Stress-induced Rise Research Articles

Alpha 2-adrenoreceptor subtypes regulate ACTH and beta-endorphin secretions during stress in the rat.

The effect of different alpha 2-adrenoreceptor subtype agonists and antagonists on adrenocorticotrop hormone (ACTH) and beta-endorphin release induced by ether stress was examined. Ether inhalation-induced ACTH and beta-endorphin increase was inhibited by i.c.v. administration of 30 micrograms but not 1 and 10 micrograms clonidine (alpha 2-adrenoreceptor agonist). I.c.v. oxymetazoline (alpha 2A-adrenoreceptor agonist; 1-10-30 micrograms) or the alpha 1-agonist methoxamine (100 micrograms/rat) failed to inhibit the stress-induced rise. Pretreatment with the alpha 1/alpha 2B.C-antagonist prazosin (0.5 mg/kg, i.p.) prevented the effect of clonidine on the ether stress, while the alpha 1/alpha 2A-antagonist WB-4101 (0.5 mg/kg, i.p.) was unable to counteract the inhibitory effect of clonidine. Prazosin alone had no effect on the ether-induced plasma ACTH and beta-endorphin elevation. These results suggest that noradrenaline in the central nervous system may inhibit the stress-induced hypothalamo-pituitary-axis and pituitary beta-endorphin activation via alpha 2B.C-adrenoceptor subtypes and prazosin may antagonize its effect on these receptors.

Naltrindole administration during the preweanling period and manipulation affect adrenocortical reactivity in young rats

The effect of a daily injection of the δ-selective opioid antagonist naltrindole (1 mg/kg), from birth to postnatal day 19, on basal and post-stress corticosterone levels in 25-day old rats of both sexes was investigated. The effects of manipulation were studied by including two control groups, one group received daily injections of saline and a second one was not manipulated. The stress protocol consisted of a 3 min swimming session in water at 20°C. Corticosterone determinations were performed by radioimmunoassay. Control non-manipulated animals showed a significant increase in corticosterone levels in response to stress. Manipulation decreased basal hormone levels in females and prevented the stress-induced rise in corticosterone in males. Functional blockade of the δ-receptor during the preweanling period by the naltrindole treatment inhibited the corticosterone response to stress in females. The results indicate the existence of sex differences in the effects of manipulation on hypothalamus–pituitary–adrenal axis activity and the involvement of the δ-opioid receptor in the modulation of the adrenocortical response to stress during the postnatal period.

Maternal Deprivation Effect on the Infant’s Neural Stress Markers Is Reversed by Tactile Stimulation and Feeding But Not by Suppressing Corticosterone

After 24 hr of maternal deprivation, significant elevations in ACTH and the naturally occurring glucocorticoid corticosterone (CORT) are observed during the stress-hyporesponsive period. The deprived pups also showed in the paraventricular nucleus (PVN) a marked increase of stress-induced c-fos mRNA and a reduction of corticotropin-releasing hormone (CRH) and glucocorticoid receptor (GR) mRNA; in hippocampal CA1, a reduction of the mineralocorticoid receptor (MR) and GR was observed. Here, we examined whether these changes are reversed by (1) preventing the elevations of CORT characteristic for the 11-d-old deprived pups by administering the synthetic glucocorticoid dexamethasone (DEX); or (2) reinstating some aspects of maternal behavior. The pups were either (1) left undisturbed, (2) stroked, or (3) stroked and episodically fed by cheek cannulation. At postnatal day 12, peripheral and neural stress markers were measured. Nondeprived animals served as controls. Experiment 1 demonstrates that although CORT was kept low by DEX, the central effects on CORT receptors, CRH, and c-fos mRNA were still present, except for MR in hippocampal CA1. Experiment 2 shows that stroking alone prevented the stress-induced rise in ACTH and c-fos mRNA and in the reduction in CRH and MR mRNA. In pups that were fed and stroked, CORT and GR mRNA resembled nondeprived controls. In conclusion, the changes in peripheral endocrine responses and in the brain cannot be attributed to the effect of elevated CORT concentrations, which are characteristic of the maternally deprived neonate. However, reinstating some components of the dams' nurturing behavior can reverse the effects evoked by maternal deprivation.

Prolonged stress-induced elevation in plasma corticosterone during pregnancy in the rat: implications for prenatal stress studies.

