Biomedical subjects

C Guaza

Publications and source records attributed to C Guaza.

At least 19 recordsLinked to original sources

PubMed2006

Adolescent exposure to nicotine modifies acute functional responses to cannabinoid agonists in rats.

We have studied functional interactions between nicotine and the cannabinoid receptor agonist CP 55,940 (CP) in the modulation of behavioural and corticosterone responses of male and female adolescent Wistar rats. The animals underwent a subchronic nicotine treatment (0.4 mg/kg i.p., once daily) during the periadolescent period (postnatal days 34-43). Twenty-four hours after the last injection of nicotine an acute dose of CP (1 or 100 microg/kg i.p.) was administered. Thirty minutes after the cannabinoid injection, the animals were tested individually in the holeboard immediately followed by the elevated plus-maze. We also measured corticosterone levels by radioimmunoassay. In males, neither CP (1 microg/kg) nor nicotine induced any modification in anxiety when administered alone. However, the combination of the two drugs resulted in a significant anxiogenic-like effect. In females, the lower dose of CP was anxiogenic and nicotine, which did not induce any effect per se, prevented this response. In the holeboard, subchronic nicotine and the acute cannabinoid treatment interacted in the modulation of horizontal activity and the nature of this interaction also showed a clear sexual dimorphism. Both, the cannabinoid agonist and nicotine increased corticosterone concentrations and the animals receiving the two drugs showed higher levels than the animals receiving the cannabinoid alone. The data provide evidence for the existence of functional interactions between nicotine and cannabinoids in the modulation of behavioural responses and adrenocortical activity in adolescent rats.

Adrenal Cortex↗

PubMed2004

Involvement of 5-HT1A receptors in behavioural effects of the cannabinoid receptor agonist CP 55,940 in male rats.

We have studied the possible interaction between the cannabinoid receptor agonist CP 55,940 (1 and 50 microg/kg) and the 5-HT1A receptor antagonist WAY 100635 (1 mg/kg) in the modulation of plus-maze and holeboard activity in Wistar adult male rats. In the plus-maze, the higher dose of CP 55,940 induced an anxiogenic-like effect, whereas the lower dose induced anxiolytic-like responses. The 5-HT1A antagonist, which was silent in this test, attenuated the anxiogenic, but not the anxiolytic, effect of CP 55,940. In the holeboard, the higher dose of CP 55,940 significantly decreased head-dipping duration, and WAY 100635, which did not affect exploratory head-dipping when administered alone, antagonized this effect. The administration of WAY 100635 significantly increased grooming behaviour, and this effect was inhibited by the two doses of CP 55,940, which did not exert any effect, per se, on this parameter. We provide the first evidence implicating 5-HT1A receptors in anxiety-related behavioural responses to a cannabinoid agonist.

Animals↗

PubMed2003

Involvement of the kappa-opioid receptor in the anxiogenic-like effect of CP 55,940 in male rats.

We have studied the possible interaction between three selective opioid-receptor antagonists, nor-binaltorphimine (NB: kappa) (5 mg/kg), cyprodime (CY: mu) (10 mg/kg) and naltrindole (NTI: delta) (1 mg/kg), and the cannabinoid receptor agonist CP 55,940, in the modulation of anxiety (plus-maze) and adrenocortical activity (serum corticosterone levels by radioimmunoassay) in male rats. The holeboard was used to evaluate motor activity and directed exploration. CP 55,940 (75 microg/kg, but not 10 microg/kg) induced an anxiogenic-like effect, which was antagonised by NB. The other effects of CP 55,940 (75 microg/kg), a decreased holeboard activity and stimulation of adrenocortical activity, were not antagonised by any of the three opioid receptor antagonists. CY and NTI, when administered alone, induced marked reductions in motor activity, anxiogenic-like effects and stimulation of adrenocortical activity. The selective kappa-opioid receptor antagonist NB, on its own, did not modify the level of anxiety but stimulated adrenocortical activity. We provide the first pharmacological evidence about the involvement of the kappa-opioid receptor in the anxiogenic-like effect of CP 55,940.

Animals↗

PubMed2001

Re-evaluation of nestin as a marker of oligodendrocyte lineage cells.

