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We previously reported that traumatic brain injury (TBI) produced by moderate controlled cortical impact (CCI) attenuates the stress response of the hypothalamic-pituitary-adrenal (HPA) axis between 21 and 70 days postinjury and enhances the sensitivity of the stress response to glucocorticoid negative feedback. In the current study, we investigated two possible mechanisms for the CCI-induced attenuation of the HPA stress response-i.e, glucocorticoid receptor (GR) and GABA-mediated inhibition of the HPA axis, with the GR antagonist, mifepristone (RU486), or the GABA(A)-receptor antagonist, bicuculline. In addition, we examined the effect of moderate CCI on GR and inhibitory neurons histologically in subfields of the hippocampus, medial prefrontal cortex, and amygdala. We show that at 30-min after onset of restraint stress, GR as well as GABA antagonism with MIFE or BIC, respectively, reversed the attenuating effects of moderate CCI on the stress-induced HPA response. Our histological results demonstrate that moderate CCI led to a loss of glutamic acid decarboxylase 67 or parvalbumin-positive inhibitory neurons within regions of the hippocampus and amygdala but did not lead to significant increases in GR in these regions. These findings indicate that suppression of the stress-induced HPA response after moderate CCI is mediated by the inhibitory actions of both GR and GABA, with a corresponding loss of inhibitory neurons within brain regions with neural pathways affecting limbic stress-integrative pathways.

Voluntary exercise increases levels of brain-derived neurotrophic factor (BDNF) after traumatic brain injury (TBI) when it occurs during a delayed time window. In contrast, acute post-TBI exercise does not increase BDNF. It is well known that increases in glucocorticoids suppress levels of BDNF. Moreover, recent work from our laboratory showed that there is a heightened stress response after fluid percussion injury (FPI). In order to determine if a heightened stress response is also observed with acute exercise, at post-injury days 0–4 and 7–11, corticosterone (CORT) and adrenocorticotropic hormone (ACTH) release were measured in rats running voluntarily or exposed to two daily 20-min periods of forced running wheel exercise. Forced, but not voluntary exercise, continuously elevated CORT. ACTH levels were initially elevated with forced exercise, but decreased by post-injury day 7 in the control, but not the FPI animals. As previously reported, voluntary exercise did not increase BDNF in the FPI group as it did in the control animals. Forced exercise did not increase levels of BDNF in any group. It did, however, decrease hippocampal glucocorticoid receptors in the control group. The results suggest that exercise regimens with strong stress responses may not be beneficial during the early post-injury period.

We have previously reported that experimental mild traumatic brain injury results in increased sensitivity to stressful events during the first post-injury weeks, as determined by analyzing the hypothalamic-pituitary-adrenal (HPA) axis regulation following restraint-induced stress. This is the same time period when rehabilitative exercise has proven to be ineffective after a mild fluid-percussion injury (FPI). Here we evaluated effects of stress on neuroplasticity. Adult male rats underwent either an FPI or sham injury. Additional rats were only exposed to anesthesia. Rats were exposed to 30 min of restraint stress, followed by tail vein blood collection at post-injury days (PID) 1, 7, and 14. The response to dexamethasone (DEX) was also evaluated. Hippocampal tissue was collected 120 min after stress onset. Brain-derived neurotrophic factor (BDNF) along with glucocorticoid (GR) and mineralocorticoid (MR) receptors was determined by Western blot analysis. Results indicated injury-dependent changes in glucocorticoid and mineralocorticoid receptors that were influenced by the presence of dexamethasone. Control and FPI rats responded differentially to DEX in that GR increases after receiving the lower dose of DEX were longer lasting in the FPI group. A suppression of MR was found at PID 1 in vehicle-treated FPI and Sham groups. Decreases in the precursor form of BDNF were observed in different FPI groups at PIDs 7 and 14. These findings suggest that the increased sensitivity to stressful events during the first post-injury weeks, after a mild FPI, has an impact on hippocampal neuroplasticity.

