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Plasma analysis of conscious rats reveals that administration of lipopolysaccharide (LPS), an intra-arterial endotoxin, initiates adrenocorticotropic hormone (ACTH) and corticosterone (Cort) swelling, along with increased hormonal response. This infusion also increases the concentration of three cytokines. Delayed increase of cytokines concentrations in the plasma influences the hypothalamic pituitary-adrenocortical (HPA) activation.

Elevated cortisol evidence in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids are involved in the development and/or maintenance of AD. We investigated the hypothalamic-pituitary-adrenal (HPA) axis activity, functionality, and reactivity for up to 6 weeks after an intracerebroventricular injection of amyloid-β(25-35) peptide (Aβ(25-35)) in rat, a validated acute model of AD. Aβ(25-35) induces memory impairment, alteration of anxiety responses, HPA axis hyperactivity, and glucocorticoid (GR) and mineralocorticoid (MR) receptor increases in brain regions related to HPA axis functions. GR are progressively translocated in neurons nucleus, while membrane version of MR is evidenced in all structures considered. The MR/GR ratio was modified in all structures considered. Aβ(25-35) induces a subtle disturbance in the feedback of the HPA axis, without modifying its functionality. The reactivity alteration is long-lasting, suggesting that amyloid toxicity affects the HPA axis adaptive response to stress. These findings are evidence of progressive HPA axis deregulation after Aβ(25-35), which is associated with an imbalance of MR/GR ratio and a disruption of the glucocorticoid receptors nucleocytoplasmic shuttling, and suggest that elevated glucocorticoids observed in AD could be first a consequence of amyloid toxicity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a neurodegenerative pathology associated with aging characterized by the presence of senile plaques and neurofibrillary tangles that finally result in synaptic and neuronal loss. The major component of senile plaques is an amyloid-β protein (Aβ). Recently, we characterized the effects of a single intracerebroventricular (icv) injection of Aβ fragment (25-35) oligomers (oAβ(25-35)) for up to 3 weeks in rats and established a clear parallel with numerous relevant signs of AD. To clarify the long-term effects of oAβ(25-35) and its potential role in the pathogenesis of AD, we determined its physiological, behavioral, biochemical and morphological impacts 6 weeks after injection in rats. oAβ(25-35) was still present in the brain after 6 weeks. oAβ(25-35) injection did not affect general activity and temperature rhythms after 6 weeks, but decreased body weight, induced short- and long-term memory impairments, increased corticosterone plasma levels, brain oxidative (lipid peroxidation), mitochondrial (caspase-9 levels) and reticulum stress (caspase-12 levels), astroglial and microglial activation. It provoked cholinergic neuron loss and decreased brain-derived neurotrophic factor levels. It induced cell loss in the hippocampic CA subdivisions and decreased hippocampic neurogenesis. Moreover, oAβ(25-35) injection resulted in increased APP expression, Aβ(1-42) generation, and increased Tau phosphorylation. In conclusion, this in vivo study evidenced that the soluble oligomeric forms of short fragments of Aβ, endogenously identified in AD patient brains, not only provoked long-lasting pathological alterations comparable to the human disease, but may also directly contribute to the progressive increase in amyloid load and Tau pathology, involved in the AD physiopathology.

Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid β protein (Aβ) formed by pathological processing of the Aβ precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated Aβ fragment 25-35 (Aβ(25-35)) in rats. Using a combined biochemical, behavioral, and morphological approach, we analyzed the peptide effects after 1, 2, and 3 weeks in the hippocampus, cortex, amygdala, and hypothalamus. The scrambled Aβ(25-35) peptide was used as negative control. The aggregated forms of Aβ peptides were first characterized using electron microscopy, infrared spectroscopy, and Congo Red staining. Intracerebroventricular injection of Aβ(25-35) decreased body weight, induced short- and long-term memory impairments, increased endocrine stress, cerebral oxidative and cellular stress, neuroinflammation, and neuroprotective reactions, and modified endogenous amyloid processing, with specific time-course and regional responses. Moreover, Aβ(25-35), the presence of which was shown in the different brain structures and over 3 weeks, provoked a rapid glial activation, acetylcholine homeostasis perturbation, and hippocampal morphological alterations. In conclusion, the acute intracerebroventricular Aβ(25-35) injection induced substantial central modifications in rats, highly reminiscent of the human physiopathology, that could contribute to physiological and cognitive deficits observed in AD., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Depression is potentially life-threatening. The most important neuroendocrine abnormality in this disorder is hypothalamo-pituitary-adrenocortical (HPA) axis hyperactivity. Recent findings suggest that all depression treatments may boost the neurotrophin production especially brain-derived neurotrophic factor (BDNF). Moreover, BDNF is highly involved in the regulation of HPA axis activity. The aim of this study was to determine the impact of chronic stress (restraint 3h/day for 3 weeks) on animal behavior and HPA axis activity in parallel with hippocampus, hypothalamus and pituitary BDNF levels. Chronic stress induced changes in anxiety (light/dark box test) and anhedonic states (sucrose preference test) and in depressive-like behavior (forced swimming test); general locomotor activity and body temperature were modified and animal body weight gain was reduced by 17%. HPA axis activity was highly modified by chronic stress, since basal levels of mRNA and peptide hypothalamic contents in CRH and AVP and plasma concentrations in ACTH and corticosterone were significantly increased. The HPA axis response to novel acute stress was also modified in chronically stressed rats, suggesting adaptive mechanisms. Basal BDNF contents were increased in the hippocampus, hypothalamus and pituitary in chronically stressed rats and the BDNF response to novel acute stress was also modified. This multiparametric study showed that chronic restraint stress induced a depressive-like state that was sustained by mechanisms associated with BDNF regulation., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Brain-derived neurotrophic factor is a neurotrophin belonging to the nerve growth factor family, which is involved in the differentiation and survival of many types of neurons. It also participates in neuroprotection and neuronal plasticity in adult rats. Our previous studies showed that a single brain-derived neurotrophic factor injection modifies hypothalamic-pituitary-adrenal axis activity in adult male rats. To investigate the effect of chronic brain-derived neurotrophic factor administration on some physiological parameters, adult rats were implanted with osmotic micro-pumps to deliver brain-derived neurotrophic factor continuously for 14 days in the lateral ventricle (12 microg/day/rat). mRNA levels were evaluated by in situ hybridization analysis, peptide contents and plasma hormone concentrations by radioimmunoassay. Animals were also equipped with telemetric transmitters to study locomotor activity and temperature rhythms modifications, since hypothalamic-pituitary-adrenal axis is known to modulate these two parameters. Decreased body weight was used as a control of brain-derived neurotrophic factor access to hypothalamic areas as already documented. In the hypothalamus the continuous brain-derived neurotrophic factor treatment increases: (i) the mRNA steady state levels of corticotropin releasing hormone and arginin-vasopressin in the paraventricular nucleus, the supraoptic nucleus, and the suprachiasmatic nucleus; (ii) the surface of corticotropin releasing hormone and arginin-vasopressin mRNA signals in these nuclei as detected by in situ hybridization, and (iii) the corticotropin releasing hormone and arginin-vasopressin contents. The plasma concentrations of adrenocorticotropic hormone and corticosterone were decreased and increased, respectively. Finally, this treatment increased daily locomotor activity and temperature, and provoked some circadian perturbations. These results obtained after chronic brain-derived neurotrophic factor administration extend data on the brain-derived neurotrophic factor involvement in the hypothalamic-pituitary-adrenal axis regulation and illustrate its effects on the locomotor and temperature rhythms. They also allow demonstrating that the regulation of the hypothalamic-pituitary-adrenal axis by brain-derived neurotrophic factor differs according to the brain-derived neurotrophic factor administration mode, i.e. acute injection or chronic administration.