Maturation of oligodendrocyte progenitors (O2A) is characterized by morphological changes and the sequential expression of specific antigens leading to the formation of myelin membrane. Monoclonal antibodies A2B5, A007, anti-vimentin, and anti-galactocerebroside, recognize oligodendroglia at different stages of development. The neuroepithelial precursor marker nestin is also expressed by the oligodendroglial lineage; we have used enriched populations of progenitors isolated from neonatal rat brain cultures to further examine the cellular distribution of this intermediate filament protein. The phenotypic distribution of nestin positive cells among the oligodendrocyte lineage showed that 65% reacted with A2B5, whereas only 5% were A007(+), and 4% galactocerebroside(+). The remaining 25% of the cells were not labeled and had small cellular bodies devoid of processes, characteristic of the pre-O2A progenitor. Further analysis of the nestin(+) population showed that the majority of the cells were also vimentin(+). Antibody-dependent complement mediated cytolysis of A2B5(+) (O2A cells) and galactocerebroside(+) (mature oligodendrocytes) cells left a population of nestin(+) cells that were induced to proliferate in the presence of growth factors and to differentiate into A2B5(+) and galactocerebroside(+) cells. Proliferating cells maintained in the presence of platelet-derived growth factor or basic fibroblast growth factor retained nestin expression along with A2B5. By contrast, in serum-free medium nestin expression decreased while postmitotic cells acquired A007 and galactocerebroside. Our results suggest that nestin expression is a marker of pre-O2A cells that is maintained in proliferating glial progenitors, but is quickly down-regulated in postmitotic oligodendrocytes (A007(+)/galacto-cerebroside(+)) along with A2B5 and vimentin. However, other glial cells including type 2 astrocytes and some amoeboid microglia also share nestin expression.

Animals↗

PubMed2001

LPS/IFN-gamma cytotoxicity in oligodendroglial cells: role of nitric oxide and protection by the anti-inflammatory cytokine IL-10.

Proinflammatory mediators have been implicated in demyelinating disorders, including multiple sclerosis, whereas it has been proposed that the anti-inflammatory cytokines interleukin- (IL-) 4 and IL-10 participate in disease recovery. The present study analysed the effect of interferon-gamma (IFN-gamma) and bacterial endotoxin (lipopolysaccharide, LPS) on proliferation and survival of progenitors and differentiated oligodendrocytes. We also investigated the presence of receptors for IL-4 and IL-10 in oligodendroglial cells and explored a possible protective action of IL-4 and IL-10 in cultures following LPS/IFN-gamma. Finally, the role of endogenous nitric oxide (NO) on cell viability and the modulatory action of IL-4 and IL-10 on inducible nitric oxide synthase (iNOS) expression were also analysed. We report that LPS and/or IFN-gamma reduced proliferation and viability of oligodendroglial cells. Cell death, presumably by apoptosis as evidence by TUNEL and Annexin V binding, was observed following LPS/IFN-gamma, progenitors being more sensitive than differentiated cells. At both developmental stages, LPS/IFN-gamma-treated cultures expressed iNOS protein and released micromolar concentrations of NO. In progenitors, LPS/IFN-gamma-mediated cell damage was partially dependent on endogenous NO production, whereas NO was fundamental for cytotoxicity of differentiated oligodendrocytes. Both cell types expressed mRNA for IL-4 and IL-10 receptors and expression of IL-10 receptors at the protein level was also demonstrated. Treatment with either cytokine inhibited the expression of iNOS resulting from the proinflammatory stimulation. IL-10 was more effective than IL-4 in suppressing iNOS expression and, interestingly, IL-10 conferred protection against oligodendroglial death evoked by LPS/IFN-gamma. Our data raise the question of whether IL-10 may play a protective role in demyelinating diseases, not only downregulating the function of inflammatory cells but also promoting survival of progenitors and differentiated oligodendrocytes.

Animals↗

PubMed2000

Induction of COX-2 and PGE(2) biosynthesis by IL-1beta is mediated by PKC and mitogen-activated protein kinases in murine astrocytes.

