Opioid activation of toll-like receptor 4 contributes to drug reinforcement.

Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4(-/-) mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.

Effects of repeated voluntary or forced exercise on brainstem serotonergic systems in rats.

Voluntary exercise increases stress resistance by modulating stress-responsive neurocircuitry, including brainstem serotonergic systems. However, it remains unknown how exercise produces adaptations to serotonergic systems. Recruitment of serotonergic systems during repeated, daily exercise could contribute to the adaptations in serotonergic systems following exercise, but whether repeated voluntary exercise recruits serotonergic systems is unknown. In this study, we investigated the effects of six weeks of voluntary or forced exercise on rat brain serotonergic systems. Specifically, we analyzed c-Fos and FosB/ΔFosB as markers of acute and chronic cellular activation, respectively, in combination with tryptophan hydroxylase, a marker of serotonergic neurons, within subregions of the dorsal raphe nucleus using immunohistochemical staining. Compared to sedentary controls, rats exposed to repeated forced exercise, but not repeated voluntary exercise, displayed decreased c-Fos expression in serotonergic neurons in the rostral dorsal portion of the dorsal raphe nucleus (DRD) and increased c-Fos expression in serotonergic neurons in the caudal DR (DRC), and interfascicular part of the dorsal raphe nucleus (DRI) during the active phase of the diurnal activity rhythm. Similarly, increases in c-Fos expression in serotonergic neurons in the DRC, DRI, and ventral portion of the dorsal raphe nucleus (DRV) were observed in rats exposed to repeated forced exercise, compared to rats exposed to repeated voluntary exercise. Six weeks of forced exercise, relative to the sedentary control condition, also increased FosB/ΔFosB expression in DRD, DRI, and DRV serotonergic neurons. While both voluntary and forced exercise increase stress resistance, these results suggest that repeated forced exercise, but not repeated voluntary exercise, increases activation of DRI serotonergic neurons, an effect that may contribute to the stress resistance effects of forced exercise. These results also suggest that mechanisms of exercise-induced stress resistance may differ depending on the controllability of the exercise.

Cardiovascular exercise intervention improves the primary antibody response to keyhole limpet hemocyanin (KLH) in previously sedentary older adults.

Based upon a prior cross-sectional study, we hypothesized that an aerobic exercise intervention in sedentary older adults would improve a primary T cell-dependent immune response. Participants were a subset of older subjects from a large, ongoing exercise intervention study who were randomly assigned to either an aerobic exercise (Cardio, n=30, 68.9+0.8 years) or flexibility/balance (Flex, n=20, 69.9+1.2 years) intervention. The intervention consisted of either three aerobic sessions for 30-60 min at 55-70% VO(2 max) or two 60 min flexibility/balance sessions weekly for 10 months. Eight months into the intervention, samples were collected before intramuscular administration of KLH (125 microg), followed by sampling at 2, 3, and 6 weeks post-KLH. Serum anti-KLH IgM, IgG1, and IgG2 was measured by ELISA. Physiological and psychosocial measures were also assessed pre- and post-intervention. While there was no difference in the anti-KLH IgG2 response between groups, Cardio displayed significantly (p<0.05) higher anti-KLH IgG1 (at weeks 2, 3, and 6 post) and IgM responses when compared to Flex. Despite cardiovascular intervention-induced improvement in physical fitness (approximately 11% vs. 1% change in VO(2 peak) in Cardio vs. Flex, respectively), we found no relationship between improved fitness and enhanced anti-KLH antibody responses. Optimism, perceived stress, and affect were all associated with enhanced immune response. We have shown for the first time that cardiovascular training in previously sedentary elderly results in significantly higher primary IgG1 and IgM antibody responses, while having no effect on IgG2 production.

Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus.

Reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus have been implicated in human affective disorders and behavioral stress responses. The current studies examined the role of BDNF in the behavioral consequences of inescapable stress, or learned helplessness. Inescapable stress decreased BDNF mRNA and protein in the hippocampus of sedentary rats. Rats allowed voluntary access to running wheels for either 3 or 6 weeks prior to exposure to stress were protected against stress-induced reductions of hippocampal BDNF protein. The observed prevention of stress-induced deceases in BDNF, however, occurred in a time course inconsistent with the prevention of learned helplessness by wheel running, which is evident following 6 weeks, but not 3 weeks, of wheel running. BDNF suppression in physically active rats was produced by administering a single injection of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg) just prior to stress. Despite reduced levels of hippocampal BDNF mRNA following stress, physically active rats given the combination of fluoxetine and stress remained resistant against learned helplessness. Sedentary rats given both fluoxetine and stress still demonstrated typical learned helplessness behaviors. Fluoxetine by itself reduced BDNF mRNA in sedentary rats only, but did not affect freezing or escape learning 24 h later. Finally, bilateral injections of BDNF (1 mug) into the dentate gyrus prior to stress prevented stress-induced reductions of hippocampal BDNF but did not prevent learned helplessness in sedentary rats. These data indicate that learned helplessness behaviors are independent of the presence or absence of hippocampal BDNF because blocking inescapable stress-induced BDNF suppression does not always prevent learned helplessness, and learned helplessness does not always occur in the presence of reduced BDNF. Results also suggest that the prevention of stress-induced hippocampal BDNF suppression is not necessary for the protective effect of wheel running against learned helplessness.

Sexual dimorphism of the intracellular heat shock protein 72 response.

The majority of previous work examining stress responses has been done in males. Recently, it has become clear that the impact of stressor exposure is modulated by sex. One stress response that may be affected by sex is the induction of intracellular heat shock protein (HSP) 72, which is a stress- responsive molecular chaperone that refolds denatured proteins and promotes cellular survival. The following study compared HSP72 in males and females and also examined whether the estrous cycle altered HSP72 induction in females. We hypothesized that females compared with males would have a constrained HSP72 response after an acute stressor and that the stress-induced HSP72 response in females would fluctuate with the estrous cycle. Male and female F344 rats were either left in their home cage or exposed to acute tail-shock stress (8-10/group). Immediately following stressor, trunk blood was collected and tissues were flash frozen. Vaginal smear and estrogen enzyme immunoassay were used to categorize the phase of estrous. Results show that female rats had a greater corticosterone response than males, that both males and females exhibit a stress-induced release of progesterone, and that males and females had equal levels of stress-induced circulating norepinephrine. Sexual dimorphism of the HSP72 (ELISA) response existed in pituitary gland, mesenteric lymph nodes, and liver such that female rats had an attenuated HSP72 response compared with males after stress. The adrenal glands, spleen, and heart did not exhibit sexual dimorphism of the HSP72 response. The estrous cycle did not have a significant effect on basal or stress-induced HSP72 in females.

Exercise and Prebiotics Produce Stress Resistance: Converging Impacts on Stress-Protective and Butyrate-Producing Gut Bacteria.

The gut microbial ecosystem can mediate the negative health impacts of stress on the host. Stressor-induced disruptions in microbial ecology (dysbiosis) can lead to maladaptive health effects, while certain probiotic organisms and their metabolites can protect against these negative impacts. Prebiotic diets and exercise are feasible and cost-effective strategies that can increase stress-protective bacteria and produce resistance against the detrimental behavioral and neurobiological impacts of stress. The goal of this review is to describe research demonstrating that both prebiotic diets and exercise produce adaptations in gut ecology and the brain that arm the organism against inescapable stress-induced learned helplessness. The results of this research support the novel hypothesis that some of the stress-protective effects of prebiotics and exercise are due to increases in stress-protective gut microbial species and their metabolites. In addition, new evidence also suggests that prebiotic diet or exercise interventions are most effective if given early in life (juvenile-adolescence) when both the gut microbial ecosystem and the brain are plastic. Based on our new understanding of the mechanistic convergence of these interventions, it is feasible to propose that in adults, both interventions delivered in combination may elevate their efficacy to promote a stress-resistant phenotype.

Mortality among patients with pulmonary non-tuberculous mycobacteria disease.