The involvement of the cervical sympathetic ganglia (SCG) on body temperature and during the occurrence of the induced febrile response was investigated in rats. Bilateral superior cervical gaglionectomy (SCGx) attenuated the daily dark-phase temperature compared to that of the sham-operated rats during the first 2 days post surgery. Body temperatures returned to pre-surgery levels by Day-3. Ten days after surgery, a febrile response was induced by lipopolysaccharide (LPS) immune challenge. SCGx significantly blunted the LPS-induced febrile response. These data suggest that obliteration of the cervical sympathetic peripheral innervation impairs the capability to produce an induced febrile response.

Having reported that traumatic brain injury (TBI), produced by moderate lateral controlled cortical impact (CCI), causes long-term dysregulation of the neuroendocrine stress response, the aim of this study was to assess short- and long-term effects of both moderate and mild CCI on stress-induced hypothalamic-pituitary-adrenal (HPA) function. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths to produce either a moderate or mild CCI. Controls underwent sham surgery without injury. Commencing at one week after recovery from surgery, rats were exposed to stressors: 30-min restraint (days 7, 34, and 70) or 15-min forced swim (days 21 and 54). Tail vein blood was analyzed for corticosterone (CORT) content by radioimmunoassay. On days 7 and 21, the stress-induced HPA responses were significantly attenuated by both mild and moderate CCI. Significant attenuation of the CORT response to stress persisted through day 70 after moderate CCI. In contrast, stress-induced CORT levels on days 34, 54, and 70 were significantly enhanced after mild CCI. Differential effects of injury severity were also observed on motor function in a forelimb test on post-injury day 12 and on cortical lesion volume and hippocampal cell loss at day 70, but not on working memory in a radial maze on day 15. The differing short- and long-term stress-induced HPA responses may be mediated by differential effects of moderate and mild CCI on the efficiency of glucocorticoid negative feedback or signaling among hypothalamic and extrahypothalamic components of the neuroendocrine stress-response system.

Background: Hypothalamic synthesis and secretion of corticotropin-releasing hormone (CRH), a putative mediator of various behavioral and physiological responses to ethanol (EtOH), is defective in inbred Lewis (LEW) rats in comparison with their genetically related inbred Fischer 344 (F344) and outbred Sprague–Dawley (S–D) strains. We aimed to characterize the effects of continuous EtOH consumption and withdrawal on circadian patterns of body temperature and spontaneous locomotor activity in males and females of these 3 strains. Methods: Adult LEW, F344, and S–D males and randomly cycling females were fed an EtOH-containing liquid diet or the control (pair-fed or lab chow and water) diet for 14 days. Biotelemetric body temperature data for the last 3 days of EtOH diet feeding and the first 3 days of withdrawal were subjected to cosinor analysis of the circadian rhythm parameters of midline-estimating statistic of rhythm (MESOR), amplitude, and acrophase. Mean dark-phase activity during these periods was also computed. Results: In the control diet condition, the MESORs and amplitudes of LEW males were lower than those of F344 males. MESORs of rhythms of LEW females were lower than those of both F344 and S–D females. Ethanol consumption caused hypothermia with reduced MESORs and amplitudes of LEW and F344 males and amplitudes of F344 and S–D females. Upon withdrawal, MESORs of the males increased during each day as the amplitudes decreased, reflective of their initial withdrawal-induced dark-phase hypothermia, which was most pronounced in the LEW males, followed by light-phase hyperthermia. MESORs of females were not affected by withdrawal; their amplitudes were differentially affected. Acrophase of LEW males shifted from dark to light on the first day of withdrawal. All rats responded to EtOH exposure with a reduction of dark-phase spontaneous locomotor activity and an immediate increase upon withdrawal. Conclusions: Body temperature rhythms of the males were generally more affected by EtOH consumption and withdrawal than the females; within each sex, LEW and F344 rats differed significantly. The specific hormonal factors that mediate the differential temperature responses remain to be defined.

