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M Fleshner

Publications and source records attributed to M Fleshner.

At least 55 records · Page 3Linked to original sources
PubMed1997

TNF-alpha-induced corticosterone elevation but not serum protein or corticosteroid binding globulin reduction is vagally mediated.

Immune activation leads to production of mediators such as cytokines, which act to induce both brain-mediated and peripheral defense processes. We used intraperitoneal administration of the cytokine tumor necrosis factor-alpha (TNF-alpha) to investigate whether defense processes induced by this cytokine are mediated by vagal afferents and/or interleukin-1 (IL-1) receptors. Because some effects of TNF-alpha are mediated, at least in part, by the brain [plasma corticosterone (CORT) elevation] and some are mediated by peripheral organs [reduction of serum protein and corticosteroid binding globulin (CBG)], we also investigated whether the effects of vagotomy are specific to those defense processes mediated by the brain. Both vagotomy and IL-1 receptor antagonist attenuated serum CORT elevation, but had no effects on serum protein or CBG reduction. These results support the idea that vagal afferents provide a true immune-to-brain pathway that may include IL-1 receptors.

Animals↗
PubMed1997

DHEA-S selectively impairs contextual-fear conditioning: support for the antiglucocorticoid hypothesis.

The authors had reported that glucocorticoids play a selective role in fear conditioning. The adrenal steroid dehydroepiandrosterone (DHEA) has been reported to act as a functional antiglucocorticoid. If DHEA has antiglucocorticoid properties, then its effects on fear conditioning might resemble those produced by adrenalectomy. The authors now report that chronic exposure to high levels of dehydroepiandrosterone sulfate (DHEA-S; converted in vivo to DHEA) produced the same pattern of results as adrenalectomy. Specifically, treatment with DHEA-S impaired contextual fear conditioning 24 hr after conditioning but not immediately after conditioning, and like adrenalectomy, DHEA-S had no effect on auditory-cue fear conditioning. Preexposure to the context before drug treatment eliminated the amnestic effects of DHEA-S, suggesting that, like adrenalectomy, DHEA-S exerted its effect by interfering with the construction of a contextual memory representation. Thus, DHEA appears to act as a functional antiglucocorticoid in the processes that mediate learning and memory.

Acoustic Stimulation↗
PubMed1997

Evidence that brief stress may induce the acute phase response in rats.

Exposing rats to a single session of inescapable tail shock (IS) reduces corticosteroid binding globulin (CBG) 24 h later (Fleshner et al., Endocrinology 136: 5336-5342, 1995). The present experiments examined whether reductions in CBG are differentially affected by controllable vs. identical uncontrollable tail shock, are mediated by IS-induced glucocorticoid elevation, or reflect IS-induced activation of the acute phase response and whether IS produces fever. The results demonstrate that 1) equivalent reductions in CBG are observed in response to escapable tail shock or yoked IS, 2) IS-induced CBG reduction is not blocked by adrenalectomy in rats that receive basal corticosteroid replacement or by pretreatment with RU-38486, and 3) IS appears to activate the acute phase response, since IS reduces serum levels of an acute-phase negative reactant (CBG), increases serum levels of acute-phase positive reactants (haptoglobin and alpha 1-acid glycoprotein), and increases core body temperature 20-24 h later.

Adrenalectomy↗
PubMed1997

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.

Acoustic Stimulation↗
PubMed1996

Synergy between chronic corticosterone and sodium azide treatments in producing a spatial learning deficit and inhibiting cytochrome oxidase activity.