SETTING: Tertiary referral center, National Institutes of Health (NIH), USA. OBJECTIVE: To estimate the mortality rate and its correlates among persons with pulmonary non-tuberculous mycobacteria (PNTM) disease. DESIGN: A retrospective review of 106 patients who were treated at the NIH Clinical Center and met American Thoracic Society/Infectious Diseases Society of America criteria for PNTM. Eligible patients were aged ⩾18 years and did not have cystic fibrosis or human immunodeficiency virus (HIV) infection. RESULTS: Of 106 patients followed for a median of 4.9 years, 27 (25%) died during follow-up, for a mortality rate of 4.2 per 100 person-years. The population was predominantly female (88%) and White (88%), with infrequent comorbidities. Fibrocavitary disease (adjusted hazard ratio [aHR] 3.3, 95% confidence interval [CI] 1.3-8.3) and pulmonary hypertension (aHR 2.1, 95%CI 0.9-5.1) were associated with a significantly elevated risk of mortality in survival analysis. CONCLUSIONS: PNTM remains a serious public health concern, with a consistently elevated mortality rate across multiple populations. Significant risk factors for death include fibrocavitary disease and pulmonary hypertension. Further research is needed to more specifically identify clinical and microbiologic factors that jointly influence disease outcome.

Exposing rats to a predator blocks primed burst potentiation in the hippocampus in vitro.

This study evaluated the effects of acute psychological stress (cat exposure) in adult male rats on electrophysiological plasticity subsequently assessed in the hippocampus in vitro. Two physiological models of memory were studied in CA1 in each recording session: (1) primed burst potentiation (PBP), a low-threshold form of plasticity produced by a total of five physiologically patterned pulses; and (2) long-term potentiation (LTP), a suprathreshold form of plasticity produced by a train of 100 pulses. Three groups of rats were studied: (1) undisturbed rats in their home cage (home cage); (2) rats placed in a chamber for 75 min (chamber); and (3) rats placed in a chamber for 75 min in close proximity to a cat (chamber/stress). At the end of the chamber exposure period, blood samples were obtained, and the hippocampus was prepared for in vitro recordings. Only the chamber/stress group had elevated (stress) levels of corticosterone. The major finding was that PBP, but not LTP, was blocked in the chamber/stress group. Thus, the psychological stress experienced by the rats in response to cat exposure resulted in an inhibition of plasticity, which was localized to the intrinsic circuitry of the hippocampus. This work provides novel observations on the effects of an ethologically relevant stressor on PBP in vitro and of the relative insensitivity of LTP to being modulated by psychological stress. We discuss the relevance of these electrophysiological findings to our behavioral work showing that predator stress impairs spatial memory.

A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine.

The present experiments examined the role of spinal proinflammatory cytokines [interleukin-1beta (IL-1)] and chemokines (fractalkine) in acute analgesia and in the development of analgesic tolerance, thermal hyperalgesia, and tactile allodynia in response to chronic intrathecal morphine. Chronic (5 d), but not acute (1 d), intrathecal morphine was associated with a rapid increase in proinflammatory cytokine protein and/or mRNA in dorsal spinal cord and lumbosacral CSF. To determine whether IL-1 release modulates the effects of morphine, intrathecal morphine was coadministered with intrathecal IL-1 receptor antagonist (IL-1ra). This regimen potentiated acute morphine analgesia and inhibited the development of hyperalgesia, allodynia, and analgesic tolerance. Similarly, intrathecal IL-1ra administered after the establishment of morphine tolerance reversed hyperalgesia and prevented the additional development of tolerance and allodynia. Fractalkine also appears to modulate the effects of intrathecal morphine because coadministration of morphine with intrathecal neutralizing antibody against the fractalkine receptor (CX3CR1) potentiated acute morphine analgesia and attenuated the development of tolerance, hyperalgesia, and allodynia. Fractalkine may be exerting these effects via IL-1 because fractalkine (CX3CL1) induced the release of IL-1 from acutely isolated dorsal spinal cord in vitro. Finally, gene therapy with an adenoviral vector encoding for the release of the anti-inflammatory cytokine IL-10 also potentiated acute morphine analgesia and attenuated the development of tolerance, hyperalgesia, and allodynia. Taken together, these results suggest that IL-1 and fractalkine are endogenous regulators of morphine analgesia and are involved in the increases in pain sensitivity that occur after chronic opiates.

Splenic norepinephrine depletion following acute stress suppresses in vivo antibody response.

Exposure to an intense acute stressor immediately following immunization leads to a reduction in anti-KLH IgM, IgG, and IgG2a, but not IgG1. Stress also depletes splenic norepinephrine (NE) content. Immunization during pharmacological (alpha-methyl-p-tyrosine) or stress-induced splenic NE depletion results in antibody suppression similar to that found in rats immunized prior to stressor exposure. Prevention of splenic NE depletion during stress by tyrosine, but not pharmacological elevation (mirtazapine) of NE, resulted in normal antibody responses. These data support the hypothesis that splenic NE depletion is necessary and sufficient for stress-induced suppression of antibody to a T-cell dependent antigen.

Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines.

Proinflammatory cytokines act at receptors in the CNS to alter physiological and behavioral responses. Exposure to stressors increases both peripheral and central proinflammatory cytokines, yet the mechanism(s) of induction remain unknown. Experiments here examined the role of catecholamines in the in vivo induction of proinflammatory cytokines following tailshock stress. Rats were pretreated i.p. with 2.0 mg/kg prazosin (alpha1-adrenoceptor antagonist), 10.0 mg/kg propranolol (beta-adrenoceptor antagonist), or 5.0 mg/kg labetalol (alpha1- and beta-adrenoceptor antagonist) 30 min prior to tailshock exposure and plasma interleukin-1beta (IL-1beta) and IL-6, along with tissue interleukin-1beta from the hypothalamus, hippocampus, and pituitary were measured immediately following stressor termination. Prazosin attenuated stress-induced plasma IL-1beta and IL-6, but had no effect on tissue IL-1beta levels, while propranolol attenuated plasma IL-6 and blocked tissue IL-1beta elevation, and labetalol, which cannot cross the blood-brain barrier, attenuated plasma IL-1beta and IL-6, blocked pituitary IL-1beta, but had no effect on central tissue IL-1beta levels. Furthermore, administration of 50.0 mg/kg N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, a neurotoxin that lesions neural projections from the locus coeruleus, prevented stress-induced elevation in hippocampal IL-1beta, a region highly innervated by the locus coeruleus, but had no effect on hypothalamic IL-1beta, a region that receives few locus coeruleus projections. Finally, i.p. injection of 5.0 mg/kg isoproterenol (beta-adrenoceptor agonist) was sufficient to induce circulating IL-1 and IL-6, and tissue IL-1beta. These data suggest catecholamines play an important role in the induction of stress-induced proinflammatory cytokines and that beta-adrenoceptors are critical for tissue IL-1beta induction, while both alpha- and beta-adrenoceptors contribute to the induction of plasma cytokines.

The immune system and memory consolidation: a role for the cytokine IL-1beta.

Interleukin-1 beta (IL-1beta), known to play a role in orchestrating the physiological and behavioral adjustments that occur during sickness, has also been shown to significantly influence memory consolidation. To support this assertion we present neurobiological evidence that the substrates for IL-1beta to influence memory processing and neural plasticity exist. We then present behavioral evidence that central IL-1beta administration and agents that induce central IL-1beta activity impair the consolidation of memories that depend on the hippocampal formation but have no effect on the consolidation of hippocampal-independent memories. Further, we demonstrate that the impairments in hippocampal-dependent memory consolidation produced by agents that induce IL-1beta activity are blocked by antagonizing the actions of IL-1beta. Finally, we discuss these data in terms of their implications for a physiological role of IL-1beta in memory consolidation processes and a potential role of IL-1beta in producing memory impairments associated with stress, aging, Alzheimer's disease, and AIDS related dementia complex.

A long-term increase in basal levels of corticosterone and a decrease in corticosteroid-binding globulin after acute stressor exposure.

Adrenal glucocorticoids play an important role in mediating many of the behavioral and physiological effects of exposure to stressors. Focus has been primarily on the acute stress-induced rise in glucocorticoids [corticosterone (CORT) in the rat]. There are reports, however, that exposure to chronic stressors can produce an increase in basal CORT and a decrease in corticotropin-binding globulin (CBG). These changes occur subsequent to the stress-induced rise in CORT. The following experiments examined whether exposure to an acute stressor (100 5-sec inescapable tail shocks; IS) could also produce long term changes in basal CORT and CBG. We report that a single session of IS results in an increase in basal total serum CORT that persists 48-96 h after IS termination. The increase is present only at the diurnal trough (morning). CBG levels ae also decreased for 24-48 h. The decrease is present at both the diurnal peak (evening) as well as the trough (morning). These changes result in an increase in the percent and amount of biologically active CORT (unbound or free). Thus, glucocorticoid-sensitive targets are exposed to high levels of free CORT for several days after IS termination. The long term increase in free CORT reported here may play an important role in mediating some of the effects produced by IS as well as those produced by other acute stressors.