We have recently shown that there is a heightened stress response after a mild traumatic brain injury (TBI) during the first 2 post-injury weeks. This corresponds to the same post-injury period when exercise does not increase brain-derived neurotrophic factor (BDNF) and autonomic dysfunction becomes evident with exercise. Here we determined stress and autonomic responses to voluntary and forced exercise at a post-injury time window when exercise has been found to elicit beneficial effects. Rats underwent a mild fluid percussion injury and were exercised at post-injury days 28-32 and 35-39. Cardiac and temperature autonomic function were evaluated. Hippocampal tissue was obtained immediately after exercise for analysis of BDNF. In contrast to the sub-acute period, corticosterone and adrenocorticotropic hormone responses to exercise were normalized in the TBI group. Irrespective of injury, forced exercise markedly stimulated the corticotrophic axis and did not increase BDNF. BDNF levels were increased with voluntary exercise in all animals. Rats exposed to forced exercise had lower activity levels during periods of non-exercise. This effect was more pronounced in the TBI rats. Cardiac and temperature autonomic responses to delayed exercise also recuperated. Rats with TBI that underwent forced exercise, however, had higher core body temperatures during experimental manipulations, thus suggesting that exposure to a potent stressor facilitates responsiveness to environmental stimulations.

Glossopharyngeal afferents may be the neural channel by which immune challenge of the posterior oral cavity conveys information to the brain. If this is the case, then bilateral transection of the glossopharyngeal nerves (GLOx) should disrupt this communication. Injection of lipopolysaccharide (LPS) or interleukin (IL)-1beta into the soft palate (ISP) of sham-operated rats induced a dose-related febrile response. GLOx significantly attenuated the febrile response induced by ISP injection of both LPS and IL-1beta. In contrast, GLOx did not affect the febrile response when LPS or IL-1beta were injected intraperitoneally, indicating that the effect of GLOx is not systemic. These results provide experimental evidence for a novel neural pathway for immune-to-brain communication.

We previously reported altered responses of thymocytes to mitogen stimulation after fetal alcohol exposure (FAE) in prepubertal male Sprague-Dawley rats. The purpose of this study was to examine the effect of FAE on the developmental pattem of thymocyte subsets. In the first experiment, we found that the proportion of double-labeled CD4 + CD8 + thymocytes is identical in fetal alcohol-exposed (E) and control (C) animals at 34 and 45 days of age. In the second experiment-at 20, 28, 35, and 48 days of age-we examined the proportion of CD4 + and CD8 + thymocytes that express or are devoid of the maturational markers, the α/β configuration of the T-cell receptor (TcR), and the restriction fragment C of the common leukocyte antigen (CD45RC). We found significant age-dependent effects on the numbers of total double-positive CD4-TcR and CD8-TcR or CD45RC thymocytes, and significantly lower numbers of total CD4 + and CD8 + cells in E than in C rats throughout this period-a finding consistent with the significantly lower total number of thymocytes in E than in C rats. The developmental patterns for both markers were similar in E and C groups, in both the rising (days 20 to 28) and declining (days 35 to 48) phases. However, on day 35, E rats had significantly lower numbers of double-positive CD8-TcR and CD8-CD45RC cells than C rats. It therefore seems that FAE tends to accelerate the decline of double-positive CD8-TcR and CD8-CD45RC cells. The contribution of this phenotypic change to the thymic functional alterations induced by FAE remains to be determined.

We previously reported altered responses of thymocytes and splenocytes to mitogen stimulation in fetal alcohol-exposed (FAE) male Sprague-Dawley rats. We also reported enhanced neuroendocrine responses to stressful stimuli in these animals. The experiments we describe herein aimed at testing whether young adult FAE rats manifest a notable dysregulation in the neuroendocrine-immune response to pathogen administration. We tested the effect of in vivo priming of the animal with a low dose of endotoxin [lipopolysaccharide (LPS), 5 micrograms/kg], considered to be suboptimal from the perspective of mounting detectable levels of circulating monokines several hours after administration, upon the production of immunoreactive tumor necrosis factor (TNF-alpha) in response to a further in vitro challenge of peripheral blood mononuclear cells with 2.5 micrograms/ml of LPS 90 min after priming. We show that the response to the LPS pathogen in vitro after priming is significantly blunted (p < 0.01) in male rats exposed prenatally to alcohol, compared with control male animals. FAE female rats and FAE ovariectomized female rats do not show significant differences in the priming response, compared with control animals. We also show that there is no correspondence between plasma corticosterone levels and TNF-alpha production after priming in any of the groups tested.