Immobilization stress induces in adult male rats rapid activation of brain derived neurotrophic factor (BDNF) expression in the hypothalamic paraventricular nucleus (PVN) preceding the increases in corticotropin releasing hormone (CRH) and arginin-vasopressin (AVP) expression. The BDNF mRNA signal belatedly co-localizes with CRH and AVP mRNA signals in the PVN, as determined by in situ hybridization. Intracerebroventricular BDNF injections (5 microg/rat) in non-anesthetized adult male rats induce a gradual increase in the CRH mRNA signal whereas AVP mRNA signal progressively decreases in the parvocellular and magnocellular PVN portions. At the same time, the CRH hypothalamic content decreases while the AVP content increases. These variations are accompanied by increases in ACTH and corticosterone plasma concentrations. These results strongly suggest that BDNF could be a stress-responsive intercellular messenger since when it is exogenously administered acts as an important and early component in the activation and recruitment of hypothalamic CRH and AVP neurons.

This study investigates if the serotoninergic system plays a role in chronotoxic effects of the anticancer agent oxaliplatin (l-OHP). Four groups of female rats (120 in total) synchronized with light-dark (12 h:12 h) were treated with: (i) saline, (ii) para-chlorophenylalanine (pCPA, an inhibitor of serotonin biosynthesis: 300 mg/kg/d, i.p. for two consecutive days), (iii) l-OHP (23 mg/kg, i.v.) at three different dosing times, or (iv) both pCPA and l-OHP. The results show pCPA (ii) obliterates the circadian rhythm in plasma ACTH but not in corticosterone or leukocytes, and (iii) l-OHP exerts circadian time-dependent toxic effects (body weight loss, leukopenia, and intestinal lesions) with greatest toxicity coinciding with treatment at the end of the nocturnal activity span (P < 0.05). In rats whose serotonin biosynthesis was blocked (iv), the circadian rhythms in the toxic effects of l-OHP and in ACTH were obliterated, while the rhythms in corticosterone and leukocytes persisted.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neuronal survival and plasticity that binds to high-affinity receptors named TrkB. In the central nervous system, brain insults, including stress, induce modifications in BDNF messenger RNA (mRNA) expression. The present study attempted to determine in the adult rat pituitary, a peripheral structure relevant for the stress response: (1) whether BDNF and TrkB mRNA expression is influenced by different durations (15, 30, 60, 180 and 300 min) of single immobilization stress; (2) the expression of BDNF transcripts containing the different exons and their possible variations after stress exposure. Plasma corticotropin (ACTH) and corticosterone concentrations were strongly and significantly increased as early as 5 min after the stress stimulus. Using RNAse protection assay and in situ hybridization, a rapid increase in BDNF mRNA occurred at 15 min. This was accompanied by an increase in BDNF protein at 60 min, and by a rapid and significant decrease in TrkB mRNA expression observed at 15 and 30 min after stress application. RT-PCR analysis of BNDF transcripts showed strong basal expression of exons III and IV, whereas transcripts containing exons I and II seemed weakly expressed. After stress application, transcripts containing exons III and IV were rapidly and significantly increased at 30 min, whereas transcripts containing exons I and II remained unchanged. These results show that pituitary BDNF transcripts expression is differentially affected by immobilization stress., (Copyright 2001 S. Karger AG, Basel)

We have investigated whether the serotonin system participates in the mechanisms underlying the corticotropic response in experimentally infected rats. Intra-arterial injection of lipopolysaccharide (LPS; 25 microg/kg b.w.) resulted in a slight but significant increase in serotonin (5-HT) metabolism, detectable 60 min after the stimulus and lasting more than 480 min. Adrenocorticotropin (ACTH) and corticosterone (CORT) responses in intact rats conformed to earlier reports, increasing as early as 30 min after LPS injection and reaching maximal concentrations in the circulation 60 min after the bacterial endotoxin injection. Plasma concentrations of interleukin-1beta (IL-1beta) increased only after 60 min, reaching maximal levels 120 min after LPS. Depletion of hypothalamic 5-HT (-93%) by pretreatment of the animals with para-chlorophenylalanine (p-CPA), resulted in a halved ACTH response to LPS, despite an overall unchanged secretory pattern. Neither CORT nor IL-1beta secretory patterns were affected in these rats pretreated with p-CPA. Complete bilateral electrochemical lesions of the suprachiasmatic nucleus (SCN), which is innervated by mesencephalic 5-HT, impaired the early phase of the ACTH (-75% at 30 min) and CORT (-40% at 30 min) responses but did not affect the later increases of the corticotropic and the plasma IL-1beta responses following the LPS injection. These results indicate that serotonin pathways and SCN are involved in the earlier mechanisms of corticotropic axis recruitment following systemic LPS endotoxemia.

