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1.
Pharmacol Biochem Behav ; 100(2): 330-9, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21893082

ABSTRACT

Several lines of research have now suggested the controversial hypothesis that the central noradrenergic system acts to exacerbate depression as opposed to having an antidepressant function. If correct, lesions of this system should increase resistance to depression, which has been partially but weakly supported by previous studies. The present study reexamined this question using two more recent methods to lesion noradrenergic neurons in mice: intraventricular (ivt) administration of either the noradrenergic neurotoxin, DSP4, or of a dopamine-ß-hydroxylase-saporin immunotoxin (DBH-SAP ITX) prepared for mice. Both agents given 2 weeks prior were found to significantly increase resistance to depressive behavior in several tests including acute and repeated forced swims, tail suspension and endotoxin-induced anhedonia. Both agents also increased locomotor activity in the open field. Cell counts of brainstem monoaminergic neurons, however, showed that both methods produced only partial lesions of the locus coeruleus and also affected the dorsal raphe or ventral tegmental area. Both the cell damage and the antidepressant and hyperactive effects of ivt DSP4 were prevented by a prior i.p. injection of the NE uptake blocker, reboxetine. The results are seen to be consistent with recent pharmacological experiments showing that noradrenergic and serotonergic systems function to inhibit active behavior. Comparison with previous studies utilizing more complete and selective LC lesions suggest that mouse strain, lesion size or involvement of multiple neuronal systems are critical variables in the behavioral and affective effects of monoaminergic lesions and that antidepressant effects and hyperactivity may be more likely to occur if lesions are partial and/or involve multiple monoaminergic systems.


Subject(s)
Biogenic Monoamines/physiology , Brain Stem/metabolism , Cell Nucleus/metabolism , Depression/metabolism , Animals , Biogenic Monoamines/metabolism , Chromatography, High Pressure Liquid , Immunohistochemistry , Locomotion , Male , Mice
2.
Neurosci Lett ; 452(2): 96-100, 2009 Mar 13.
Article in English | MEDLINE | ID: mdl-19383422

ABSTRACT

Animal models are used to decipher the pathophysiology of IFN-alpha-induced psychiatric complications in humans. However, the behavioral effects of IFN-alpha in rodents remain highly controversial. In contrast to homologous IFN-alpha, our recent study revealed that human IFN-alpha, which was used in many previous investigations, had no biological activity in mice. To evaluate the behavioral effects of homologous IFN-alpha in mice, adult C57BL/6J mice were treated with carrier-free murine IFN-alpha and tested on a number of behavioral paradigms. Surprisingly, contrary to previous reports, IFN-alpha treatment decreased the time spent immobile in the forced-swimming test after a single intraperitoneal injection at 2 x 10(6)IU/kg, whereas general locomotor activity was not altered. The elevated plus-maze (EPM) test showed a trend toward an increased anxiety profile in IFN-alpha-treated mice. The tail-suspension and light dark exploration test revealed no difference between IFN-alpha-treated and control animals. Interestingly, neurochemical analysis revealed significantly increased concentrations of tryptophan and 5-hydroxyindoleacetic acid (5-HIAA)/serotonin (5-HT) ratios following IFN-alpha treatment in selected brain regions. Thus, systemic murine IFN-alpha treatment increases swimming time in mice. Increased cerebral serotonin turnover as well as increased tryptophan concentrations, induced by IFN-alpha, implicates serotonergic neurotransmission in behavioral dysfunction caused by this innate immune mediator.


Subject(s)
Anxiety Disorders/chemically induced , Brain/drug effects , Illness Behavior/drug effects , Interferon-alpha/pharmacology , Serotonin/metabolism , Tryptophan/metabolism , Animals , Anxiety/chemically induced , Anxiety/immunology , Anxiety/physiopathology , Anxiety Disorders/immunology , Anxiety Disorders/physiopathology , Brain/immunology , Brain/metabolism , Brain Chemistry/drug effects , Brain Chemistry/immunology , Down-Regulation/drug effects , Down-Regulation/immunology , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Illness Behavior/physiology , Male , Mice , Mice, Inbred C57BL , Motor Activity/drug effects , Motor Activity/immunology , Movement/drug effects , Movement/physiology , Neuropsychological Tests
3.
Synapse ; 62(7): 516-23, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18435418

ABSTRACT

alpha(1)-Adrenoceptors of the locus coeruleus (LC) have been implicated in behavioral activation in novel surroundings, but the endogenous agonist that activates these receptors has not been established. In addition to the canonical activation of alpha(1)-receptors by norepinephrine (NE), there is evidence that dopamine (DA) may also activate certain brain alpha(1)-receptors. This study examined the contribution of DA to exploratory activity in a novel cage by determining the effect of infusion of various dopaminergic and adrenergic drugs into the mouse LC. It was found that the D2/D3 agonist, quinpirole, which selectively blocks the release of CNS DA, produced a dose-dependent and virtually complete abolition of exploration and all movement in the novel cage test. The quinpirole-induced inactivity was significantly attenuated by coinfusion of DA but not by the D1 agonist, SKF38390. Furthermore, the DA attenuation of quinpirole inactivity was blocked by coinfusion of the alpha(1)-adrenergic receptor antagonist, terazosin, but not by the D1 receptor antagonist, SCH23390. LC infusions of either quinpirole or terazosin also produced profound inactivity in DA-beta-hydroxylase knockout (Dbh -/-) mice that lack NE, indicating that their behavioral effects were not due to an alteration of the release or action of LC NE. Measurement of endogenous DA, NE, and 5HT and their metabolites in the LC during exposure to the novel cage indicated an increase in the turnover of DA and NE but not 5HT. These results indicate that DA is a candidate as an endogenous agonist for behaviorally activating LC alpha(1)-receptors and may play a role in the activation of this nucleus by novel surroundings.