Interleukin-1 (IL-1) is an important mediator of immunoinflammatory responses in the brain. In the present study, we examined whether prostaglandin E(2) (PGE(2)) production after IL-1beta stimulation is dependent upon activation of protein kinases in astroglial cells. Astrocyte cultures stimulated with IL-1beta or the phorbol ester, PMA significantly increased PGE(2) secretion. The stimulatory action of IL-1beta on PGE(2) production was totally abolished by NS-398, a specific inhibitor of cyclo-oxygenase-2 activity, as well as by the protein synthesis inhibitor cycloheximide, and the glucocorticoid dexamethasone. Furthermore, IL-1beta induced the expression of COX-2 mRNA. This occurred early at 2 h, with a maximum at 4 h and declined at 12 h. IL-1 beta treatment also induced the expression of COX-2 protein as determined by immunoblot analysis. In that case the expression of the protein remained high at least up to 12 h. Treatment of cells with protein kinase C inhibitors (H-7, bisindolylmaleimide and calphostin C) inhibited IL-1beta stimulation of PGE(2). In addition, PKC-depleted astrocyte cultures by overnight treatment with PMA no longer responded to PMA or IL-1. The ablation of the effects of PMA and IL-1beta on PGE(2) production, likely results from down-regulation of phorbol ester sensitive-PKC isoenzymes. Immunoblot analysis demonstrated the translocation of the conventional isoform cPKC-alpha from cytosol to membrane following treatment with IL-1beta. In addition, IL-1beta treatment led to activation of extracellular signal-regulated kinase (ERK1/2) and p38 subgroups of MAP kinases in astroglial cells. Interestingly, the inhibition of ERK kinase with PD 98059, as well as the inhibition of p38 MAPK with SB 203580, prevented IL-1beta-induced PGE(2) release. ERK1/2 activation by IL-1beta was sensitive to inhibition by the PKC inhibitor bisindolylmaleimide suggesting that ERK phosphorylation is a downstream signal of PKC activation. These results suggest key roles for PKC as well as for ERK1/2 and p38 MAP kinase cascades in the biosynthesis of PGE(2), likely by regulating the induction of cyclo-oxygenase-2, in IL-1beta-stimulated astroglial cells.

Animals↗

PubMed1999

Increased cerebrospinal fluid cAMP levels in Alzheimer's disease.

Since increasing evidence suggests that upregulation of the cAMP-second messenger system may be implicated in Alzheimer's disease neurodegeneration, we have compared the cAMP and cGMP levels in cerebrospinal fluid (CSF) from patients with dementia of the Alzheimer type (DAT, n=10) with those from nondemented age-matched controls (n=10). Our results show that cAMP levels, but not cGMP, are significantly (p<0.01) elevated in CSF from patients with DAT compared to those from nondemented controls. Moreover, a linear regression analysis demonstrated a significant correlation (r=0.62; p<0.01) between cAMP and tau protein levels in CSF when controls and patients with DAT were studied together. These results suggest that upregulation of cAMP-signaling pathway is implicated in Alzheimer's disease physiopathology.

Aged↗

PubMed1999

Dexamethasone regulation of interleukin-1-receptors in the hippocampus of Theiler's virus-infected mice: effects on virus-mediated demyelination.

Intracerebral (i.c.) inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelinating disease. Interleukin-1 receptors are expressed in the brain of mice, in particular in the hippocampus, and have been implicated in neuroimmunoendocrine interactions. In the present study we investigated the regulation of interleukin-1 receptors in the hippocampus of a susceptible (SJL/J) and a resistant (BALB/c) strain of mice infected with TMEV, at different time intervals of the disease. Our results show that interleukin-1 receptors in the hippocampus were decreased in TMEV-infected mice at early times post-infection (10 and 14 days p.i.). The reduction in interleukin-1 receptors only occurred in the susceptible strain of mice (SJL/J), whereas interleukin-1 binding in the hippocampus of TMEV-infected resistant mice (BALB/c) showed values similar to those in control animals. The TMEV-induced down-regulation of interleukin-1 receptors was secondary to a marked decrease in the affinity of the receptor (control: Kd = 10.5 pM; TMEV: Kd = 1.30 pM) accompanied by a decrease in receptor number (control: Bmax = 2.189 fmol/mg protein; TMEV: B max = 0.84 fmol/mg protein). We also investigated the effects of glucocorticoid treatment on the regulation of hippocampal interleukin-1 receptors of TMEV-infected mice. Dexamethasone treatment in the early phase (500 microg/kg or 1 mg/kg during days 5-10 p.i.) of the disease significantly reversed the deficits in hippocampal interleukin-1 receptors observed at 10 days p.i. in SJL/J mice, and suppressed neurological signs of demyelination. These results suggest that: (i) the reduction of interleukin-1 receptors may be a consequence, at least in part, of local production of interleukin-1 at early times during TMEV infection; (ii) interleukin-1 seems to be a critical factor for the susceptibility to TMEV-induced demyelination and (iii) the protective effect of dexamethasone appears to be related to its ability to reverse the reduction in interleukin-1 receptors during the early disease. These results suggest that interleukin-1 is a pivotal mediator in TMEV-induced demyelination.