Exposure to alcohol in utero can lead to long-lasting impairments of immune functions and to decreased resistance to infectious agents. We have previously reported that fetal alcohol-exposed rats show markedly decreased lipopolysaccharide-induced fever and suggested that fetal alcohol exposure (FAE) impairs the communication between the immune and the nervous systems. The present study examined the effects of interleukin-1 beta (IL-1) on body temperature, motor activity, ingestive behavior, and pituitary-adrenal activation in fetal alcohol-exposed and control rats. Transmitters for continuous biotelemetric recording of body temperature and motor activity were implanted i.p. in normal (N) adult rats, offspring of dams fed a liquid diet supplemented with ethanol (E), and pair-fed control offspring (P). In one experiment, rats were injected with either IL-1 (2 micrograms/kg, i.p.) or saline at the beginning of the light period. IL-1 produced a marked increase in body temperature, which was significantly lower in E rats than in N and P rats. In a second experiment, rats were administered either IL-1 (10 micrograms/kg, i.p.) or saline at the beginning of the dark period. IL-1 produced an initial transient hypothermia followed by a longer-lasting hyperthermia. During the hyperthermic phase, fever in the E rats was lower than in the P rats, but comparable to fever in the N rats. IL-1 significantly reduced motor activity, during both the hypothermic and hyperthermic phases. This effect was similar in all prenatal treatment groups. IL-1 also suppressed 24-h food consumption in N and P rats and water consumption in P rats, but it did not produce significant anorexia and adypsia in E rats. A third experiment demonstrated that IL-1 (2 micrograms/ kg, ip) significantly increased ACTH and corticosterone release in all prenatal treatment groups. IL-1-induced corticosterone secretion was attenuated in P offspring, compared to both E and N rats. Together, these findings indicate that exposure to ethanol in utero produces impairments in mechanisms that mediate the effects of IL-1 on body temperature (particularly during the light period) and ingestive behavior, but not on motor activity and pituitary-adrenal activation. In view of the adaptive role of IL-1-induced fever and anorexia, these impairments may contribute to the decreased resistance to infections observed in animals and humans following FAE.

The effects of a mild traumatic brain injury range from white matter disruption to affective disorders. We set out to determine the response to restraint-induced stress after a mild fluid-percussion injury (FPI), an experimental model for brain injury. Hypothalamic-pituitary-adrenal (HPA) axis regulation of corticosterone (CORT) and adrenocorticotropic hormone (ACTH) was determined during the first post-injury weeks, which corresponds to the same time period when rehabilitative exercise has been shown to be ineffective after a mild FPI. Adult male rats underwent either an FPI or sham injury. Additional rats were only exposed to anesthesia. HPA regulation was evaluated by measuring the effects of dexamethasone (DEX) treatment on CORT and ACTH. Tail vein blood was collected following 30-min restraint stress, at post-injury days (PID) 1, 7 and 14, prior to (0 min) and at 30, 60, 90 and 120 min after stress onset. Results from these studies indicate that the stress response was significantly more pronounced after FPI in that CORT and ACTH restraint-induced increases were more pronounced and longer lasting compared to controls. DEX suppression of CORT and ACTH was observed in all groups, suggesting that stress hyper-responsiveness after mild FPI is not attributable to reduced sensitivity of CORT feedback regulation. The increased sensitivity to stressful events in the first two post-injury weeks after a mild FPI may have a negative impact on early rehabilitative therapies.