Subject(s)
Arousal/physiology , Dopamine/metabolism , Exploratory Behavior/physiology , Locus Coeruleus/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Synaptic Transmission/physiology , Adrenergic alpha-1 Receptor Agonists , Animals , Arousal/drug effects , Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Dopamine beta-Hydroxylase/genetics , Dose-Response Relationship, Drug , Drug Interactions/physiology , Exploratory Behavior/drug effects , Female , Locus Coeruleus/drug effects , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Norepinephrine/biosynthesis , Serotonin/metabolism , Synaptic Transmission/drug effects
4.
Eur J Pharmacol ; 583(2-3): 186-93, 2008 Apr 07.
Article in English | MEDLINE | ID: mdl-18281033

ABSTRACT

Substantial evidence indicates that brain neurons containing and secreting noradrenaline and corticotropin-releasing factor (CRF) are activated during stress, and that physiological and behavioural responses observed during stress can be induced by exogenous administration of CRF and adrenoceptor agonists. This review focusses on the evidence for the involvement of these two factors in stress-related responses, and the inter-relationships between them. The possible abnormalities of these two systems in depressive illness are also discussed.


Subject(s)
Corticotropin-Releasing Hormone/metabolism , Norepinephrine/metabolism , Stress, Physiological/physiopathology , Animals , Brain/metabolism , Brain/physiopathology , Humans , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/physiopathology , Mood Disorders/physiopathology , Pituitary-Adrenal System/metabolism , Pituitary-Adrenal System/physiopathology
5.
Neurochem Int ; 52(6): 1220-5, 2008 May.
Article in English | MEDLINE | ID: mdl-18280616

ABSTRACT

Noradrenergic and corticotropin-releasing factor (CRF) neuronal systems within the brain have been implicated in stress and anxiety. Synaptic release of cerebral norepinephrine (NE) is increased during stress, and following intracerebral CRF administration. Benzodiazepines are commonly used anxiolytic drugs but information on their effects on the stress- and CRF-related release of NE is limited. We have used in vivo microdialysis to test the effects of the benzodiazepine, chlordiazepoxide (CDP) on the noradrenergic responses to footshock and intracerebroventricular CRF in the medial hypothalamus and the medial prefrontal cortex (PFM) of freely moving rats. Footshock (60 x 0.1-0.2 mA shocks in 20 min) significantly increased microdialysate concentrations of NE in the first sample collected after initiating the footshock. In the hypothalamus, microdialysate NE was augmented 64% above baseline. A second footshock session (100 min after the first footshock) increased microdialysate NE to 313% of the baseline. Thus the noradrenergic responses to footshock were enhanced by preceding footshocks. CRF (100 ng) administered into the locus coeruleus (LC) almost tripled microdialysate concentrations of NE in the PFM. CDP (5mg/kg, i.p.) had no statistically significant effects on the basal dialysate concentrations of NE, but it significantly attenuated both footshock- and CRF-induced increases in dialysate NE. CDP may exert a direct inhibitory effect on the noradrenergic neurons, alter the input to LC noradrenergic neurons, or alter the ability of CRF to activate the LC noradrenergic system.


Subject(s)
Cerebral Cortex/drug effects , Chlordiazepoxide/pharmacology , Corticotropin-Releasing Hormone/metabolism , Hypothalamus/drug effects , Norepinephrine/metabolism , Stress, Psychological/drug therapy , Adrenal Cortex Hormones/metabolism , Animals , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/therapeutic use , Anxiety Disorders/drug therapy , Anxiety Disorders/metabolism , Anxiety Disorders/physiopathology , Cerebral Cortex/metabolism , Chlordiazepoxide/therapeutic use , Corticotropin-Releasing Hormone/pharmacology , Drug Interactions/physiology , Electric Stimulation , Extracellular Fluid/drug effects , Extracellular Fluid/metabolism , Hypothalamus/metabolism , Injections, Intraventricular , Locus Coeruleus/drug effects , Locus Coeruleus/metabolism , Male , Microdialysis , Neural Pathways/drug effects , Neural Pathways/metabolism , Rats , Rats, Sprague-Dawley , Stress, Psychological/metabolism , Stress, Psychological/physiopathology , Treatment Outcome
6.
Ann N Y Acad Sci ; 1148: 118-26, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19120099