The involvement of histaminergic transmission in the rapid and sustained plasma ACTH and corticosterone (CORT) responses induced in conscious rats by intra-arterial infusions of 25 micrograms.kg-1 Escherichia coli lipopolysaccharide (LPS) was investigated. LPS challenge produced a rapid and transient increase (+ 62%) in the amount of histamine (HA) in the median eminence 15 min after LPS administration, which contrasted with constant concentrations of plasma HA throughout the entire study (up to 480 min). Blockade of histaminergic receptors by intra-arterial pretreatment with H1 or H2 antagonists (mepyramine, 1 mg/rat, and cimetidine, 2 mg/rat), administered separately, did not affect either ACTH or CORT responses to LPS. Pretreatment with the same doses of the two antagonists in combination very significantly but transiently impaired the earliest phase (30 min) of the ACTH and CORT responses, without any apparent effect on the late phase of these responses. Pretreatment of the animals with an H3-receptor agonist (R alpha-methylhistamine dihydrochloride, 1 mg/rat) similarly blunted the early corticotropic responses to LPS, and also slightly depressed the long-lasting CORT response. These findings support the view that activated central HA transmission may be a key intermediate mechanism triggering the CRH41-ACTH-CORT responses to LPS, in addition to the previously demonstrated activating role of catecholaminergic afferences to the CRH41 neurons during this early complex phase of corticotropic response to LPS.

In a parallel study in 10 individual rats, three time series of plasma concentrations of ACTH, corticosterone (CORT), and interleukin-1 beta (IL-1 beta) were measured before (time 0) and at intervals between 15 and 480 min following intra-arterial (i.a.) infusions of 25 microgram/kg lipopolysaccharide (LPS). All LPS injections were given at 9 AM. The first time series was performed on naive rats (day 1). A sequence of six daily injections (days 3-8) of the same dose of LPS followed. The post-LPS time course of the plasma ACTH, CORT and IL-1 beta levels were studies on days 3 (second injection) and 8 (seventh injection). The first LPS injection induced a rapid (30 min) eightfold rise in plasma ACTH and CORT, culminating in concentrations 30 times the baseline at 60 min (ACTH) and 15 times baseline at 120 min (CORT). Both hormones receded back to the initial basal level at 480 min. On the other hand, IL-1 beta increased slowly to peak at 13 times baseline 120 min before declining to minimal seven- to ninefold basal levels, 480 min and even 48 h post-LPS. During the second phase of the experiment starting 48 h after the initial LPS priming sequence, the ACTH and CORT responses to daily recurrent LPS injections again differed from those of IL-1 beta. The post-LPS time courses of the ACTH and CORT reaction displayed a typical pattern of a progressive attenuation studied at days 3 and 8. The peak amplitudes at days 3 and 8 were reduced to 60 and 10%, respectively, for ACTH, and to 85 and 45% for CORT of those observed at the first LPS test. The duration of the response (both) was also shortened from 480 min (first LPS test) to 300 min at days 3 and 8. The post-LPS patterns of the IL-1 beta responses were characterized, first by basal levels seven to nine times higher than the initial baseline values (day 1), and by a rapid suppression of the post-LPS response, with only a slight (30%) increase at day 3 and no increase at day 8. Thus, after both acute and recurrent LPS administration, ACTH/CORT and IL-1 beta reacted differently to the endotoxin challenge. The two LPS reactive systems were not correlated. This is inconsistent with the often proposed role of increased plasma IL-1 beta release as an intermediary factor in the LPS-induced recruitment of the corticotropic axis in general infections.