Exercise does not modify spatial memory, brain autoimmunity, or antibody response in aged F-344 rats.

Old F-344 rats were given endurance training over a 10-week period on a motorized treadmill. This treatment resulted in substantial heart-to-body weight ratio increases, indicative of effective training. To determine whether endurance training might alter some of the known immune system and cognitive changes observed during aging, exercised old rats were compared to nonexercised old and young controls on three variables: in vivo antigen-specific immune activity, brain-reactive antibody formation, and spatial memory. The exercise training did not influence any of these measures in the old rats. Both groups of old rats showed poorer antibody response to a specific antigen, more brain-reactive antibody formation, and poorer spatial memory than the young controls. There was, however, a significant relationship between brain-reactive antibody formation and spatial memory performance, regardless of training condition.

Specific changes in lymphocyte subpopulations: a potential mechanism for stress-induced immunomodulation.

The mechanisms by which stressors alter immune function are not well understood. One hypothesis for stress-induced immunomodulation is that since immune responses require cooperation of different cell types, stress-induced shifts in cell populations might affect an organism's ability to mount an immune response. We sought to determine if inescapable shock (IS) could alter lymphocyte subpopulations and if so, whether this could be a mechanism for shock-induced immunomodulation. Our results suggest that IS produces changes in lymphocyte subpopulations and that these shifts could be responsible for modulation of in vivo antibody production. Exposure to IS resulted in an increase in the percent of CD4+ mesenteric lymphocytes and a decrease in the percent of CD8+ mesenteric lymphocytes when examined immediately after the cessation of IS. The stressor reduced antibody production to antigen processed at the altered mesenteric nodes, but did not alter antibody production to antigen processed at other sites. No measurable shifts were found in other compartments examined. The changes in CD4+ and CD8+ mesenteric lymphocytes resulted in an increased CD4+/CD8+ ratio that persisted for 1-24 h after stressor termination, becoming absent 48 h after IS termination. The stress-induced reduction in antibody production occurred only when antigen was given immediately prior to but not when antigen was given 48 h post stress. These findings suggest that the effects of a stressor could be specific to the manner in which the antigen enters the body, and that the stress-induced decrease in antibody production could be due to altered lymphocyte subpopulations as reflected by an increased CD4+/CD8+ ratio.

Stress-induced reduction in the rat mixed lymphocyte reaction is due to macrophages and not to changes in T cell phenotypes.

Exposure to aversive events or stressors modulates various aspects of immune function. We have previously reported that exposure to an acute stressor, inescapable tail shock (IS), resulted in a shift in T cell subpopulations in rat mesenteric lymph nodes but not in cervical lymph nodes (Fleshner et al. (1992) J. Neuroimmunol. 41, 131-142). The mesenteric CD4+/CD8+ ratio was increased immediately after exposure to IS and was due primarily to an increase in the percent of CD4+ cells. The present experiments were designed to determine the relationship between the IS-associated phenotypic shift and its significance in the function of CD4+ T cells. The function assessed was the in vitro proliferative response to alloantigens coded for by the Major Histocompatibility Complex (MHC). Using the mixed lymphocyte reaction (MLR), we report that exposure to IS resulted in a decrease in the MLR response of cells from both cervical and mesenteric lymph nodes. Depletion of macrophages (nylon wool adherent cells) eliminated the IS-induced reduction and co-culture of macrophages (irradiation-insensitive cells) from shocked rats produced the suppression. One interpretation of these data is that exposure to IS resulted in the activation of macrophages and the release of a suppressive factor which reduced the MLR response of peripheral lymph node lymphocytes.

Thermogenic and corticosterone responses to intravenous cytokines (IL-1beta and TNF-alpha) are attenuated by subdiaphragmatic vagotomy.