ABSTRACT

Depressive illness is frequently associated with life stress. Corticotropin-releasing factor (CRF) is believed to be a key brain mediator of behaviors associated with stress, and abnormalities in the function of CRF have been associated with depression. Therefore, we have studied the effects of acute and chronic footshock and restraint in tests used in rodents to assess depression-like activity and antidepressant effects: the forced swim test in rats and mice, and the tail suspension test in mice. We also tested the effect of intracerebroventricular (icv) CRF administration. The results were complex. In the forced swim test in rats, acute footshock and restraint reduced floating, whereas chronic footshock increased floating as did icv CRF. However, chronic restraint induced opposite effects, decreasing floating in the forced swim test. The results from mice were significantly different. In the forced swim test, acute footshock and restraint decreased floating, while chronic footshock increased floating, and chronic restraint decreased floating as it did in rats. However, icv CRF decreased floating. The results from the tail-suspension test paralleled those from the forced swim test except that chronic footshock tended to decrease the time spent immobile. Thus in rats, the behavioral effects of the chronic footshock in the forced swim test could be explained by a desensitization of the CRF systems, either decreased activation of CRF, or desensitization of its receptors. However, such an effect cannot explain the responses to restraint, nor the behavioral effects of chronic footshock and restraint in mice.


Subject(s)
Behavior, Animal , Corticotropin-Releasing Hormone , Depression/physiopathology , Stress, Psychological , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Corticotropin-Releasing Hormone/metabolism , Corticotropin-Releasing Hormone/pharmacology , Disease Models, Animal , Humans , Mice , Motor Activity/drug effects , Motor Activity/physiology , Rats , Restraint, Physical
7.
Behav Brain Res ; 186(1): 32-40, 2008 Jan 10.
Article in English | MEDLINE | ID: mdl-17716752

ABSTRACT

The effects of chronic footshock (CFS) on behavioral responses of CD1 mice to acute footshock and restraint were studied in tests commonly used to assess antidepressant treatments. Adult male mice were subjected to 20 min of footshock daily for 14-16 days, and then tested in the tail suspension test (TST) and the forced swim test (FST). CFS treatment did not alter immobility in the TST when mice were tested before the footshock on that day. However, when the TST was performed after the footshock, immobility decreased in both control and CFS mice. In the FST, chronic footshock significantly increased the time spent floating when mice were tested before footshock on that day. However, when the FST was performed immediately after the footshock, floating decreased in the CFS mice, but not in previously unshocked mice. Restraint, shortly before the FST, decreased floating in both CFS and unshocked mice. Thus, CFS induced depression-like activity in the FST, but not in the TST, whereas acute footshock or restraint immediately before testing induced antidepressant-like effects in both the TST and the FST. In unshocked mice, intracerebroventricular corticotropin-releasing factor (CRF) consistently decreased immobility in the TST and the FST, with significant effects at the 100ng dose. The same dose of CRF depressed activity in the open field, so that these changes in immobility are unlikely to reflect a change in overall activity. CRF thus mimicked the effects of the acute stressors in the TST and the FST. Responses to icv CRF were attenuated by chronic footshock suggesting that CFS desensitizes the brain to CRF. CFS treatment did not alter basal concentrations of ACTH and corticosterone in blood plasma. Acute footshock increased the plasma concentrations of the hormones but in CFS mice these responses were attenuated, significantly for plasma ACTH. Acute footshock activated brain dopamine, norepinephrine and serotonin metabolism, and increased tryptophan concentrations in the brain. In CFS mice, these responses were attenuated, significantly for hypothalamic NE.


Subject(s)
Corticotropin-Releasing Hormone/physiology , Depression/metabolism , Exploratory Behavior/physiology , Immobility Response, Tonic/physiology , Stress, Psychological/metabolism , Acute Disease , Adaptation, Psychological , Adrenocorticotropic Hormone/blood , Analysis of Variance , Animals , Brain/metabolism , Chronic Disease , Corticosterone/blood , Corticotropin-Releasing Hormone/administration & dosage , Disease Models, Animal , Dopamine/metabolism , Injections, Intraventricular , Male , Mice , Norepinephrine/metabolism , Restraint, Physical , Serotonin/metabolism , Statistics, Nonparametric
8.
Behav Brain Res ; 183(2): 178-87, 2007 Nov 02.
Article in English | MEDLINE | ID: mdl-17645963