Experiments were conducted to test the hypothesis that exposure to uncontrollable stress during pregnancy results in a heightened elevation of plasma glucocorticoids. Rats were exposed to uncontrollable electric tail shocks every other day during the 3 weeks of pregnancy. Plasma corticosterone concentrations in stressed dams increased significantly from gestation days 4 to 20. Importantly, this increase in plasma corticosterone occurred 24- and 48-h after exposure to stress suggesting a prolonged elevation in stress-induced glucocorticoid secretion. In addition, the stress-induced rise in plasma corticosterone was accompanied by a significant decrease in maternal levels of corticosteroid binding globulin which suggests increased circulating levels of free corticosterone. Significant stress-induced elevations in plasma corticosterone also occurred in fetuses that were examined on gestation day 20. Furthermore, a significant positive correlation was found between maternal and fetal plasma corticosterone. Results demonstrate that repeated exposure to uncontrollable stress increases plasma concentrations of glucocorticoids throughout pregnancy. In the unbound state, corticosterone may be highly effective in producing alterations in brain development of offspring. These data have important implications for understanding the process underlying the effects of prenatal stress.

Does Carbohydrate-rich, Protein-poor Food Prevent a Deterioration of Mood and Cognitive Performance of Stress-prone Subjects when Subjected to a Stressful Task?

This study investigates whether in stress-prone subjects, carbohydrate-rich, protein-poor food (CR/PP) prevents a deterioration of mood and performance under uncontrollable laboratory stress conditions. The assumption was that in stress-prone subjects there is a higher risk of serotonin deficiency in the brain and that carbohydrates may prevent a functional shortage of central serotonin during acute stress, due to their potentiating effect on brain tryptophan. Twenty-four subjects with a high stress-proneness (HS) and 24 subjects with a low stress-proneness (LS) participated in an uncontrollable stress situation under both a CR/PP and a protein-rich, carbohydrate-poor (PR/CP) diet condition. The plasma ratio of tryptophan to the other large neutral amino acids (LNAA) (ratio Tryptophan/∑LNAA) was determined as a measure indicating the dietary effect on brain tryptophan and serotonin levels. Significant increases were found in the ratio tryptophan/∑LNAA during the CR/PP diet compared with the PR/CP diet. Experimental stress had significant effects on pulse rate, skin conductance, cortisol and mood in all subjects. During the CR/PP diet only the HS subjects did not show the stress-induced rise in depression, decline in vigour and cortisol elevation that they showed after the PR/CP diet. With respect to cognitive performance, significant dietary effects were found on reaction time. It is suggested that CR/PP food in HS subjects may increase personal control, probably under the influence of higher levels of brain tryptophan and serotonin.

Role of the Hypothalamic Pituitary Adrenal Axis and IL-6 in Stress-Induced Reactivation of Latent Herpes Simplex Virus Type 1

Hyperthermic stress induces reactivation of herpes simplex virus type 1 (HSV-1) in latently infected mice and also stimulates corticosterone release from the adrenals via activation of the hypothalamic pituitary adrenal axis. In the present study, we tested the hypothesis that stress-induced elevation of corticosterone potentiates HSV-1 reactivation in latently infected mice. Because of the putative role of IL-6 in facilitating HSV-1 reactivation in mice, the effect of hyperthermic stress and cyanoketone treatment on IL-6 expression in the trigeminal ganglion was also measured. Preadministration of cyanoketone, a glucocorticoid synthesis inhibitor, blocked the stress-induced elevation of corticosterone in a dose-dependent manner. Furthermore, inhibition of corticosterone synthesis was correlated with reduced levels of HSV-1 reactivation in latently infected mice. Hyperthermic stress elicited a transient rise in IL-6 mRNA levels in the trigeminal ganglion, but not other cytokine transcripts investigated. In addition, there was a significant reduction in MAC-3+, CD8+, and DX5+ (NK cell marker) cells in the trigeminal ganglion of latent HSV-1-infected mice 24 h after stress. Cyanoketone blocked the stress-induced rise in IL-6 mRNA and protein expression in the trigeminal ganglion latently infected with HSV-1. Collectively, the results indicate that the activation of the hypothalamic pituitary adrenal axis plays an important role in stimulating IL-6 expression and HSV-1 reactivation in the trigeminal ganglion following hyperthermic stress of mice.

Attenuated neuroendocrine responses to emotional and physical stressors in pregnant rats involve adenohypophysial changes.