We have reported differential short- and long-term dysregulation of the neuroendocrine stress response after traumatic brain injury (TBI) produced by controlled cortical impact (CCI). We have now investigated three possible mechanisms for this TBI-induced dysregulation: (1) effects on the sensitivity of negative-feedback systems to glucocorticoids; (2) effects on the sensitivity of pituitary corticotrophs to corticotropin-releasing hormone (CRH); and (3) effects on neuronal loss in the hilar region of the dentate gyrus and in the CA3b layer of the dorsal hippocampus. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths, to produce either moderate or mild CCI. At 7 and 35 days after surgery, the rats were injected SC with the synthetic glucocorticoid analog dexamethasone (DEX; 0.01, 0.10, or 1.00 mg/kg) or saline, and 2 h later were subjected to 30 min of restraint stress and tail vein blood collection. Whereas all doses of DEX suppressed corticosterone (CORT) and adrenocorticotropic hormone (ACTH) responses to stress on both days, CORT and ACTH were significantly more suppressed after 0.01 mg/kg DEX in the moderate TBI group than in the mild TBI or sham groups. At both 7 and 35 days post-TBI, CRH (1.0 and 10.0 microg/kg IP) stimulated CORT and ACTH in all rats, regardless of injury condition. Hippocampal cell loss was greatest at 48 days after moderate TBI. Enhanced sensitivity to glucocorticoid negative feedback and greater hippocampal cell loss, but not altered pituitary responses to CRH, contribute to the short- and long-term attenuation of the neuroendocrine stress response following moderate TBI. The role of TBI-induced alterations in glucocorticoid receptors in limbic system sites in enhanced glucocorticoid feedback sensitivity requires further investigation.

Background: Human and animal findings indicate that males and females display major differences in risk for and consequences of alcohol abuse and alcoholism. These differences are in large part mediated by sex-specific hormonal environments. Gonadal and adrenal secretory products are known to modulate the neurobehavioral responses of ethanol (EtOH) dependence and withdrawal. However, the effects of these steroids on physiological adaptations, such as thermoregulation, are less well established. To study the role of sex-related hormones in mediating sex differences in the hypothermic response to acute challenge with EtOH, we compared the EtOH-induced hypothermic responses of EtOH-naive male and female rats and EtOH-dependent (on the third day of withdrawal) male and female rats before (intact) and after depletion of all gonadal and adrenal steroids by gonadectomy (GDX) with or without adrenalectomy (ADX). Methods: Intact and GDX male and female rats, with or without ADX, were fed an EtOH-containing liquid diet for 15 days while control (EtOH-naive) rats were pairfed the isocaloric liquid diet without EtOH or fed normal rat chow and water. On the third day of withdrawal from the EtOH diet we tested the hypothermic response to EtOH challenge (1.5 g/kg BWt, ip). Blood alcohol content (BAC) and corticosterone (CORT) content were analyzed in a separate series of intact and GDX males and females with and without ADX in response to the EtOH challenge. Results: Ethanol-induced hypothermia was significantly greater and its duration significantly longer in intact males than females when subjects were EtOH-naive. EtOH-induced hypothermia was significantly greater in intact females than males by the third day of withdrawal from EtOH dependence. GDX in males significantly shortened the duration of the hypothermic response and tended to blunt EtOH-induced hypothermia while response duration was significantly extended by GDX in females that tended to enhance EtOH-hypothermia. EtOH-induced hypothermia was significantly enhanced and its duration significantly lengthened by combined GDX and ADX in EtOH-naive and -withdrawn males and by combined GDX and ADX in EtOH-naive but not EtOH-withdrawn females. These differential EtOH-induced hypothermic responses did not appear to be caused by differences in EtOH handling among the groups. The absence of adrenal activation by EtOH in the GDX–ADX males and females contributes to their enhanced EtOH-induced hypothermic responses. Conclusions: These results implicate the direct and indirect effects of removal of gonadal and adrenal secretory products as mediators of the thermoregulatory actions of EtOH.