ABSTRACT

The effects of chronic footshock (CFS) or chronic restraint (CRS) on the behavioral responses to acute footshock and corticotropin-releasing factor (CRF) were studied. Male rats were subjected to either footshock or restraint daily, or left undisturbed (Quiet). After 7 or 14 days treatment, they were placed in an unfamiliar footshock chamber and three footshocks administered at 20s intervals and subsequent freezing and ultrasonic vocalizations (USV's) were recorded. Context-conditioned freezing and USV's were recorded when rats were replaced in the chamber in which they had received the three footshocks. Prior CFS treatment decreased acute footshock-induced freezing and USV's, whereas it increased conditioned freezing and slightly increased conditioned USV's. CRS did not affect footshock-induced freezing, but in contrast to CFS, strongly increased USV's. Intracerebroventricular CRF (30 or 100ng) alone did not elicit freezing in either Quiet or CFS rats, nor did it have any effect on shock-induced freezing in either group. However, CRF increased conditioned freezing in Quiet, but not in CFS rats. CRF alone did not trigger USV's, but slightly increased shock-induced USV's in both Quiet and CFS rats, and significantly increased conditioned USV's in CFS rats. In the forced swim test (FST), chronic footshock did not induce consistent effects, although there was a trend to increased immobility. However, CRF increased immobility. In striking contrast to CFS, chronic restraint consistently decreased immobility. It is concluded that chronic stress has lasting effects on defensive responses. However, not all chronic stress procedures exert the same effects and thus different forms of stress may activate different neural mechanisms. The fact that CFS diminished shock-induced freezing and the effects of CRF on conditioned freezing suggests that CFS desensitizes the brain to CRF. On the other hand, the enhancement of conditioned freezing by CFS, and of conditioned USV's by CRF in CFS rats, indicates more complex effects.


Subject(s)
Corticotropin-Releasing Hormone/administration & dosage , Electroshock , Freezing Reaction, Cataleptic/drug effects , Restraint, Physical , Stress, Psychological/drug therapy , Stress, Psychological/etiology , Vocalization, Animal/drug effects , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Disease Models, Animal , Dose-Response Relationship, Drug , Freezing Reaction, Cataleptic/physiology , Male , Rats , Rats, Sprague-Dawley , Swimming , Time Factors , Ultrasonics , Vocalization, Animal/physiology
9.
Pharmacol Biochem Behav ; 86(4): 651-9, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17360031

ABSTRACT

It has been postulated that infections, inflammatory processes and resulting cytokines may be causative factors in emotional disorders, including depression and anxiety. Support for this possibility has been sought in studies of animal behavior following administration of interleukin-1 (IL-1) and lipopolysaccharide (LPS). However, such treatments induce a variety of behavioral responses, collectively known as sickness behavior, some of which could affect the performance in tests used to assess anxiety and depression. Thus the effects of peripheral administration of IL-1beta and LPS on the behavior of mice were studied in the elevated plus-maze (EPM) and the open field (OF). Mouse IL-1beta (30, 100, 300, and 1000 ng) was injected intraperitoneally 30 or 60 min, and LPS (0.5, 1 and 5 microg) 120 min before the tests. IL-1beta and LPS induced dose-dependent decreases in open arm entries and the time spent on the open arms in the EPM, effects considered to reflect anxiety-like behavior. However, entries to all arms were also reduced in a dose-dependent manner, indicating a decrease in general activity. In the OF, IL-1beta and LPS decreased the number of line crossings in the center of the field, that can also be considered to reflect anxiety-like behavior. However, this effect was accompanied by a similar decrease in line crossings in the periphery, as well as in rears and climbs. Thus the doses of IL-1beta and LPS necessary to induce these effects also decreased locomotor activity in the EPM and OF. Therefore, the behavioral responses induced by IL-1beta and LPS in the EPM and the OF considered to reflect anxiety must be interpreted in the light of this reduction in overall activity. Thus the results do not provide unequivocal support for the suggestion that LPS or IL-1 mediate anxiety. Nevertheless, because infections, endotoxins, and the ensuing cytokines cause alterations in CNS norepinephrine and serotonin, they may contribute to emotionality, and perhaps to anxiety.


Subject(s)
Behavior, Animal/drug effects , Interleukin-1beta/pharmacology , Lipopolysaccharides/pharmacology , Maze Learning/drug effects , Animals , Anxiety/etiology , Anxiety/physiopathology , Behavior, Animal/physiology , Cytokines/physiology , Disease Models, Animal , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Humans , Infections/complications , Infections/physiopathology , Inflammation/complications , Inflammation/physiopathology , Male , Maze Learning/physiology , Mice , Motor Activity/drug effects , Motor Activity/physiology , Recombinant Proteins/pharmacology
10.
Neuroimmunomodulation ; 13(2): 96-104, 2006.
Article in English | MEDLINE | ID: mdl-17047394

ABSTRACT

UNLABELLED: Previous studies have shown that interleukin-1 (IL-1) and lipopolysaccharide (LPS) administration to animals induces behavioral changes, including a reduction in feeding. These effects of IL-1 and LPS have been shown to be sensitive to inhibitors of cyclooxygenase (COX). OBJECTIVES: To determine the relationships between induction of COX-2 in the brain with IL-1beta- and LPS-induced changes in body temperature, plasma corticosterone and feeding. METHODS: Mice were injected with intraperitoneal doses of IL-1beta and LPS that decreased feeding. The induction of COX-2 was studied immunocytochemically in the brain, in parallel with core body temperature, the drinking of sweetened milk, and plasma concentrations of corticosterone. RESULTS: COX-2 immunoreactivity (ir) was sparse in the brains of the untreated mice, but IL-1beta and LPS both increased its expression. This COX-2 induction appeared to be confined to blood vessels, and was not markedly region specific. Induction was evident 30 min after IL-1 or LPS, and was greater at 90 than at 30 min. COX-2-ir in the parenchyma did not change significantly. Thus induction of COX-2 occurred in brain endothelia in parallel with the reduction in feeding. This is consistent with the previously determined sensitivity of IL-1-induced changes in feeding to selective COX-2 inhibitors, and the responses to IL-1 in COX-2-deficient mice. The time courses of the IL-1- and LPS-induced increases in plasma corticosterone paralleled those in the reduction in milk drinking, however, the changes in body temperature appeared later. CONCLUSIONS: Endothelial COX-2 may be involved in IL-1- and LPS-induced decreases in milk drinking, and possibly in the HPA axis activation. The decreased milk drinking may occur when IL-1 and LPS bind to receptors on brain endothelial cells subsequently inducing COX-2 and the production of prostanoids which elicit the reductions in milk drinking. Thus the behavioral effects of peripherally administered IL-1 and LPS appear to be mediated by multiple mechanisms, including endothelial COX-2, and vagal afferents.


