in rats. After treatment of LPS (100 μg/kg) or exposure to the FS [ten times (0.8 mA) foot shocks for 5 sec each and 90 sec interval], body temperature and IL-1β levels in plasma, spleen and brain were measured. Both LPS and FS stimuli elicited increased body temperature but showed different patterns of peripheral IL-1 β levels. LPS produced a widespread increase in IL-1β levels in the plasma, spleen and brain, whereas FS produced a significant increase in IL-1β levels only in the brain regions but not in plasma and spleen. The present study suggests that IL-1β is, centrally or peripherally in different patterns, regulated by immune stimulation or exposure to stressors and IL-1β plays an important role in mediating responses of sickness-like behaviors induced by immune stimuli or stressors.

Dexamethasone and stressor-magnitude regulation of stress-induced transcription of HPA axis secretagogues in the rat

Regulation of the production of hypothalamic-pituitary-adrenal (HPA) axis secretagogues, corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), may be differentially sensitive to the negative feedback effects of glucocorticoids. We chose to study this phenomenon by examining the ability of dexamethasone to influence CRH and AVP heteronuclear RNA (hnRNA) levels in an escapable/inescapable (ES/IS) foot-shock stress paradigm. On Day 1, adult male rats were subjected to either ES or IS foot-shock; on Day 2, saline or dexamethasone (100 μg/kg) was administered 2 h prior to the stressor. We found that ES/IS foot-shock stimulated similar robust increases in plasma adrenocorticotrophic hormone (ACTH) and corticosterone concentrations, and medial parvocellular division of the paraventricular nucleus (mpPVN) AVP and CRH hnRNA and c-fos mRNA levels in saline-treated ES/IS rats. Dexamethasone pretreatment suppressed ACTH and corticosterone levels similarly in IS and ES animals. Dexamethasone pretreatment also suppressed mpPVN CRH and AVP hnRNA levels at 30 min. However, by 120 min, the mpPVN AVP hnRNA levels in dexamethasone-treated rats were similar to those measured in the saline group. We also found that rats that received the most shocks on Day 1 had greater HPA axis activation on Day 2. We conclude that the magnitude of the foot-shock stressor, determined by learned and immediate cues, is important in determining the magnitude of the HPA response.

Footshock stress reinstates cocaine seeking in rats after extended post-stress delays

Exposure to footshock stress reinstates drug seeking in rats when tests for reinstatement are conducted immediately after termination of the stressor. It is not known, however, whether footshock is effective in inducing reinstatement if a post-stress delay is imposed before testing for reinstatement. The objectives of the study were to determine for how long footshock remains effective in inducing the reinstatement of cocaine seeking if testing is delayed after termination of the stressor and to determine whether the context in which a post-stress delay is carried out influences the magnitude of reinstatement. Rats self-administered cocaine (1.0 mg/kg per infusion) for 8-10 days. After extinction, tests for reinstatement by intermittent footshock (20 min; 0.8 mA) were conducted after post-stress delays of up to 60 min. Although footshock was always administered in the self-administration (SA) chamber, delays were given either in the SA chamber or home cage (HC). Footshock induced reinstatement after post-stress delays of up to 40 min. No differences in responding during tests for reinstatement were observed between animals in the SA chamber and under HC conditions. Within a limited time window, footshock is effective in reinstating cocaine seeking, when testing is delayed after termination of the stressor. Together with previous work from this laboratory, the findings are consistent with the idea that stress can induce the reinstatement of drug seeking by conditioning excitation to the context in which it is administered and that this conditioned excitation can overcome the inhibitory processes maintaining extinction responding, even after a post-stress delay.

Cross-sensitization and cross-tolerance between exogenous cannabinoid antinociception and endocannabinoid-mediated stress-induced analgesia

Footshock stress induces both endocannabinoid mobilization and antinociception. The present studies investigated behavioral plasticity in cannabinoid antinociceptive mechanisms following repeated activation using the tail-flick test. A secondary objective was to ascertain whether blockade of stress antinociception by the CB1 antagonist rimonabant could be attributed to changes in locomotor activity. The cannabinoid agonist WIN55,212-2 induced hypoactivity in the open field relative to vehicle-treated controls. By contrast, rimonabant, administered at a dose that virtually eliminated endocannabinoid-mediated stress antinociception, failed to alter locomotor behavior (i.e. time resting, ambulatory counts, distance traveled) in rats subjected to the same stressor. Rats exposed acutely to footshock were hypersensitive to the antinociceptive effects of WIN55,212-2 and Δ9-tetrahydrocannabinol (Δ9-THC). The converse was also true; acute Δ9-THC and WIN55,212-2 administration potentiated stress antinociception, suggesting a bidirectional sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception. Stress antinociception was also attenuated following chronic relative to acute treatment with WIN55,212-2 or Δ9-THC. Repeated exposure to footshock (3min/day for 15days), however, failed to attenuate antinociception induced by either footshock stress or WIN55,212-2. Our results demonstrate that endocannabinoid-mediated stress antinociception cannot be attributed to motor suppression. Our results further identify a functional plasticity of the cannabinoid system in response to repeated activation. The existence of cross-sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception suggests that these phenomena are mediated by a common mechanism. The observation of stress-induced hypersensitivity to effects of exogenous cannabinoids may have clinical implications for understanding marijuana abuse liability in humans.

