Anna N. Taylor

Stress increases metastatic spread of a mammary tumor in rats: Evidence for mediation by the immune system

Causal relationships among stress, immune suppression, and enhanced tumor development have often been suggested, but direct evidence is scant. We studied stress effects in Fischer 344 rats using a tumor model in which lung metastases of a syngeneic mammary tumor (MADB106) are controlled by natural killer (NK) cells. Animals exposed to acute stress showed a substantial decrease in NK cell cytotoxicity against this tumor in an in vitro assay and, when intravenously injected with this tumor, showed a twofold increase in surface lung metastases. The critical period during which stress increases metastases appears to be the same as that during which this tumor is known to be controlled by NK cells. These findings support the hypothesis that stress can facilitate the metastatic process via suppression of the immune system.

Long-term effects of fetal ethanol exposure on pituitary-adrenal response to stress ☆

Pregnant female rats were fed either a 5.0-5.5% w/v ethanol-containing liquid diet ad lib or pair-fed the isocaloric control diet during gestation weeks 2 and 3. At 75-105 days of age, female offspring of the ethanol-treated dams showed significantly greater corticosterone responses than pair-fed- or normally-derived offspring to the stress of cardiac puncture or of noise and shaking, while pituitary-adrenal responses to exposure to a novel environment, cold or 2-3 days of fasting were normal. Adrenal sensitivity to ACTH in dexamethasone-suppressed adult offspring was unaffected by the prenatal treatment. The results demonstrate that fetal ethanol exposure enhances adult pituitary-adrenal responses to certain stressors, including alcohol as demonstrated previously, and suggest that the long-term effects may be mediated by developmental actions of alcohol on central neural mechanisms involved in the regulation of this neuroendocrine system.

Elevated plasma corticosterone level and depressive behavior in experimental temporal lobe epilepsy

Depression is frequently reported in epilepsy patients; however, mechanisms of co-morbidity between epilepsy and depression are poorly understood. An important mechanism of depression is disinhibition within the hypothalamo-pituitary-adrenocortical (HPA) axis. We examined the functional state of the HPA axis in a rat model of co-morbidity between temporal lobe epilepsy and depression. Epilepsy was accompanied by the interictal elevation of plasma corticosterone, and by the positively combined dexamethasone/corticotropin releasing hormone test. The extent of the HPA hyperactivity was independent of recurrent seizures, but positively correlated with the severity of depressive behavior. We suggest that the observed hyperactivity of the HPA axis may underlie co-morbidity between epilepsy and depression.

The glossopharyngeal nerve as a novel pathway in immune-to-brain communication: relevance to neuroimmune surveillance of the oral cavity.

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.

Prenatal ethanol and ontogeny of pituitary-adrenal responses to ethanol and morphine

The development of pituitary-adrenal activity was examined in the offspring of rat dams fed a 5.0% w/v ethanol-containing liquid diet or pair-fed an isocaloric diet, as a nutritional control, from day 8 of gestation to parturition. Serum corticosterone responses of the pups to challenges with ethanol (1.5 g/kg) or morphine (3.0 mg/kg) were determined at 5, 7, 10, 12 and 18 days of age. The pituitary-adrenal axis of normal neonates was activated by the drugs at each age, with a characteristic biphasic developmental pattern in which a trough occurred at day 7. The overall pattern was unaffected by prenatal ethanol exposure or pair-feeding. However, both prenatal treatments intensified the trough. Already on day 5 and also on day 7, corticosterone responses of both the ethanol-exposed and pair-fed offspring to ethanol were significantly lower than responses of normal pups. Additionally, on day 7, ethanol-exposed offspring had significantly lower responses to ethanol than pair-fed offspring and significantly lower responses to morphine than normal pups. Thus, both the prenatal ethanol and pair-feeding treatments suppressed pituitary-adrenal responsiveness of 5 and 7 day-old neonates to the drug challenges. This is in marked contrast to our previous findings for adult prenatally ethanol-exposed offspring whose pituitary-adrenal responses to the same drugs, as well as to other stressors, are consistently enhanced in comparison to pair-fed derived rats, whose responses in adulthood no longer differ from normals.