Subject(s)
Brain/enzymology , Cyclooxygenase 2/metabolism , Endothelial Cells/enzymology , Feeding and Eating Disorders/enzymology , Feeding and Eating Disorders/immunology , Sick Role , Animals , Appetite Regulation/drug effects , Appetite Regulation/immunology , Body Temperature/drug effects , Body Temperature/immunology , Brain/blood supply , Brain/physiopathology , Cerebral Arteries/drug effects , Cerebral Arteries/enzymology , Cerebral Arteries/immunology , Corticosterone/blood , Corticosterone/metabolism , Cyclooxygenase 2/drug effects , Cyclooxygenase 2/immunology , Disease Models, Animal , Endothelial Cells/immunology , Feeding Behavior/drug effects , Feeding Behavior/physiology , Feeding and Eating Disorders/physiopathology , Hypothalamo-Hypophyseal System/immunology , Hypothalamo-Hypophyseal System/physiopathology , Immunohistochemistry , Inflammation/chemically induced , Inflammation/complications , Inflammation/immunology , Inflammation Mediators/pharmacology , Interleukin-1/pharmacology , Lipopolysaccharides/pharmacology , Male , Mice , Milk/metabolism , Time Factors , Vagus Nerve/drug effects , Vagus Nerve/immunology , Visceral Afferents/drug effects , Visceral Afferents/immunology
11.
Brain Res ; 1101(1): 73-84, 2006 Jul 26.
Article in English | MEDLINE | ID: mdl-16784727

ABSTRACT

The vagus nerve is thought to participate in signal transduction from the immune system to the CNS. The role of the vagus in the physiological, behavioral and neurochemical responses to intraperitoneally (ip) injected interleukin-1beta (IL-1beta) was studied using awake subdiaphragmatically vagotomized rats. The rats were injected ip with saline and IL-1beta (1 microg/rat) in random order. For the next 2-4 h, they were monitored for locomotor activity, body temperature via abdominally implanted telethermometers, hypothalamic norepinephrine (NE) secretion using in vivo microdialysis and blood sampled via intravenous catheters to determine concentrations of ACTH and corticosterone to assess hypothalamo-pituitary-adrenocortical (HPA) axis activation. Saline injections were followed by transient increases in locomotor activity, body temperature, dialysate NE and plasma concentrations of ACTH and corticosterone. These responses were not significantly altered by vagotomy. IL-1beta injections resulted in short-lived increases in shivering and longer decreases in locomotor activity, as well as a delayed modest fever. IL-1beta also induced prolonged elevations of hypothalamic microdialysate NE, as well as plasma ACTH and corticosterone. Similar responses were observed regardless of the order of the saline and IL-1beta injections. Subdiaphragmatic vagotomy prevented the IL-1-induced increases in body temperature and the increase in dialysate NE, and markedly attenuated the increases in plasma ACTH and corticosterone. The results indicate close temporal relationships between the apparent release of NE and the increase in body temperature and the HPA activation. This together with the effects of vagotomy suggests that the activation of NE in turn increases body temperature and activates the HPA axis. However, because IL-1beta induces a limited HPA activation in subdiaphragmatically vagotomized rats, the vagus nerve does not appear to be the only route by which ip IL-1beta can activate the HPA axis. It is suggested that IL-1beta-induced vagal activation of hypothalamic NE is the major mechanism of HPA activation at low doses of IL-1beta. However, IL-1beta can also exert direct effects on IL-1 receptors on cerebral blood vessels, activating cyclooxygenases and hence synthesis of prostaglandins which in turn can affect body temperature, behavior and HPA axis activation.