1. The responsiveness of the rat hypothalamo-pituitary-adrenal (HPA) axis and hypothalamo-neurohypophysial system (HNS) to emotional (elevated plus-maze) and physical (forced swimming) stressors and to administration of synthetic corticotrophin-releasing hormone (CRH) was investigated during pregnancy and lactation. In addition to pregnancy-related adaptations at the adenohypophysial level, behavioural responses accompanying the neuroendocrine changes were studied. 2. Whereas basal (a.m.) plasma corticosterone, but not corticotrophin (adrenocorticotrophic hormone; ACTH), levels were increased on the last day (i.e. on day 22) of pregnancy, the stress-induced rise in both plasma hormone concentrations was increasingly attenuated with the progression of pregnancy beginning on day 15 and reaching a minimum on day 21 compared with virgin control rats. A similar attenuation of responses to both emotional and physical stressors was found in lactating rats. 3. Although the basal plasma oxytocin concentration was elevated in late pregnancy, the stress-induced rise in oxytocin secretion was slightly lower in day 21 pregnant rats. In contrast to vasopressin, oxytocin secretion was increased by forced swimming in virgin and early pregnant rats indicating a differential stress response of these neurohypophysial hormones. 4. The blunted HPA response to stressful stimuli is partly due to alterations at the level of corticotrophs in the adenohypophysis, as ACTH secretion in response to CRH in vivo (40 ng kg-1, i.v.) was reduced with the progression of pregnancy and during lactation. In vitro measurement of cAMP levels in pituitary segments demonstrated reduced basal levels of cAMP and a lower increase after CRH stimulation (10 nM, 10 min) in day 21 pregnant compared with virgin rats, further indicating reduced corticotroph responsiveness to CRH in pregnancy. 5. The reduced pituitary response to CRH in late pregnancy is likely to be a consequence of a reduction in CRH receptor binding as revealed by receptor autoradiography. [125I] CRH binding in the anterior pituitary was significantly reduced in day 11, 17 and 22 pregnant rats compared with virgin controls. 6. Anxiety-related behaviour of the animals as revealed by the time on and entries into the open arms of the elevated plus-maze was different between virgin and pregnant rats with decreased number of entries indicating increased anxiety with the progression of pregnancy (except on pregnancy day 18). The emotional behaviour, however, was not correlated with the neuroendocrine responses. 7. The results indicate that the reduced response of the HPA axis to stressors described previously during lactation is already manifested around day 15 of pregnancy in the rat and involves physiological adaptations at the adenohypophysial level. However, alterations in stressor perception at higher brain levels with the progression of pregnancy may also be involved.

Exposure to Acute Stress Induces Brain Interleukin-1β Protein in the Rat

Peripheral immune stimulation such as that provided by lipopolysaccharide (LPS) has been reported to increase brain levels of IL-1beta mRNA, immunoreactivity, and bioactivity. Stressors produce many of the same neural and endocrine responses as those that follow LPS, but the impact of stressors on brain interleukin-1beta (IL-1beta) has not been systematically explored. An ELISA designed to detect IL-1beta was used to measure levels of IL-1beta protein in rat brain. Brain IL-1beta was explored after exposure to inescapable shock (IS; 100 1.6 mA tail shocks for 5 sec each) and LPS (1 mg/kg) as a positive control. Rats were killed either immediately or 2, 7, 24, or 48 hr after IS. Brains were dissected into hypothalamus, hippocampus, cerebellum, posterior cortex, and nucleus tractus solitarius regions. LPS produced widespread increases in brain IL-1beta, but IS did not. Adrenal glucocorticoids are known to suppress IL-1beta production in both the periphery and brain. Thus, it was possible that the stressor did provide stimulus input to the brain IL-1beta system(s), but that the production of IL-1beta protein was suppressed by the rapid and prolonged high levels of glucocorticoids produced by IS. To test this possibility rats were adrenalectomized or given sham surgery, with half of the adrenalectomized rats receiving corticosterone replacement to maintain basal corticosterone levels. IS produced large increases in brain IL-1beta protein in the adrenalectomized subjects 2 hr after stress, whether basal corticosterone levels had been maintained. Thus elimination of the stress-induced rise in corticosterone unmasked a robust and widespread increase in brain IL-1beta.