Foot shock stress prolongs the telogen stage of the spontaneous hair cycle in a non‐depilated mouse model

There is an increasing evidence to indicate that stress can influence skin disease and cutaneous functions. Previous studies have shown that stress alters the murine hair cycle; however, these studies have been carried out by using mouse models in which the hair cycle is forcibly synchronized after depilation. To examine whether foot shock stress (FS) changes the spontaneous hair cycle in a non-depilated animal model, and to evaluate the role of mast cells and substance P (SP) in the influence of stress on the hair cycle. Changes in the spontaneous hair cycle and the inhibitory effects of a specific SP NK1 receptor antagonist were examined in non-depilated mice during 3-4 weeks of FS. Foot shock stress prolonged the telogen stage of the hair cycle and delayed the induction of the subsequent anagen stage in the animal model. FS caused an increase in the ratio of de-granulated mast cells in the skin, an increase in the number of TUNEL-positive cells, and a decrease in the number of Ki67-positive cells. The NK1 receptor antagonist, WIN 62577, inhibited these stress responses. Our results strongly support previous work, demonstrating that stress alters active hair-cycling in vivo through the action of SP.

Body composition and endocrine status of long-term stress-induced binge-eating rats

Clinical binge eating runs a protracted course. The etiology of binge eating remains perplexing in part because, in humans, it is difficult to isolate and assess the independent and aggregate impact of various contributing variables. Using rats, we found that footshock stress and a history of caloric restriction (S + R), combine synergistically to induce binge eating. Stress and dieting are also strong antecedents and relapse factors in human eating disorders. Here we report further behavioral and physiological parallels to human binge eating. Like the protracted course of human binge eating, young female Sprague–Dawley rats continued to binge eat after 23 restriction/stress cycles (7 months) and this despite experiencing no significant weight loss during the restriction phases. Stress alone reduced adiposity by 35% ( p < 0.001) but S + R rats had no significant fat loss. An endocrine profile of normal plasma leptin and insulin levels but marked elevation of plasma corticosterone levels was found only in the binge-eating (S + R) rats ( p < 0.01), also paralleling endocrine profiles reported in clinical binge-eating studies. These behavioral and physiological similarities between this animal model and clinical binge eating increase its utility in understanding binge eating. Importantly, our findings also highlight the stubborn nature of binge eating: once a critical experience with dieting and stress is experienced, little if any further weight loss or food restriction is necessary to sustain it.

Neural, endocrine and electroencephalographic hyperreactivity to human contact: A diathesis-stress model of seizure susceptibility in El mice

The El mouse strain provides a non-induced model of idiopathic, multifactorial epilepsy in which seizures are elicited in response to stressful environmental stimuli such as tail suspension handling. In the present studies, genetically seizure susceptible El and non-susceptible ddY control mice were exposed to tail suspension, foot-shock and social stressors in order to test the hypothesis that neural and physiological responses to such stimuli would be exaggerated in the El strain. The first experiment assessed neural cell density, stress neuropeptide (corticotropin releasing factor—CRF) levels, and plasma corticosterone activation in El and ddY mice in an unhandled control condition or following exposure to tail suspension or foot-shock stressors. The second experiment assessed brain electroencephalographic activity using telemetrically monitored skull surface electrodes in El and ddY mice exposed to tail suspension or social interaction stressors. Assessment of El mouse brains revealed higher cell counts in amygdala and elevated CRF peptide content in the paraventricular thalamic nucleus relative to ddY controls. El mice exhibited significantly elevated plasma corticosterone levels 60 min following exposure to tail suspension and foot-shock stressors relative to ddY controls. Finally, El mice exhibited significantly elevated brain electroencephalographic (1–4 Hz) activity in response to tail suspension, but not social interaction, relative to ddY controls. These results indicate that potentiated neural, endocrine and physiological activation arises in the El strain following exposure to a known seizure trigger stimulus, involuntary tail suspension handling. The findings support a diathesis-stress hypothesis in which genetically seizure susceptible El mice exhibit a multifaceted hyperreactivity to noxious environmental stimuli.