Subject(s)
Hypothalamo-Hypophyseal System/drug effects , Interleukin-1/administration & dosage , Norepinephrine/metabolism , Pituitary-Adrenal System/drug effects , Vagotomy , Adrenocorticotropic Hormone/blood , Analysis of Variance , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Body Temperature/drug effects , Chromatography, High Pressure Liquid/methods , Corticosterone/blood , Hypothalamo-Hypophyseal System/metabolism , Injections, Intraperitoneal/methods , Male , Microdialysis/methods , Motor Activity/drug effects , Motor Activity/physiology , Pituitary-Adrenal System/metabolism , Rats , Rats, Sprague-Dawley , Shivering/drug effects
12.
Behav Brain Res ; 171(1): 94-108, 2006 Jul 15.
Article in English | MEDLINE | ID: mdl-16677721

ABSTRACT

Interleukin-6 (IL-6) has been implicated in behavioral responses associated with inflammation, sickness behavior and various nervous system disorders. We studied a range of different behaviors in IL-6-knockout (IL-6ko) and wild-type (WT) male mice. No significant differences were observed in ambulatory, exploratory, and stereotypic activities in home or novel cages, in an open field (OF), in the multicompartment chamber (MCC), or in the elevated plus-maze (EPM). IL-6ko mice shed fewer fecal boli than WT mice in the OF, in novel cages and in the MCC although this effect was not statistically significant in the OF. In novel cages, intraperitoneal (i.p.) injection of IL-6 (1 microg) depressed ambulatory activity slightly more in IL-6ko than in WT mice. Restraint and interleukin-1beta (IL-1beta, 100 ng i.p.) decreased exploration of mice in the MCC and EPM, but there was no indication of altered sensitivity in IL-6ko mice. No significant differences were detected in the tail suspension and the Porsolt forced swim tests. IL-1beta and lipopolysaccharide (LPS 1 microg i.p.) injection depressed sweetened milk and solid food intake similarly in IL-6ko and WT mice, but IL-6 had no effect, suggesting that IL-6 is not involved in these effects of IL-1 or LPS. However, IL-1beta and LPS depressed body weight more in WT than in IL-6ko mice. Plasma corticosterone and basal concentrations of catecholamines, indoleamines and their metabolites in several brain regions were similar. The responses in these measures to IL-1beta and LPS were also similar, except that there were no significant changes in tryptophan and serotonin metabolism in IL-6ko mice. This may reflect a role for IL-6 in the tryptophan and serotonin responses to IL-1 and LPS. It is concluded that the lack of IL-6 is not associated with substantial alterations in several different mouse behaviors, and in the responses to restraint, IL-1beta, IL-6 and LPS.


Subject(s)
Anxiety/blood , Depression/blood , Exploratory Behavior/physiology , Feeding Behavior/physiology , Interleukin-6/immunology , Adrenocorticotropic Hormone/blood , Analysis of Variance , Animals , Anxiety/immunology , Biogenic Amines/metabolism , Brain/immunology , Brain/metabolism , Corticosterone/blood , Depression/immunology , Eating/immunology , Interleukin-1/physiology , Interleukin-6/genetics , Lipopolysaccharides/immunology , Male , Mice , Mice, Inbred BALB C , Mice, Knockout , Motor Activity/immunology , Restraint, Physical , Sick Role , Stress, Psychological/immunology , Stress, Psychological/metabolism
13.
Brain Behav Immun ; 20(5): 477-87, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16330180

ABSTRACT

Peripheral administration of interleukin-1 (IL-1) is known to activate the hypothalamo-pituitary-adrenal axis (HPA axis) and brain noradrenergic systems. We studied the relationship between these responses using in vivo microdialysis to assess the release of hypothalamic norepinephrine (NE), while simultaneously sampling blood for ACTH and corticosterone, and monitoring body temperature and behavior in freely moving rats. Rats were implanted with microdialysis probes in the medial hypothalamus, with intravenous catheters, and with telethermometers in the abdomen. Each rat was injected with saline and IL-1beta (1 microg ip) in random order, monitoring microdialysate NE, body temperature and plasma ACTH and corticosterone for 2-4 h after injection. Saline injections were followed by transient increases in microdialysate NE and in plasma ACTH and corticosterone. IL-1beta injections resulted in prolonged elevations of microdialysate NE, as well as plasma ACTH and corticosterone, and body temperature. IL-1beta also induced shivering and a prolonged depression of locomotor activity. Pretreatment with indomethacin (10 mg/kg sc) prevented the IL-1beta-induced increases in body temperature and the apparent increase in hypothalamic NE release, but only attenuated the IL-1beta-induced shivering and the increase in plasma ACTH. The results indicate a close temporal relationship between the release of NE and HPA axis activation. Such a relationship is also supported by the similar effects of indomethacin pretreatment on NE and ACTH. The shivering is likely involved in the increase in body temperature, but indomethacin only attenuated the shivering while it blocked the fever. However, the effects of indomethacin clearly indicate that neither the increase in body temperature nor the increase in hypothalamic NE release was essential for HPA axis activation. These results suggest that hypothalamic NE is involved in the IL-1-induced HPA axis activation, but that this is not the only mechanism by which the HPA axis is activated by intraperitoneally injected IL-1.