Previous morphological and physiological studies have suggested that the adrenergic innervation of the dorsal motor nucleus of the vagus nerve (dmnX) is involved in direct synaptic inhibition of parasympathetic preganglionic neurones of the vagus that control secretion of pancreatic insulin. We investigated the effects of bilateral 6-hydroxydopamine (6-OHDA) lesions of adrenergic innervation of the dmnX on pancreatic insulin secretion and glycaemia in normal and vagotomized rats. After two weeks the 6-OHDA lesions produced a marked increase in circulating insulin levels, but no change in glycaemia. Hyperinsulinaemia after adrenergic denervation of the dmnX was more pronounced when a glucose bolus was injected intraarterially. Bilateral subdiaphragmatic vagotomy reversed the observed hyperinsulinaemia. This targeted pharmacological lesion of the adrenergic innervation of dmnX thus causes hypersecretion by pancreatic B cells, an effect which requires an intact vagus nerve.

To explore the interactions between the hypothalamic-pituitary-adrenocortical axis and the immune system under stress conditions, we used an experimental rat model for chronic tail-restraint devised earlier for ground studies in space physiology. The system was used in two positions: (1) the orthostatic restraint position (OR) and (2) the antiorthostatic position (AOR) after the rat hind limbs had been raised by a head-down tilt. After 7 days of either restraint, sequential blood samples were taken via an indwelling aortic cannula, before and at various time intervals between 15 and 300 min after an intravascular infusion of 25 micrograms/kg lipopolysaccharide (LPS). The plasma titers of adrenocorticotropin (ACTH), corticosterone (CORT) and interleukin-1 beta (IL-1 beta) were assayed. Under basal conditions, both OR and AOR restraints induced a 5-fold increase in IL-1 beta with no significant changes in ACTH and CORT levels. A robust increase in all three variables was observed after LPS injection. However, the IL-1 beta response to LPS was significantly higher in both restrained groups than in controls. Both the amplitude and the percentage of individually restrained rats displaying elevated IL-1 beta levels were increased up to 5 h. In contrast, the ACTH and CORT post-LPS responses were normal in the OR group. They were unusually dissociated in the AOR rats, which displayed depressed ACTH levels associated with slightly increased CORT levels. Our results suggest that immune-neuroendocrine responses to chronic restraint stress may differ from those generally observed in acute stress.

We recently showed that bilateral neurotoxic microlesions (6-OH-DA) of the ventral noradrenergic ascending bundle (VNAB-X) at stereotaxic coordinates that blocked corticotropic stress responses did not affect the ACTH surge after bilateral intra-paraventricular (i.PVN) injections of interleukin-1 beta (IL-1 beta), and that lesioning at these stereotaxic coordinates obliterated the dorsal axonal populations of the VNAB (dVNAB-X), but spared the bundle's most ventral axons (vVNAB). The present study compares the effects of IL-1 beta given i.PVN (2 x 5 ng) of intra-arterially (i.a.) (100 ng) on plasma ACTH in rats with bilateral 6-OH-DA microlesions placed in the dVNAB or the vVNAB, or in an intermediary central position (cVNAB-X). Unlike our previous results, in which dVNAB-X did not alter the biphasic ACTH response to i.PVN IL-1 beta, both vVNAB-X and cVNAB-X reduced by 50-75% the early and delayed ACTH surges which are typical of the i.PVN route. On the other hand the swift monophasic ACTH surge usually occurring after an i.a. injection of IL-1 beta was 65% smaller after dVNAB-X, but was doubled after vVNAB-X or cVNAB-X. Hence, the release of ACTH after both i.PVN or i.a. IL-1 beta requires brainstem afferences conveyed to the hypothalamus by the VNAB. However, the VNAB appears to include at least two functionally different subsets of axons, the roles of which in the ACTH response to IL-1 beta depend on the route by which the cytokine is given.