Animals↗

PubMed1999

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

The effect of a daily injection of the delta-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 degrees 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 delta-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 delta-opioid receptor in the modulation of the adrenocortical response to stress during the postnatal period.

Adrenal Cortex↗

PubMed1999

Changes in several functions of murine peritoneal macrophages by N-acetylcysteine and thioproline ingestion. Comparative effect between two strains of mice.

The administration of the thiol compounds, N-acetylcysteine (NAC) and in particular thioproline (thiazolidine-4-carboxylic acid) at 0.1% w/w concentration in the diet, improves lymphocyte functions in old female Swiss mice, as has been shown in our previous studies. In the present work, adult mice from two different strains, namely BALB/c (an inbred strain) and OF1-Swiss (noninbred strain), were fed a diet supplemented with the above dose of each thiol compound jointly for five weeks. At 28 weeks of age, peritoneal cell suspensions were obtained and different steps of the phagocytic process, the most representative activity of macrophages, as well as interleukin-1beta (IL-1beta) production, were studied. Thus, adherence to substrate, mobility directed to a chemoattractant gradient (chemotaxis), ingestion of inert particles and superoxide anion production were analysed. The results show that diet supplementation with NAC plus thioproline increased all macrophage functions studied with the exception of superoxide anion production, which was decreased. These effects were more evident in macrophages from Swiss mice, whereas in BALB/c mice the stimulation of phagocytosis and IL-1beta production was lower and no differences were seen after treatment in adherence and superoxide anion production. These data suggest that immune function can be improved in adult mice by administration of the above thiol compounds, especially in the noninbred strain of OF1-Swiss mice.

Acetylcysteine↗

PubMed1999

N-Acetyl-cysteine inhibition of encephalomyelitis Theiler's virus-induced nitric oxide and tumour necrosis factor-alpha production by murine astrocyte cultures.

The pathological mechanisms that cause central nervous system (CNS) dysfunction in most neurological diseases are not well established. Theiler's murine encephalomyelitis virus (TMEV) is known to interact with cells of the CNS and its intracerebral inoculation to susceptible mice strains causes neurological disorders resembling multiple sclerosis (MS). In this study, we reported that primary astrocyte cultures from SJL/J susceptible mice when infected with TMEV released important amounts of nitrites (NO2-) to the culture medium, as measured in the supernatants 24 hours after infection. In addition, we observed an increment in the production of tumour necrosis factor alpha (TNF-alpha) by susceptible SJL/J strain derived astrocytes infected with TMEV. The treatment with the thiolic antioxidant N-acetyl-cysteine partially suppressed the virus-stimulated production of nitric oxide and TNF-alpha, in a dose response fashion. These results indicate that during viral infection astrocytes are an important cellular source of nitric oxide and TNF-alpha, substances which play important roles during CNS inflammatory events. The effects of the antioxidant N-acetyl-cysteine, modulating the production of the above compounds by TMEV-infected astrocytes may be a significant factor in preventing CNS demyelination.

Acetylcysteine↗

PubMed1998

The endogenous cannabinoid anandamide potentiates interleukin-6 production by astrocytes infected with Theiler's murine encephalomyelitis virus by a receptor-mediated pathway.