Intracerebroventricular injection-induced increase in plasma corticosterone levels in the mouse: a stress model

The method of intracerebroventricular (i.c.v.) injection of drugs to conscious mice is a simple and useful technique for studying the central actions of drugs in mice. However, the use of this technique to dissect the central regulatory mechanisms of stress-activated hypothalamo-pituitary-adrenocortical (HPA) axis may produce confusing results difficult to interpret, because i.c.v. injection itself induces an increase in plasma corticosterone in mice due to the traumatic nature of the technique. Here we propose to use the i.c.v. injection itself as a stress stimulus in mice. An i.c.v. saline injection induced an increase in plasma corticosterone levels in mice, which reached a maximum of 38.0 ± 1.9 μg/100 ml at 30 min after the i.c.v. injection. α-Helical corticotropin-releasing factor (CRF) 9-41, a CRF antagonist, injected i.c.v. (1, 3 μg), effectively inhibited the injection stress-induced rise in plasma corticosterone levels, suggesting the involvement of CRF in this response. This i.c.v. injection stress model permits the evaluation of the effects of drugs administered i.c.v. simultaneously.

Protein synthesis blockade differentially affects the stress- induced transcriptional activation of neuropeptide genes in parvocellular neurosecretory neurons

Corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) are synergistically interacting ACTH secretagogues that are co-expressed by parvocellular neurosecretory neurons of the hypothalamic paraventricular nucleus (PVH). To shed light on the mechanisms that mediate the stress-induced transcriptional activation of these neuropeptide genes, quantitative hybridization histochemical methods were used to assess the effects of systemic treatment with the protein synthesis inhibitor, cycloheximide, on the ether stress-induced upregulation of primary CRF and AVP transcripts, in vivo. Pretreatment with cycloheximide prevented the induction of Fos, but not CREB phosphorylation, normally seen in response to acute ether exposure, and significantly attenuated the stress-induced rise in AVP, but not CRF, heteronuclear RNA expression in the parvocellular division of the PVH. These results support the view that distinct molecular mechanisms govern the expression of the two principal corticotropin-releasing factors, in vivo.

Corticosterone Peak is Responsible for Stress-Induced Elevation of Glutamate in the Hippocampus

Effect of ether stress on dialysate concentration of extracellular amino acids in the hippocampus was studied by microdialysis in freely moving rats that have been either sham operated (SHAM) or adrenalectomized and supplemented with subcutaneous steroid pellets (ADX+CORT) providing constant corticosterone (CORT) plasma levels. In SHAM rats, ether stress resulted in a peak of glutamate and taurine 30 min after stress, while extracellular aspartate concentration was increased 120 min after challenge. These changes in amino acid levels as well as in glutamate/glutamine ratio were paralleled by stress-induced rise of plasma CORT. No significant alterations were detected in the concentration of hippocampal arginine, alanine, glicine, glutamine, threonine or serine. In contrast to SHAM animals, ether stress failed to have an effect on dialysate concentration of amino acid transmitters in the hippocampus of adrenalectomized rats supplemented with 50 mg CORT-pellets. Our results demonstrate that ether stress alters aspartate, glutamate, glutamate/glutamine ratio and taurine concentration in the hippocampus and indicate that stress-induced CORT release in plasma may be responsible for these amino acid alterations. These changes may also contribute to negative feedback effect of CORT on hypothalamo-pituitary-adrenocortical (HPA) axis via the hippocampus during stress.

Chapter 11 Immunological and neuroendocrine modulation of fever in stress

Publisher Summary This chapter summarizes the current opinions on the mediators and mechanisms involved in the generation of fever, emphasizing the different hypotheses on the transfer of febrile signals from the periphery of the body into the brain. The different endogenous antipyretic systems are introduced, and the modulation of the activity of the immune system and the changes of the febrile response under the influence of different stressors are analyzed. The chapter discusses that if the stress-induced rise of core temperature, which is accompanied by the release of soluble immune mediators and possibly stimulated by some stress hormones, represents a condition of fever under nonpathological conditions. Fever is one of the most common components of the array of host defence responses in an infected organism. Under the conditions of an activated immune system, sympathetic nerve fibers to lymphoid tissue or spleen, as well as a stimulation of the hypothalamic-pituitary-adrenal (HPA)-axis, represent the most important negative-feedback loops, which may help in which the potentially dangerous machinery of the immune system is restricted in its activity to limited time periods and finally turned off again.