Previously, we developed a rat model of persistent mitochondrial dysfunction based upon the chronic partial inhibition of the mitochondrial enzyme cytochrome oxidase (EC 1.9.3.1). Continuous systemic infusion of sodium azide at approximately 1 mg/kg per hr inhibited cytochrome oxidase activity and produced a spatial learning deficit. In other laboratories, glucocorticoids have been reported to exacerbate neuronal damage from various acute metabolic insults. Therefore, we tested the hypothesis that corticosterone, the primary glucocorticoid in the rat, would potentiate the sodium azide-induced learning deficit. To this end, we first identified nonimpairing doses of sodium azide (approximately 0.75 mg/kg per hr) and corticosterone (100-mg pellet, 3-week sustained-release). We now report that chronic co-administration of these individually nonimpairing treatments produced a severe learning deficit. Moreover, the low dose of corticosterone, which did not elevate serum corticosterone, acted synergistically with sodium azide to inhibit cytochrome oxidase activity. The latter result represents a previously unidentified effect of glucocorticoids that provides a candidate mechanism for glucocorticoid potentiation of neurotoxicity induced by metabolic insult. These results may have the clinical implication of expanding the definition of hypercortisolism in patient populations with compromised oxidative metabolism. Furthermore, they suggest that glucocorticoid treatment may contribute to pathology in disease or trauma conditions that involve metabolic insult.

Analysis of Variance↗
PubMed1996

The neurosteroid dehydroepiandrosterone sulfate (DHEAS) enhances hippocampal primed burst, but not long-term, potentiation.

Dehydroepiandrosterone sulfate (DHEAS), which is synthesized in the brain and in the periphery, is known to affect the excitability of hippocampal neurons. However, its influence on electrophysiological plasticity has not been addressed. We have studied the effects of DHEAS on primed burst (PB) and long-term (LTP) potentiation, two electrophysiological models of memory. PB potentiation is a lasting increase in the amplitude of the CA1 population spike produced by minimal (threshold) electrical stimulation; LTP is produced by more extensive (supra-threshold) stimulation. Whereas intermediate doses (24 and 48 mg/kg, s.c.) of DHEAS given to rats enhanced PB potentiation, low (6 mg/kg) and high (96 mg/kg) doses were ineffective. LTP was not affected by any dose of DHEAS. The inverted-U relationship between DHEAS and PB potentiation is consistent with previous work demonstrating an inverted-U dose-dependent enhancement of memory by DHEAS. The present findings suggest that DHEAS could enhance memory by facilitating the induction of neural plasticity.

Animals↗
PubMed1996

Macrophage stimulation reduces the cholesterol levels of stressed and unstressed rats.

Male, Sprague-Dawley rats were either treated with zymosan, a nonspecific macrophage stimulator, or saline vehicle. Half of each group were then subjected to a stress procedure, the other half remained in their home cage. Results indicate that zymosan-treated animals had lower levels of total, low-density/very-low-density, and high-density lipoprotein than vehicle controls. Stressed animals had higher levels of the cholesterol parameters than did home cage controls. Manipulation of macrophage levels may be a prophylactic manipulation to combat stress-induced increases in cholesterol.

Animals↗
PubMed1996

Psychological stress impairs spatial working memory: relevance to electrophysiological studies of hippocampal function.

Stress blocks hippocampal primed-burst potentiation, a low threshold form of long-term potentiation, thereby suggesting that stress should also impair hippocampal-dependent memory. Therefore, the effects of stress on working (hippocampal-dependent) and reference (hippocampal-independent) memory were evaluated. Rats foraged for food in seven arms of a 14-arm radial maze. After they ate the food in four of the seven baited arms, they were placed in an unfamiliar environment (stress) for a 4-hr delay. At the end of the delay they were returned to the maze to locate the food in the 3 remaining baited arms. Stress impaired only working memory. Stress interfered with the retrieval of previously stored information (retrograde amnesia), but did not produce anterograde amnesia. Stress appears to induce a transient disruption of hippocampal function, which is revealed behaviorally as retrograde amnesia and physiologically as a blockade of synaptic plasticity.

Amnesia, Retrograde↗
PubMed1996

RU-486 blocks differentially suppressive effect of stress on in vivo anti-KLH immunoglobulin response.