Subject(s)
Adrenocorticotropic Hormone/blood , Hypothalamus/metabolism , Interleukin-1/physiology , Norepinephrine/metabolism , Pituitary-Adrenal System/metabolism , Analysis of Variance , Animals , Body Temperature/drug effects , Corticosterone/blood , Cyclooxygenase Inhibitors/administration & dosage , Drug Administration Schedule , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/metabolism , Hypothalamus/drug effects , Indomethacin/administration & dosage , Interleukin-1/administration & dosage , Male , Microdialysis , Motor Activity/immunology , Pituitary-Adrenal System/drug effects , Random Allocation , Rats , Rats, Sprague-Dawley , Shivering/drug effects , Shivering/immunology , Statistics, Nonparametric , Time Factors
14.
Clin Neurosci Res ; 6(1-2): 52-68, 2006 Aug.
Article in English | MEDLINE | ID: mdl-18079991

ABSTRACT

Administration of cytokines to animals can elicit many effects on the brain, particularly neuroendocrine and behavioral effects. Cytokine administration also alters neurotransmission, which may underlie these effects. The most well studied effect is the activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, especially that by interleukin-1 (IL-1). Peripheral and central administration of IL-1 also induces norepinephrine (NE) release in the brain, most markedly in the hypothalamus. Small changes in brain dopamine (DA) are occasionally observed, but these effects are not regionally selective. IL-1 also increases brain concentrations of tryptophan, and the metabolism of serotonin (5-HT) throughout the brain in a regionally nonselective manner. Increases of tryptophan and 5-HT, but not NE, are also elicited by IL-6, which also activates the HPA axis, although it is much less potent in these respects than IL-1. IL-2 has modest effects on DA, NE and 5-HT. Like IL-6, tumor necrosis factor-α (TNFα) activates the HPA axis, but affects NE and tryptophan only at high doses. The interferons (IFN's) induce fever and HPA axis activation in man, but such effects are weak or absent in rodents. The reported effects of IFN's on brain catecholamines and serotonin have been very varied. However, interferon-γ, and to a lesser extent, interferon-α, have profound effects on the catabolism of tryptophan, effectively reducing its concentration in plasma, and may thus limit brain 5-HT synthesis.Administration of endotoxin (LPS) elicits responses similar to those of IL-1. Bacterial and viral infections induce HPA activation, and also increase brain NE and 5-HT metabolism and brain tryptophan. Typically, there is also behavioral depression. These effects are strikingly similar to those of IL-1, suggesting that IL-1 secretion, which accompanies many infections, may mediate these responses. Studies with IL-1 antagonists, support this possibility, although in most cases the antagonism is incomplete, suggesting the existence of multiple mechanisms. Because LPS is known to stimulate the secretion of IL-1, IL-6 and TNFα, it seems likely that these cytokines mediate at least some of the responses, but studies with antagonists indicate that there are multiple mechanisms. The neurochemical responses to cytokines are likely to underlie the endocrine and behavioral responses. The NE response to IL-1 appears to be instrumental in the HPA activation, but other mechanisms exist. Neither the noradrenergic nor the serotonergic systems appear to be involved in the major behavioral responses. The significance of the serotonin response is unknown.

15.
Neurochem Res ; 30(12): 1543-8, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16362773

ABSTRACT

Changes in brain tryptophan concentrations may affect the synthesis of brain serotonin (5-hydroxytryptamine, 5-HT). Concentrations of tryptophan are regulated more than those of any other amino acid. Such stimuli as acute stress, carbohydrate ingestion, and treatment with various drugs increase the brain content of tryptophan. Treatment of rats and mice with interleukin-1 (IL-1), interleukin-6 (IL-6), lipopolysaccharide (LPS), and beta-adrenoceptor agonists, as well as a variety of stressors, such as footshock and restraint, all increase brain concentrations of tryptophan. The peak effect following both acute stress and beta-adrenoceptor agonist administration occurs within 30-60 min, whereas the peak effect following LPS and the cytokines occurs much later at around 4-8 h. Experiments using the ganglionic blocker chlorisondamine, and beta-adrenoceptor antagonists suggest that the sympathetic nervous system plays an important role in the modulation of brain tryptophan concentrations. The mechanisms involved in the increases observed in brain tryptophan are discussed, as well as their possible biological significance.


Subject(s)
Brain/metabolism , Tryptophan/metabolism , Animals , Receptors, Adrenergic, beta/metabolism , Stress, Physiological/metabolism
16.
Physiol Behav ; 85(4): 500-11, 2005 Jul 21.
Article in English | MEDLINE | ID: mdl-15996692

ABSTRACT

It is well established that peripheral administration of interleukin-1 (IL-1) and lipopolysaccharide (LPS) can activate the hypothalamo-pituitary-adrenocortical (HPA) axis, alter brain catecholamine and indoleamine metabolism, and affect behavior. However, the mechanisms of these effects are not fully understood. Stimulation of afferents of the vagus nerve has been implicated in the induction of Fos in the brain, changes in body temperature, brain norepinephrine, and some behavioral responses. In the present study, the IL-1beta- and LPS-induced changes in certain behaviors, HPA axis activation, and catecholamine and indoleamine metabolism were studied in mice following subdiaphragmatic vagotomy. IL-1beta and LPS induced the expected decreases in sweetened milk, food intake, and locomotor activity, and the responses to IL-1beta, but not LPS, were slightly attenuated in vagotomized mice. Subdiaphragmatic vagotomy also attenuated the IL-1beta- and LPS-induced increases in plasma ACTH and corticosterone, but the attenuations of the responses to IL-1beta were only marginally significant. There were also slight reductions in the responses in catecholamine and serotonin metabolism, and the increases in brain tryptophan in several brain regions. These results indicate that the vagus nerve is not the major pathway by which abdominal IL-1beta and LPS effect behavioral, HPA and brain catecholamine and indoleamine responses in the mouse. These results resemble those we observed in subdiaphragmatically vagotomized rats, but in that species the subdiaphragmatic vagotomy markedly attenuated the ACTH and corticosterone responses, and prevented the hypothalamic noradrenergic activation, as well as the fever. Overall the results indicate that the various responses to peripheral IL-1 and LPS involve multiple mechanisms including vagal afferents, and that there are species differences in the relative importance of the various mechanisms.