Traumatic brain injury (TBI) is a principal cause of long-term physical, cognitive, behavioral, and social deficits in young adults, which frequently coexist with a high incidence of substance abuse disorders. However, few studies have examined the long-term effects of TBI on the neuroendocrine-immune system. TBI was induced in adult male rats under isoflurane anesthesia by cortical contusion injury with a pneumatic piston positioned stereotaxically over the left parietal cortex. Controls underwent sham surgery without injury. At 4 weeks post-injury, the plasma corticosterone response to 30-min restraint stress was significantly blunted in TBI rats compared to the sham controls. One week later, transmitters were implanted for continuous biotelemetric recording of body temperature and spontaneous locomotor activity. At 6 weeks post-injury, the febrile response to i.p. injection of the bacterial endotoxin, lipopolysaccharide (LPS; 50 microg/kg), was significantly lower in TBI than in sham rats. At 8 weeks, swimming in the forced swim test was significantly less in TBI than sham rats. At 9 weeks, rats were rendered ethanol (EtOH) dependent by feeding an EtOH-containing liquid diet for 14 days. Cosine rhythmometry analysis of circadian body temperature Midline Estimating Statistic of Rhythm (MESOR), amplitudes, and acrophases indicated differential effects of EtOH and withdrawal in the two groups. Light- and dark-phase activity analysis indicated that TBI rats were significantly more active than the sham group, and that EtOH and withdrawal differentially affected their activity. Given the extensive interactions of the neuroendocrine-immune systems, these results demonstrate that TBI produces lasting dysregulation amidst the central substrates for allostasis and circadian rhythmicity.

The acute-phase febrile responses of the inbred Lewis (LEW) and Fischer 344 (F344) rat strains and their parent Sprague-Dawley (S-D) strain to immune challenge with lipopolysaccharide (LPS) were compared. LEW and S-D males and females displayed a biphasic febrile response with a markedly attenuated second phase in F344 rats. At 2 h after LPS (50 microg/kg), corticosterone was significantly higher in F344 than in LEW rats, but serum interleukin-1beta was higher only in F344 than LEW males. These data suggest that the greater LPS-induced corticosterone response of F344 rats mediates differences between febrile responses of F344 and LEW males and females.

Clinical and animal studies indicate that hyperthermia during or after traumatic brain injury (TBI) is associated with poor outcome. Alcohol intoxication, a complicating risk factor in many cases of head injury, has been found to both worsen or attenuate posttraumatic neural damage and outcome. The purpose of the present study was to determine whether chronic ethanol consumption would affect TBI-induced hyperthermia and deficits in spatial learning. TBI was produced by cortical contusion injury in adult male rats. We first characterized the TBI-induced febrile response using probes implanted intraperitoneally (ip) or intracerebroventricularly for continuous biotelemetric recording of core body and brain temperatures and locomotor activity. In another experiment, rats, implanted with ip probes, were fed a liquid diet containing ethanol (5% w/v, 35% ethanol-derived calories); control rats were pair-fed the isocaloric liquid diet (P-P). At 14 days after commencement of diet feeding, TBI or sham surgery was performed, and the ethanol-fed rats were divided into two groups: half were transferred to the isocaloric diet (E-P) and the other half remained on the ethanol-containing diet (E-E). TBI produced a significant febrile response in all rats, that persisted for at least 6 days in the E-P and P-P groups but lasted for only 2 days in the E-E group. When tested at 3-4 weeks after TBI, E-E rats required significantly fewer trials than E-P rats to reach criterion in the Morris water maze. In sum, continuous consumption of ethanol before and after TBI attenuated TBI-induced hyperthermia and deficits in spatial learning. Whereas the results suggest that this ethanol regimen may be neuroprotective, a causal relationship between the two outcomes remains to be determined.