Theiler's murine encephalomyelitis virus (TMEV) infection of a susceptible strain of mice results in virus persistence in the brain and chronic primary immune-mediated demyelination, which resembles multiple sclerosis. Recent attention has focused on the anti-inflammatory and immunosuppressive properties of interleukin-6, a pleiotropic cytokine involved in the regulation of immunological responses, acute phase protein production and hematopoiesis. Anandamide (arachidonoyl ethanolamine) is a natural brain constituent that binds a specific brain cannabinoid receptor. In this study we investigated whether anandamide can modify interleukin-6 production by primary cultures of murine brain cortical astrocytes infected with TMEV. Astrocytes from susceptible (SJL/J) and resistant (BALB/c) strains of mice infected with TMEV (10(5)PFU/well) increased IL-6 release over a period of 24 h. Anandamide caused an enhancement of the release of IL-6 by TMEV-infected astrocytes in a concentration-dependent manner (1-25 microM). Treatment of TMEV-infected astrocytes with 10 microM arachidonyl trifluoromethyl ketone, a potent inhibitor of the amidase that degrades anandamide, was found to potentiate the effects of anandamide on IL-6 release. A novel and selective cannabinoid receptor antagonist, SR 141617A, blocked the enhancing effects of anandamide on IL-6 release by TMEV-infected astrocytes, suggesting a cannabinoid receptor-mediated pathway. The physiological implications of these results are unknown, but may be related to the hypothesis of the protective effects of cannabinoids on neurological disorders like multiple sclerosis.

Animals↗

PubMed1998

Effect of endotoxin and interleukin-1beta on corticotropin-releasing-factor and prostaglandin release by rat brainstem slices.

This study investigated the effects of lipopolysaccharide (LPS) and interleukin-1beta (IL-1beta) on corticotropin releasing factor (CRF) and prostaglandin E2 (PGE2) release by brainstem slices in vitro. First, we characterized our experimental model and demonstrated that high potassium stimulates CRF release from rat brainstem slices in a calcium dependent way. The direct stimulation of brainstem slices with IL-1beta (3-25 pM) did not modify basal or potassium-stimulated CRF release, although IL-1beta at the dose of 25 pM increased PGE2 production. Peripheral injection (i.p.) of LPS (1-10 microg/kg) or IL-1beta (1-10 microg/kg) evoked a dose-related potentiation of the ex-vivo release of CRF and PGE2 from brainstem slices. However, central (i.c.v.) administration of LPS (10-500 ng/rat) potentiated the release of CRF and PGE2 only at the dose of 500 ng/rat, whereas IL-1beta (1-100 ng/rat) failed to modify significantly the ex vivo production of both CRF and PGE2. The results of the present study provide evidence that peripheral, rather than central, endotoxin and IL-1beta administration induce the activation of brainstem CRF and PGE2, supporting the hypothesis that peripheral cytokine signalling to the CNS is mediated by stimulation of peripheral afferents.

Animals↗

PubMed1997

Anandamide suppresses nitric oxide and TNF-alpha responses to Theiler's virus or endotoxin in astrocytes.

Astrocytes are an important cell population in the CNS, involved in cytokine homeostasis and participating in a variety of important physiological and pathological processes. In the present study we showed that primary cultures of neonatal mouse cortical astrocytes stimulated with lipopolysaccharide (Balb/c mice strain, LPS: 1 microgram/ml, 18 h) or Theiler's virus, TMEV (SJL/J mice strain, TMEV: 10(5) PFU/well, 24 h) released an increased amount of nitrites (NO2-) and tumour necrosis factor-alpha (TNF-alpha) into the culture medium. Exogenous cannabinoids are known to modulate the function of immune cells. Anandamide, an endogenous ligand for the cannabinoid receptor, blocked the release of NO2- and TNF-alpha induced by LPS in a dose-dependent manner. In TMEV-stimulated astrocytes anandamide also suppressed, in a dose-related manner, the stimulatory effects of TMEV on both NO2- and TNF-alpha. It is suggested that anandamide exerts an immunoregulatory role in the CNS. These results could have important implications in the modulation of immunological and inflammatory processes by cannabinoid agents.

Animals↗

PubMed1997

Experience-dependent facilitating effect of corticosterone on spatial memory formation in the water maze.