Full length article

Opiates and opioids have complex effects on the hypothalamic-pituitary-adrenal axis, and they stimulate the sympathetic nervous system. This study was designed to clarify the role of brain beta-endorphin in the mechanism by which stress increases plasma concentrations of adrenocorticotropin (ACTH), epinephrine (E), and norepinephrine (NE). Intracerebroventricular (i.c.v.) administration of beta-endorphin to rats significantly increased plasma ACTH levels at doses of 0.09, 0.3, and 1.5 nmol, and plasma E and NE levels at doses of 0.3 and 1.5 nmol. The rise of plasma ACTH, E, and NE levels by 0.3 nmol beta-endorphin was inhibited by intravenous (i.v.) administration of 2 mg/kg b.wt. naloxone. I.v. administration of anti-rat corticotropin-releasing hormone (CRH) rabbit serum completely blocked the beta-endorphin-induced ACTH secretion without affecting the secretion of E and NE. I.c.v. administration of anti-beta-endorphin rabbit gamma-globulin attenuated a 30-min restraint stress-induced rise of plasma ACTH levels without significant influence on the rise of E and NE levels, whereas i.v. administration of naloxone attenuated the restraint stress-induced rise of plasma ACTH, E and NE levels. These results suggest that i.c.v. administration of beta-endorphin stimulates the secretion of ACTH, E, and NE through opiate receptor, and that brain CRH mediates the beta-endorphin-induced secretion of ACTH. The results also suggest that brain beta-endorphin is, at least in part, involved in the restraint stress-induced stimulation of the hypothalamic-pituitary-adrenal axis, and that some opioids other than beta-endorphin are involved in the stimulatory mechanism of the autonomic nervous system and the adrenal medulla in the rat.

Actions of serotonergic agents on hypothalamic-pituitary-adrenal axis activity in the rat

1. 1. The effects of ipsapirone, nefazodone, tiaspirone, BMS-20661, buspirone and gepirone on the hypothalamic-pituitary-adrenal (HPA) axis were studied. These drugs were selected because they have serontonin IA (5-HT 1A) receptor-binding capability and have the potential for therapeutic activity in the treatment of major affective or anxiety disorders or both. 2. 2. Plasma corticosterone level was used as the end point for determining the effect of each drug on the HPA axis. Each drug increased the plasma corticosterone levels in a dose-dependent manner. The ED 50 values were 0.8 mg/kg for BMS-20661, 3.5 mg/kg for gepirone, 3.9 mg/kg for buspirone, 5.3 mg/ kg for tiaspirone, 10.5 mg/kg for ipsapirone and 73.5 mg/kg for nefazodone. Ipsapirone and buspirone were more efficacious than the other four drugs. 3. 3. The effect of a 10-mg/kg (35 mg/kg for nefazodone) test dose of each drug reached a peak between 30 min and 1 hr, and plasma corticosterone levels generally returned to control levels after 2 hr. 4. 4. When the drugs were given 30 min before decapitation, in conjunction with a rotatory stress, BMS-20661 significantly inhibited the stress-induced rise, whereas ipsapirone and gepirone caused a significant increase in plasma corticosterone levels. However, when the drugs were given 2 hr before decapitation, nefazodone caused a significant decrease, whereas ipsapirone, BMS-20661 and gepirone produced significant increases in HPA axis activity. An 0800 hr dose of 0.1 mg/kg of dexamethasone suppressed the 1500 hr HPA activity by 73.1%. The 0.1-mg/kg dose of dexamethasone significantly reduced the drug-activated HPA axis activity of all of the drugs from their saline-control levels. The rank order, from least to greatest inhibitory effect, produced by this dexamethasone treatment on the drug-control levels was gepirone (−42.6%), tiaspirone (−48.9%), buspirone (−56.1%), nefazodone (−68.5%), ipsapirone (−70.0%), and BMS-20661 (−74.3%).

Stress-Induced Rise in Serum Anti-Brain Autoantibody Levels in the Rat

Sera from Wistar rats subjected to different stress procedures were tested by ELISA for the presence of autoantibodies with specificity for neuron-specific enolase (NSE) and S100 protein that are preferentially localized in neurons and glia, respectively. Autoantibodies were present in sera ol animals before exposure to stress, and raised with age. Anti-NSE and anti-SlOO autoantibody levels were increased one day after termination of restraint (2 hours daily, 10 days) and electric tail shock (80 shocks daily, 19 days), and in fifth and tenth week of overcrowding stress. Differences between stressed and control animals were not present one month following restraint and electric tail shock and in twentieth week of overcrowding.