The brain orchestrates changes in behavior and physiology as a consequence of peripheral immune activation and infection. These changes require that the brain receives signals from the periphery that an immunological challenge has occurred. Previous research has established that cytokines play a role in signalling the brain. What remains unclear, however, is how peripheral cytokines signal the central nervous system. A recent proposal is that cytokines signal the brain by stimulating peripheral nerves. The hypothesis states that following infection and the release of cytokines such as IL-1beta into local tissue or microvasculature, IL-1beta stimulates IL-1 receptors on vagal afferent terminals, or more likely on cells of vagal paraganglia. Vagal afferents, in turn, signal the brain. Previous work has demonstrated that transection of the vagus below the level of the diaphragm blocks or attenuates many illness consequences of intraperitoneally (i.p.) administered lipopolysaccharide (LPS) or IL-1beta. The present studies extend these findings by examining the effect of subdiaphragmatic vagotomy on illness consequences following intravenously (i.v.) administered IL-1beta and TNF-alpha. Subdiaphragmatic vagotomy attenuated both the fever response and corticosterone response produced by i.v. administered cytokines. This effect was dose dependent. The results add support to the hypothesis that vagal afferents are involved in peripheral cytokine-to-brain communication.

Voluntary freewheel running selectively modulates catecholamine content in peripheral tissue and c-Fos expression in the central sympathetic circuit following exposure to uncontrollable stress in rats.

Modulation of sympathetic drive to the spleen is one potential mechanism whereby physical activity prevents stress-induced splenic immune suppression in rats. The current study tested the hypothesis that voluntary freewheel running reduces peripheral sympathetic drive by modulating stress-induced activity of brain regions synaptically linked to sympathetically innervated peripheral organs, including the adrenals and spleen. To this end, adrenal and splenic catecholamine content and activity of the central sympathetic circuit indexed by c-Fos protein induction, elicited by acute exposure to inescapable tail shock, were measured. Stressor exposure depleted adrenal and splenic norepinephrine content and elicited a robust increase in c-Fos in the brains of sedentary rats. Physical activity status had no effect on adrenal norepinephrine content. Indicative of attenuated sympathetic drive to the spleen, however, 6 weeks of voluntary freewheel running diminished stress-induced splenic norepinephrine depletion, and significantly attenuated stress-induced c-Fos in specific brain regions responsible for sympathetic regulation, including tyrosine hydroxylase-immunoreactive neurons of the locus coeruleus, A5 cell group and rostral ventrolateral medulla. Results suggest that voluntary activity attenuates sympathetic drive to the spleen during stressor exposure by selectively modulating stress-induced activity of the central sympathetic circuit. The attenuation of sympathetic responses observed in this study may be one important mechanism for the protective effect of physical activity against stress-related illness and immunosuppression.

Blockade of the hypothalamic-pituitary-adrenal response to stress by intraventricular injection of dexamethasone: a method for studying the stress-induced peripheral effects of glucocorticoids.

Interest in the mechanisms whereby stressors can influence behavior and physiological functioning has involved the use of a variety of methods to prevent the stress-induced release of glucocorticoids, an important and commonly studied stress hormone. We examined the effect of intracerebral ventricular dexamethasone (ICV DEX) on the stress-induced release of adrenocorticotropic hormone (ACTH), corticosterone, plasma epinephrine (E), and plasma norepinephrine (NE). Male Sprague-Dawley rats were stereotaxically implanted with third ventricle ICV cannulae, administered DEX or vehicle, and exposed to 100 1.6-mA tail shocks. Stress hormones were assessed from blood taken during and after the cessation the shock. We report an ICV DEX injection protocol (10 microgram given four times) that results in blocking the stress-induced release of ACTH and corticosterone, and attenuating the stress-induced release of plasma E and NE. We hypothesize that ICV DEX reduces hypothalamic corticotropin releasing hormone (CRH) synthesis and/or release. This method would be especially useful for those studying the effect of pituitary-adrenal hormones on steroid sensitive peripheral targets, such as the immune system.

A selective role for corticosterone in contextual-fear conditioning.

The contribution of corticosterone to contextual- and auditory-cue fear conditioning was examined. Adrenalectomized rats showed reduced contextual-fear conditioning when tested 24 hr after conditioning; however, neither immediate contextual- nor auditory-cue fear conditioning was impaired. Contextual-fear conditioning in adrenalectomized rats with corticosterone replacement during the 4-day interval separating surgery and conditioning matched the level of controls. Moreover, rats exposed to the context prior to adrenalectomy showed normal long-term contextual-fear conditioning. Corticosterone replacement administered after the conditioning episode also negated the effects of adrenalectomy. Thus, corticosterone's role in fear conditioning is selective: It appears to contribute to the neural processes that support the consolidation of a long-term memory representation of the context.