Stress-related adrenal steroid hormones modulate brain and cognitive function. Electrophysiological studies, including primed burst potentiation and long-term potentiation, have indicated concentration-dependent inverted U-shape effects of corticosterone in hippocampal function and plasticity. Here, we explored the role of corticosterone in the consolidation and long-term retrieval of spatial learning in the Morris water maze task in rats. We postulated that corticosterone actions might be experience-dependent with regard to stimulus intensity, such as differential water temperatures. Indeed, rats trained at 19 degrees C showed a quicker rate of acquisition and better long-term retention than rats trained at 25 degrees C water. In addition, post-training corticosterone levels, on the first training day, were significantly higher in rats in the 19 degrees C group than in the 25 degrees C group. Performance of rats trained at 25 degrees C, but not at 19 degrees C, water was improved by injecting them i.p. with corticosterone immediately after each training session. Thus, the effect of exogenously administered corticosterone appears to be experience-dependent, with the experience-induced corticosterone concentrations as a critical factor determining the cognitive consequences of steroid treatment. Therefore, this work indicates a facilitating corticosterone action, during the post-training period, on the neural mechanisms determining the strength of information storage under acute, physiological conditions.

Analysis of Variance↗

PubMed1996

Regional and temporal modulation of brain glycoprotein synthesis by corticosterone.

Corticosterone has a biphasic effect on memory formation, short-term effects being facilitating and long-term effects resulting in cognitive impairments. The effects of different patterns of temporal exposure to corticosterone-previously shown to biphasically modulate water maze performance-on glycoprotein synthesis were evaluated in four rat brain regions: hippocampus, striatum, frontal cortex and hypothalamus. Acute corticosterone administration resulted in decreased glycoprotein synthesis in hippocampus and striatum, which might be related to the memory facilitating effects of the steroid. However, sustained exposure to corticosterone in a subchronic (7 days) or chronic (21 days) regimen indicated the hypothalamus as the only region displaying reduced fucosylation after chronic treatment. These findings suggest that detrimental effects of chronic corticosterone treatment on hippocampal neurones and memory might be not related to an initial steroid action on fucosyl-glycoprotein expression.

Animals↗

PubMed1996

Fibroblast growth factor decreases locomotor activity in rats.

The spontaneous locomotor behavior of rats receiving subcutaneous administration of either acidic or basic fibroblast growth factors was recorded in an activity cage. We report that doses between 1 and 100 micrograms/kg significantly decreased the horizontal and vertical activity, as well as the exploratory and stereotypy behavior of the rats. These effects of fibroblast growth factors seem to be specific since (i) they were cancelled by protein hydrolysis and anti-fibroblast growth factor antibodies, (ii) they were unrelated to their hypotensive activity and (iii) they were not attributable to their high structural similarity with the cytokine interleukin-1. Thus fibroblast growth factors did not show any thermogenic activity, did not affect the hypothalamic output of corticotropin-releasing factor and did not change the plasma levels of corticosterone. Pretreatment of the rats with a specific inhibitor of brain nitric oxide synthase prevented the effects of fibroblast growth factors, suggesting the involvement of nitric oxide in these behavioral modifications. Our results contribute to the accumulating evidence describing non-mitogenic activities of fibroblast growth factors.

Animals↗

PubMed1996

Endotoxin administration induced differential neurochemical activation of the rat brain stem nuclei.

Lipopolisaccharide (LPS) is a potent activator of the immune system, but also activates the hypothalamic-pituitary-adrenocortical (HPA) axis and cerebral catecholamine systems. In the present study, the effect of peripheral LPS administration on catecholaminergic and serotonergic neurotransmission in discrete brainstem nuclei was examined. Two hours following systemic administration of LPS (1, 10, or 100 micrograms/kg) norepinephrine (NE) content in the locus coeruleous (LC) was significantly increased in a dose related manner. An increased dopamine (DA) turnover as reflected by the 3,4-dihydroxyphenylacetic (DOPAC) + Homovanillic acid (HVA)/DA ratio, [DO-PAC + HVA]/[DA], was also observed at the LC with the medium and high doses of LPS administered. Endotoxin caused the main effects in the nucleus of the tractus solitarii (NTS) in which (a) it was found NE content increased in a dose related fashion, (b) DA turnover index was elevated with 10 and 100 micrograms/kg LPS doses, and (c) levels of serotonin (5-HT) and its catabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), were also significantly elevated following the injection of 10 or 100 micrograms/kg LPS. By contrast, a consistent lack of catecholaminergic and serotonergic responses to endotoxin treatment was observed at the level of midbrain Raphe nuclei (MRN). These results demonstrate that differential neurochemical changes may occur in the brainstem region with a rank order of activation by LPS that was NTS > LC > MRN, suggesting different neural substrate for central effects of peripheral immune activation.

Analysis of Variance↗