Ketanserin selectively blocks acute stress-induced changes in NGFI-A and mineralocorticoid receptor gene expression in hippocampal neurons.

Serotonin and glucocorticoids interact at the hippocampus to alter neuronal function. Serotonin and antidepressant drugs increase glucocorticoid receptor and mineralocorticoid receptor gene expression in hippocampal neurons over a few days. The effects of serotonin are mediated via ketanserin-sensitive "serotonin-2 type" receptors and induction of cyclic AMP, although the subsequent molecular mechanisms are unclear. Recently, we have shown that chronic environmental manipulations which induce glucocorticoid receptor gene expression in specific hippocampal subfields of the rat are associated with congruent induction of the transcription factor NGFI-A (zif268, krox24, egr-1) and repression of AP-2; both factors may bind to the glucocorticoid receptor gene promoter. However, any relationship between serotonin and these transcription factors is unknown. Here, we show that acute restraint stress, which causes serotonin release at the hippocampus, induces hipppocampal NGFI-A, but represses activator protein-2 and mineralocorticoid receptor gene expression within 90 min. These changes are sustained for 4 h, but not 12 h. Ketanserin attenuates the stress-induced rise in NGFI-A and fall in mineralocorticoid receptor gene expression, and partly also the fall in AP-2 messenger RNA expression. These data suggest that restraint stress, acting via serotonin release and ketanserin-sensitive serotonin receptors, produces rapid, transient and specific changes in transcription factor gene expression in hippocampal neurons. Any link between these effects and the control of glucocorticoid and mineralocorticoid receptor expression with chronic serotonin or antidepressant treatment remains to be elucidated.

Involvement of NMDA receptor in the regulation of plasma interleukin-6 levels in mice

MK-801 ((+)-5-methyl-10,11-dihydro-5 H-dibenzo( a,d)cyclopepten-5,10-imine maleate), a non-competitive NMDA receptor antagonist (0.01–1 μg), injected intracerebroventricularly (i.c.v.) dose dependently increased the baseline levels of plasma interleukin-6 in mice. In the 1-h immobilization-stressed animals, MK-801 (1 μg) administered i.c.v. produced an additive increase of plasma interleukin-6. NMDA ( N-methyl- d-aspartate) (3, 10 ng) administered i.c.v. attenuated dose dependently the 1-h immobilization stress-induced rise in plasma interleukin-6 level. Neither 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) (0.01–0.5 μg) nor α-methyl-4-carboxyphenylglycine (MCPG) (1–20 μg), antagonists of non-NMDA and metabotropic glutamate receptors, respectively, i.c.v. administered, affected the basal and stress-induced plasma interleukin-6 levels. These data indicate that NMDA receptors may be involved in the suppressive regulation of the plasma interleukin-6 levels.

O-17-6 - Comparative effects of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder

1.1. The effects of ipsapirone, nefazodone, tiaspirone, BMS-20661, buspirone and gepirone on the hypothalamic-pituitary-adrenal (HPA) axis were studied. These drugs were selected because they have serontonin IA (5-HT1A) receptor-binding capability and have the potential for therapeutic activity in the treatment of major affective or anxiety disorders or both.2.2. Plasma corticosterone level was used as the end point for determining the effect of each drug on the HPA axis. Each drug increased the plasma corticosterone levels in a dose-dependent manner. The ED50 values were 0.8 mg/kg for BMS-20661, 3.5 mg/kg for gepirone, 3.9 mg/kg for buspirone, 5.3 mg/ kg for tiaspirone, 10.5 mg/kg for ipsapirone and 73.5 mg/kg for nefazodone. Ipsapirone and buspirone were more efficacious than the other four drugs.3.3. The effect of a 10-mg/kg (35 mg/kg for nefazodone) test dose of each drug reached a peak between 30 min and 1 hr, and plasma corticosterone levels generally returned to control levels after 2 hr.4.4. When the drugs were given 30 min before decapitation, in conjunction with a rotatory stress, BMS-20661 significantly inhibited the stress-induced rise, whereas ipsapirone and gepirone caused a significant increase in plasma corticosterone levels. However, when the drugs were given 2 hr before decapitation, nefazodone caused a significant decrease, whereas ipsapirone, BMS-20661 and gepirone produced significant increases in HPA axis activity. An 0800 hr dose of 0.1 mg/kg of dexamethasone suppressed the 1500 hr HPA activity by 73.1%. The 0.1-mg/kg dose of dexamethasone significantly reduced the drug-activated HPA axis activity of all of the drugs from their saline-control levels. The rank order, from least to greatest inhibitory effect, produced by this dexamethasone treatment on the drug-control levels was gepirone (−42.6%), tiaspirone (−48.9%), buspirone (−56.1%), nefazodone (−68.5%), ipsapirone (−70.0%), and BMS-20661 (−74.3%).