Exposure to stressors can affect various aspects of immune function, including the antibody response. We have previously reported that rats exposed to an acute session of inescapable tail shock (IS) show long-term reductions in anti-keyhole limpet hemocyanin (KLH) immunoglobulin (Ig) M and IgG and a failure to expand Th1-like cells in response to KLH. To further investigate the potential role of decreased Th1-like cells in the IS-induced reduction of anti-KLH Ig, we examined two isotypes of IgG, IgG1 and IgG2a. Isotype switching is under cytokine control. Interleukin-4 helps B cells switch from making IgM to making IgG1, whereas interferon (IFN)-gamma helps B cells switch from making IgM to making IgG2a. In this paper we report that IS exposure reduces IFN-gamma levels 4 days after exposure to IS+KLH compared with immunized home cage controls. In addition, IS exposure reduced the Th1 cytokine-sensitive anti-KLH IgG2a but not Th2 cytokine-sensitive anti-KLH IgG1. This pattern of isotype reduction suggests that a failure to expand the Th1 cell, which results in less IFN-gamma, may contribute to the the IS-induced reduction in anti-KLH Ig. Glucocorticoids (GCs) differentially regulate Th1 and Th2 cells. Administration of the type II GC receptor antagonist RU-486 before IS blocked the IS-induced suppression in anti-KLH IgM, IgG, and IgG2a. Corticosterone (2.5 mg/kg), however, did not produce the suppression in anti-KLH Ig. These results support a role of corticosterone in mediating IS-induced reductions in in vivo antibody.

Adjuvants, Immunologic↗
PubMed1995

Stressed rats fail to expand the CD45RC+CD4+ (Th1-like) T cell subset in response to KLH: possible involvement of IFN-gamma.

Exposure to stressors effects various aspects of immune function, including the in vivo antibody response. We have previously reported that rats exposed to an acute session of inescapable tail shock (IS) show long-term reductions in anti-KLH (keyhole limpet hemocyanin) IgM and IgG. The mechanisms responsible for this suppression are currently unknown. Previous work has suggested changes in CD4+ T cells could be important. We report here that exposure to IS results in a reduction in Con A-stimulated IFN-gamma levels in mesenteric lymphocytes and splenocytes taken immediately after IS termination. In addition, IS exposure prevents the KLH-induced increase in the number of CD45RC+CD4+ T cells (Th1-like) in both the mesenteric lymph nodes and the spleen 4 days after immunization. The failure of KLH to expand the CD45RC+CD4+ subset could be due to the stress-induced reduction in IFN-gamma levels reported in cells taken at the time of immunization. Implications of these findings as a mechanism for the decrease in the in vivo antibody response previously reported is discussed.

Animals↗
PubMed1995

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.

Animals↗
PubMed1995

Interleukin-1 beta induced corticosterone elevation and hypothalamic NE depletion is vagally mediated.

Processes occurring within the immune system can alter neural function. Cytokines released by cells of the immune system during illness are key messengers in immune-to-brain communication. Interleukin-1 beta (IL-1 beta) is particularly important in this regard and is known to stimulate a myriad of illness-related outcomes such as fever, sickness behavior, aphagia, adipsia, hypothalamic-pituitary-adrenal activation, and changes in pain reactivity. Thus peripherally released IL-1 beta has potent neural effects and is a critical mediator of the impact of immune processes on brain. There is, however, uncertainty concerning the communication pathways involved. We provide evidence that a primary route of peripheral cytokine signalling is through stimulation of peripheral vagal afferents rather than or in addition to direct cytokine access to brain. Subdiaphragmatic, but not hepatic vagotomy, blocked rhIL-1 beta-induced hypothalamic norepinephrine depletion and attenuated rhIL-1 beta-induced increases in serum corticosterone. These data suggest that rhIL-1 beta activates the hypothalamic-pituitary-adrenal axis via stimulation of peripheral vagal afferents and further support the hypothesis that peripheral cytokine signalling to the CNS is mediated primarily by stimulation of peripheral afferents.

Animals↗
PubMed1995

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.

Animals↗
PubMed1994

A permissive role of corticosterone in an opioid form of stress-induced analgesia: blockade of opiate analgesia is not due to stress-induced hormone release.