Fetal alcohol exposure (FAE) has been shown to blunt the febrile component of the primary host-defense response to infection induced experimentally by systemic administration of interleukin (IL)-1beta. Given that maternal adrenalectomy (ADX) can prevent various postnatal effects of FAE, the present experiments were designed to determine whether maternal ADX would prevent the blunted IL-1beta-induced febrile response of fetal alcohol-exposed offspring and whether the effects of maternal ADX would be gender related. Timed-pregnant rats underwent ADX or were sham-operated on gestation day (GD) 7, or remained intact (without any surgery), and were fed ethanol-containing (E) or pair-fed (PF) liquid diets or normal (N) rat chow and water from GD 8 to GD 21. As adults, male and female E, PF and N offspring were injected with saline on day 1 and with IL-1beta (2 microg/kg, i.p.) on day 2 at 09.00 h and the body temperature was recorded biotelemetrically for 8.5 h. IL-1beta produced significantly lower febrile responses in female than in male offspring of intact dams, irrespective of prenatal diet. Furthermore, prenatal surgical stress differentially affected the IL-1beta-induced febrile response of male and female normally fed offspring. Additionally, in both male and female offspring of intact dams, FAE significantly attenuated the IL-1beta-induced febrile response. In males, FAE also attenuated the febrile response in the offspring of maternal sham-operated dams, and this effect was completely reversed by maternal ADX. In females, both maternal sham surgery and ADX reversed the effect of FAE on the febrile response. These findings suggest that maternal adrenal mediators are essential for the long-term effect of FAE on the febrile response in male offspring. In females, early prenatal surgical stress is sufficient to reverse the effects of FAE, possibly via adrenal-independent mechanisms that affect the thermoregulatory system.

Chronic and acute alcohol use exert profound modulatory effects on the immune system which manifest as impaired host defense against infections. An important feature of this response is the interaction between the immune and the central nervous systems. This study investigated the effects of 14 days of alcohol exposure on cytokine-mediated neuroimmune interactions that affect the febrile component of the host-defense response.Adult male rats were fed a liquid diet containing ethanol (EtOH, 5% w/v) for 14 days. Pair-fed and normal chow- and water-fed rats served as controls. Continuous biotelemetric recordings of body temperature and locomotor activity commencing after 14 days of EtOH feeding were used to determine the effects of chronic EtOH on the circadian pattern of temperature and activity, on the febrile response to intraperitoneal (ip) administration of lipopolysaccharide (LPS) and interleukin (IL)-1beta, and on fever induced by IL-1beta administered intracerebroventricularly. We also examined the effects of EtOH consumption on LPS-induced hypothalamic production of the pyrogenic cytokines IL-1beta and tumor necrosis factor-alpha (TNFalpha) and on the blood levels of IL-1beta, TNFalpha, IL-6, adrenocorticotropin, and corticosterone at 2, 4, and 6 hr after ip LPS.Fourteen days of EtOH consumption blunted the circadian increases in temperature and activity that normally occur in the dark phase of the light/dark cycle without affecting light-phase temperature or activity. EtOH consumption attenuated fever induced by LPS or IL-1beta administered ip during the light phase and significantly reduced hypothalamic production of IL-1beta. LPS-induced increases in hypothalamic TNFalpha and blood cytokines, adrenocorticotropin, and corticosterone were unaffected. Central administration of IL-1beta produced a normal febrile response in chronic-EtOH rats.The attenuated LPS- and IL-1beta-induced febrile responses in EtOH-consuming rats and the corresponding deficit in hypothalamic production of IL-1beta suggest that alcohol may impair IL-1beta-mediated neuroimmune communication.

Fetal alcohol exposure (FAE) produces profound alterations in immunological and neuroendocrine functions. The present study examined the effects of FAE on the secretion of tumor necrosis factor (TNF-alpha) and corticosterone following administration of lipopolysaccharide (LPS) in normal (N) adult rats, in adult offspring of dams fed a liquid diet supplemented with ethanol (E), and in pair-fed control offspring (P). LPS-induced TNF-alpha secretion was not affected by either gender or prenatal treatment. In contrast, LPS-induced corticosterone secretion was significantly greater in female than in male rats, and at 60-min post-LPS was significantly higher in E and P, compared to N females. Ovariectomy significantly inhibited LPS-induced TNF-alpha secretion in E, but not in P and N, rats and chronic replacement with 17-beta-estradiol markedly inhibited TNF-alpha secretion in ovariectomized E and N, but not in P, rats. In contrast, ovariectomy reduced the effects of LPS on corticosterone secretion in all groups, and chronic replacement with 17-beta-estradiol reversed this effect. These findings indicate that LPS-induced secretion of corticosterone, but not TNF-alpha, is affected by prenatal manipulations and by gender. In addition, alterations in the hormonal environment in females modulate LPS-induced corticosterone secretion in all prenatal treatment groups, but differentially influence TNF-alpha secretion in rats exposed to alcohol, restricted feeding, or normal diets in utero.