Fever response in lean (Fa/-) and obese (fa/fa) Zucker rats and its lack to repeated injections of LPS

The thermal responses of Fa/- and fa/fa Zucker rats to injections of sterile saline and to four injections of 20 μg/kg LPS at 3-day intervals were measured by means of radiotelemetry. In response to injections of saline, only the Fa/- rats developed a short stress-induced increase in abdominal temperature. Such a stress-induced rise of core temperature was also monitored in Fa/- rats after a change of the animals' cages. In response to the first injection of LPS, the Fa/- rats developed the same stress-induced rise in abdominal temperature as observed after injection of solvent followed by a biphasic fever, the first phase within 100 and 225 min, and the second phase within 240 and 480 min after LPS injection. In the fa/fa rats the stress-induced rise in body temperature and the first phase of LPS-induced fever were significantly suppressed, whereas the second phase of LPS-fever was identical in Fa/- and fa/fa rats. In response to further injections of LPS no febrile response was measurable at all; just the short stress-induced rise in abdominal temperature remained manifest in the Fa/− rats. When the first injection of 20 μg/kg LPS was followed by injections of 100 and 1000 μg/kg LPS, a febrile response remained manifest, but the second phase of fever was attenuated in response to the repeated challenge with higher doses of LPS. The complete endotoxin tolerance observed in response to the second and further injections of 20 μg/kg seems thus to be due to a strongly reduced sensitivity to LPS after its first administration. Because data from the literature indicate a reduced sympathetic outflow to brown adipose tissue of fa/fa rats in general and during fever in particular, we tried to determine the activity of the sympathetic nervous system by measurement of excreted amounts of noradrenaline. Attempts failed to determine noradrenaline excretion during fever in lean and in obese animals. The daily excretion of noradrenaline at an ambient temperature of 22°C (basal values) was 53.8 ± 4.7 nmol/kg in Fa/- and 25.9 ± 3.4 nmol/kg in fa/fa rats. These values were increased by a cold exposure (5°C) for 24 h to 123.1 ± 12.4 nmol/kg in Fa/- rats (229% of the basal value) vs. just 48.7 ± 2.5 nmol/kg in fa/fa rats (188% of the basal value). This small, but significantly larger rise of cold-stimulated noradrenaline excretion in Fa/- rats is indicative of a reduced sympathetic function in the fa/fa rats, but does not explain the lack of stress-induced rise in body temperature and of the first phase of LPS-induced fever in the obese animals.

Sex differences in corticosteroid binding in the rat brain: an in vitro autoradiographic study

Several previous studies have raised the possibility of sex differences in the distribution of corticosteroid receptors in the brain. The direction and magnitude of these differences have, however, remained controversial. In the present study, we have re-examined the concentrations of mineralocorticoid (MR) and glucocorticoid (GR) receptors in the brains of male and female rats at varying times (1 to 6 days) after combined gonadectomy (GDX) and adrenalectomy (ADX). Cytosol binding assays confirmed the presence of higher MR levels in short-term (3-day) GDX-ADX males. This difference disappeared by 6 days after surgery, as receptor levels in females rose to be equivalent to those in males. Using an improved in vitro autoradiographic method, the distribution of MR and GR was studied in males and females 3 days after GDX-ADX. The distribution of MR and GR in the brains of these rats was similar in the two sexes. MR binding in the male, however, was significantly greater than that in the female throughout the principal cell fields of the hippocampus. Measurements of circulating corticosterone levels at the time of GDX-ADX suggest that this sex difference may reflect a more rapid recovery of the MR system in males than in females following the stress-induced rise in corticosterone secretion occurring at the time of surgery.