The 100 inescapable tail-shock paradigm produces three sequential analgesic states as the number of shocks increases: an early opioid analgesia (after 2 shocks) that is attenuated by systemic naltrexone, a middle analgesia (after 5-40 shocks) that is unaffected by systemic naltrexone, and a late opioid analgesia (after 80-100 shocks) that is attenuated by systemic naltrexone. In order to determine whether the absence of adrenal hormones would affect any of these analgesias, we tested adrenalectomized (ADX) versus sham-operated control rats 2 weeks post-surgery. Pain threshold was assessed using the tail-flick (TF) test. ADX attenuated both the early (2 shock) and late (80-100 shock) opiate analgesias and failed to reduce the naltrexone-insensitive analgesia after 5-40 shocks. We demonstrated that a loss of adrenomedullary catecholamines does not underlie the ADX-induced attenuation of opioid analgesia since sympathetic blockade using systemic chlorisondamine (6 mg/kg) failed to reduce analgesia at any point in the shock session. It was further shown that stress levels of adrenal hormones are not critical since (a) analgesia was unaffected when animals were tested 48 h after ADX, (b) 2 shocks do not produce a surge in corticosterone (CORT) over and above levels observed in animals restrained and TF tested in preparation for shock, and (c) basal CORT replacement in drinking water fully restored analgesia in ADX rats. These experiments demonstrate that basal CORT, rather than adrenomedullary substances, is critical to the expression of analgesia. The function of CORT here is not linked to a shock-induced surge of the steroid. CORT appears to play a permissive role in the expression of analgesia. Potential effects of the absence of corticosteroids on neurotransmitter biosynthesis important in analgesia production are discussed.

Adrenal Medulla↗
PubMed1994

Psychological stress repeatedly blocks hippocampal primed burst potentiation in behaving rats.

Primed burst (PB) potentiation is a long-term increase in CA1 population spike amplitude produced by brief physiologically patterned electrical stimulation of the hippocampal commissure. Exposure of rats to a novel environment resulted in a blockade of short-term (Post-tetanic potentiation, PTP) and long-term (PB potentiation) plasticity in all cases (n = 6). When the animals had extensive exposure to the environment (14 consecutive days), PTP and PB potentiation occurred. With placement of the rats in a second novel environment, once again, neither PTP nor PB potentiation was observed. Placement of rats in each of the two novel environments produced a significant increase in serum corticosterone levels, while placement in the familiar environment produced no increase in response. These findings support the hypothesis that hippocampal plasticity is repeatedly susceptible to modulation by the stress of forced exposure to a novel environment.

Animals↗
PubMed1994

Morphine-induced decreases in in vivo antibody responses.

Endogenous opioids have been shown to be released during acute stress and could play a role in immune modulation and activation of the hypothalamo-pituitary-adrenal axis. We investigated the ability of morphine sulfate to mimic stressor effects on decreases in in vivo antibody responses. Sprague-Dawley and Fischer 344 rats were given an intraperitoneal injection of an antigen, Keyhole limpet hemocyanin (KLH), followed by a single intravenous injection of either saline or varying doses of morphine sulfate. The corticosterone and anti-KLH IgG antibody responses to morphine were measured. A dose-dependent increase in corticosterone was observed. Significantly lower levels of anti-KLH IgG antibodies were observed in morphine-treated animals but these effects were strain and dose dependent. In Sprague-Dawley rats, 3 and 10 mg/kg doses of morphine decreased antibody levels while 1.5, 5, and 15 mg/kg did not change antibody responses. In Fischer 344 rats a dose of 5 mg/kg of morphine decreased antibody levels while 10 and 15 mg/kg did not change antibody responses. These results indicate that morphine can decrease antibody levels and that these decreases are not correlated with elevated levels of corticosterone. To determine if opioid binding is critical to these changes, animals received naltrexone prior to the administration of morphine. Naltrexone partially attenuated corticosterone levels, but completely blocked morphine-induced changes in immune function.

Animals↗
PubMed1994

Psychoneuroimmunology. The interface between behavior, brain, and immunity.

Psychoneuroimmunology is the study of interactions between behavior, the brain, and the immune system. This article is designed to provide an overview of this new field for the general psychologist. The existence of bidirectional communication pathways between the brain and the immune system and the implications of this network for behavior are emphasized. Implications are that behavioral-psychological processes ought to be capable of altering immune function and that events that occur as part of immune responses should modulate behavior. Evidence for influences in both of these directions is reviewed. The discussion of psychological modulation of immunity focuses on classical conditioning and stress, whereas that of immune modification of behavior highlights behavioral effects produced by substances released by the immune system. Finally, the adaptive role that such changes might play is considered.

Behavior↗