The effects of acute food restriction (i.e. 24-72 h) on (1) the colonization of MADB106 tumor cells; (2) the response of specific T cell subsets in peripheral blood (i.e. CD4+ and CD8+ cells), and (3) natural killer cell activity (NKCA) in the spleen were studied in the Fischer 344 rat. Previous studies have demonstrated that the spread of this tumor cell is enhanced by exposure to an acute stressor within 24 h of tumor inoculation. Consistent with these reports, 72-hour food restricton after tumor inoculation enhanced colonization of tumor cells to the lungs when assessed 4 weeks after inoculation. Food restriction was found to markedly influence the percentage of T cell subsets (i.e. CD4+ and CD8+ cells) and NKCA in the early (24-72 h) postinoculation stage. At 72 h after inoculation, food restriction was associated with a significant reduction in the percentage of CD4+ cells in tumor- or saline-inoculated animals. The percentage of CD8+ cells was significantly increased at 24 and 72 h after tumor inoculation in ad libitum, but not in food-deprived animals. NKCA at 72 h was significantly reduced in saline-treated food-deprived animals compared to animals fed ad libitum. Given that glucocorticoids are typically increased during acute food deprivation and that glucocorticoids are in some instances associated with depressed NKCA, the present study investigated whether there was a relationship between plasma glucocorticoid levels (i.e. corticosterone) and NKCA; however, no significant relationship was found. In conclusion, the present findings demonstrate that 72-hour food deprivation is associated with enhancement of tumor metastasis. This outcome is mediated, at least in part, by the modulatory effect of the physiological response to acute food restriction upon the distribution of circulating T cells and NKCA in the spleen during the early (24-72 h) postinoculation phase.

Restriction of food availability is a reliable stimulus that leads to significant hypothalamo-pituitary-adrenal (HPA) activation to which rats do not habituate. Based on our previous data that indicated that the HPA response to some, but not all, stressful stimuli is significantly greater in adult offspring of Sprague-Dawley dams exposed to 35% alcohol during the last 2 weeks of gestation than that of control rats and on the mounting neuroendocrine-immune literature that describes the role of pituitary-adrenal products in modulating cellular immunity, we hypothesized that the outcomes of food restriction would be significantly more marked in fetal alcohol-exposed (FAE) offspring, compared with control rats. Data we report herein show that-whereas food restriction at 30-35 days of age produced significant changes in body weight, thymus weight-to-body weight ratio, adrenal weight-to-body weight ratio, plasma corticosterone levels, and in thymocyte number, as well as in the percentage and absolute number of CD4 + and CD8 + thymocytes that express CD4SRC-FAE and control rats were equally affected. We conclude that food restriction is another example of a stressful stimulus that fails to distinguish satisfactorily between FAE and control rats of prepubertal age.

Growth retardation, both in the prenatal and the early neonatal period, is a consistent feature of fetal alcohol exposure, but the mechanism by which alcohol affects growth has not been elucidated. Because other stressors--such as maternal restraint and neonatal glucocorticoid treatment--can also affect growth, we examined the effect of ethanol on pup birthweight under two experimental conditions that altered maternal adrenal function. In the first study when dams were adrenalectomized and given low replacement doses of dexamethasone, the ethanol-exposed offspring of the adrenalectomized dams had birthweights similar to those of dams maintained on regular lab chow diets. In a second study, we found that maternal adrenal demedullation did not alter the reduction in birthweight produced by fetal ethanol exposure. The results suggest that the effects of ethanol on fetal growth may be mediated in part through ethanol-induced changes in the function of the maternal adrenal cortex.