Serum levels of sex hormones and corticosterone throughout 4- and 5-day estrous cycles in Fischer 344 rats and their simulation in ovariectomized females

Among inbred strains of rats, The Fischer 344 (F344) is commonly used in im-munological and behavioral studies. However, Little is known about patterns of sex hormones and corticosterone (CORT) secretion throughout the estrous cycle in this strain, Which is characterized by a marked CORT response to stress and variable length of cycles. In the current study, using radioimmunoassays, we assessed serum levels of progesterone, estradiol, LH, testosterone, prolactin and CORT, at 1-h intervals throughout the estrous cycle in F344 female rats with 4- and 5-day cycles, as well as in males. Vaginal smears were obtained from 268 females for 15 consecutive days to determine individual length of the estrous cycle and the exact estrous phase upon blood withdrawal, which was conducted once in each rat on the 12th day of smearing. The results indicated that both 4- and 5-day cyclers have two distinct and marked surges of progesterone, one on proestrus day and the other on diestrous-1 day. Testosterone levels in 5-day cyclers peaked on diestrus-3, one day earlier than in 4-day cyclers. Daily peak levels of CORT gradually increased from estrus day to proestrous day, whereas daily nadir levels of CORT remained unchanged. To simulate the natural kinetics of specific sex hormones in ovaries-tomized females, different doses of estradiol, progesterone, testosterone, prolactin or CORT were injected sc or ip, or 90-day sustained release pellets containing different doses of estradiol or progesterone were implanted. The findings indicated dose- and time-dependent effects, suggesting regimens for modeling the estrous cycle or replacement therapy.

Maternal Alcohol Consumption and Stress Responsiveness in Offspring

It is now generally acknowledged that pre- and/or postnatal environmental factors, such as stress and drugs, can exert long-lasting neurobehavioral effects in the individual. These factors may influence the development of central regulatory systems by acting directly on the fetal brain or indirectly through changes in the internal environment of the mother and fetus. The Fetal Alcohol Syndrome which has been recognized as a clinical entity for the past 15 years (1) is a case in point. Adverse effects of maternal alcohol consumption during pregnancy on growth and development of the offspring have been well documented in humans and laboratory animals (2). Mental retardation and behavioral deficits, such as hyperactivity, jitteriness, irritability and marked attentional and learning problems, are consistently observed in children who were exposed to alcohol in utero (3).

Comorbidity between epilepsy and depression: Role of hippocampal interleukin-1β

Depression is a frequent comorbidity of temporal lobe epilepsy (TLE); however, its mechanisms remain poorly understood and effective therapies are lacking. Augmentation of hippocampal interleukin-1beta (IL-1beta) signaling may be a mechanistic factor of both TLE and clinical depression. We examined whether pharmacological blockade of hippocampal interleukin-1 receptor exerts antidepressant effects in an animal model of comorbidity between TLE and depression, which developed in Wistar rats following pilocarpine status epilepticus (SE). In post-SE animals, depression-like state was characterized by behavioral equivalents of anhedonia and despair; dysregulation of the hypothalamo-pituitary-adrenocortical axis; compromised raphe-hippocampal serotonergic transmission. Two-week long bilateral intrahippocampal infusion of human recombinant Interleukin-1 receptor antagonist (IL-1ra) improved all of the examined depressive impairments, without modifying spontaneous seizure frequency and without affecting normal parameters in naïve rats. These findings implicate hippocampal IL-1beta in epilepsy-associated depression and provide a rationale for the introduction of IL-1beta blockers in the treatment of depression in TLE.

Involvement of brain cytokines in the neurobehavioral disturbances induced by HIV-1 glycoprotein120.

Intracerebroventricular (i.c.v.) administration of HIV-1 glycoprotein 120 (gp120), the envelope protein used by the virus to gain access into immune cells, induces neurobehavioral alterations in rats. To examine the role of proinflammatory cytokines in mediating these effects, we measured the effects of gp120 on brain proinflammatory cytokine expression and the effects of anti-inflammatory agents, including interleukin-1 receptor antagonist (IL-1ra), pentoxifylline (a TNFalpha synthesis blocker) and IL-10, on gp120-induced sickness behavior. I.c.v. administration of gp120 induced the expression of IL-1beta, but not TNFalpha, mRNA in the hypothalamus, 3 h after the injection. Pretreatment of rats with IL-1ra, but not with pentoxifylline, significantly attenuated gp120-induced anorexia and loss in body weight, whereas both agents had no effect on gp120-induced reduction in locomotor activity in the open field. Pretreatment with either IL-1ra and pentoxifylline simultaneously, or with IL-10, produced effects that were similar to the effects of IL-1ra alone. Together, these findings indicate that IL-1, but not TNFalpha, mediates some of the behavioral effects of acute gp120 administration, suggesting that brain IL-1 may be involved in some of the neurobehavioral abnormalities evident in AIDS patients.

Heightening of the stress response during the first weeks after a mild traumatic brain injury.

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.