Subject(s)
Behavior, Animal/drug effects , Hypothalamo-Hypophyseal System/drug effects , Interleukin-1/administration & dosage , Lipopolysaccharides/administration & dosage , Pituitary-Adrenal System/drug effects , Vagotomy , 3,4-Dihydroxyphenylacetic Acid/blood , Adrenocorticotropic Hormone/blood , Analysis of Variance , Animals , Body Weight/drug effects , Brain/anatomy & histology , Brain/drug effects , Brain Chemistry/drug effects , Catecholamines/blood , Corticosterone/blood , Eating/drug effects , Eating/physiology , Hydroxyindoleacetic Acid/metabolism , Hypothalamo-Hypophyseal System/physiology , Male , Mice , Milk/metabolism , Motor Activity/drug effects , Motor Activity/physiology , Pituitary-Adrenal System/physiology
17.
Pharmacol Biochem Behav ; 81(3): 688-93, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15982728

ABSTRACT

Male CD-1 mice were administered interleukin-1beta (IL-1beta) and bacterial endotoxin (lipopolysaccharide, LPS) and subsequently tested in the tail suspension test (TST), the Porsolt forced swim test (FST), and in the open field. IL-1beta (100, 300 and 1000 ng/mouse) injected intraperitoneally (i.p.) 90 min before the test induced a dose-dependent increase in the time spent immobile in the TST and the time spent floating in the FST. These responses were statistically significant only at the higher doses of IL-1beta (300 and 1000 ng). Nevertheless, all three doses of IL-1beta significantly decreased line crossings and rears in the open field and depressed food intake and body weight. Very similar effects were induced by LPS. Doses of 1 and 5 mug i.p. increased immobility time in the TST and floating time in the FST, but the same doses strongly depressed locomotor activity and body weight. These results indicate that both IL-1beta and LPS can induce depression-like effects in the TST and the FST. However, the doses necessary to induce these changes reduced feeding and activity in an open field, so that the effects observed in the FST and TST could be attributed to a general reduction in locomotor activity. Thus the results obtained in these two animal tests commonly used to test antidepressant properties do not provide strong support for an IL-1 hypothesis of depression.


Subject(s)
Interleukin-1/pharmacology , Lipopolysaccharides/pharmacology , Motor Activity/drug effects , Animals , Behavior, Animal/drug effects , Body Weight/drug effects , Dose-Response Relationship, Drug , Eating/drug effects , Hindlimb Suspension/physiology , Hindlimb Suspension/psychology , Injections, Intraperitoneal , Interleukin-1/administration & dosage , Lipopolysaccharides/administration & dosage , Male , Mice , Swimming/physiology , Swimming/psychology
18.
Neurosci Biobehav Rev ; 29(4-5): 891-909, 2005.
Article in English | MEDLINE | ID: mdl-15885777

ABSTRACT

It has recently been postulated that cytokines may cause depressive illness in man. This hypothesis is based on the following observations: 1. Treatment of patients with cytokines can produce symptoms of depression; 2. Activation of the immune system is observed in many depressed patients; 3. Depression occurs more frequently in those with medical disorders associated with immune dysfunction; 4. Activation of the immune system, and administration of endotoxin (LPS) or interleukin-1 (IL-1) to animals induces sickness behavior, which resembles depression, and chronic treatment with antidepressants has been shown to inhibit sickness behavior induced by LPS; 5. Several cytokines can activate the hypothalamo-pituitary-adrenocortical axis (HPAA), which is commonly activated in depressed patients; 6. Some cytokines activates cerebral noradrenergic systems, also commonly observed in depressed patients; 7. Some cytokines activate brain serotonergic systems, which have been implicated in major depressive illness and its treatment. The evidence for each of these tenets is reviewed and evaluated along with the effects of cytokines in classical animal tests of depression. Although certain sickness behaviors resemble the symptoms of depression, they are not identical and each has distinct features. Thus the value of sickness behavior as an animal model of major depressive disorder is limited, so that care should be taken in extrapolating results from the model to the human disorder. Nevertheless, the model may provide insight into the etiology and the mechanisms underlying some symptoms of major depressive disorder. It is concluded that immune activation and cytokines may be involved in depressive symptoms in some patients. However, cytokines do not appear to be essential mediators of depressive illness.


Subject(s)
Cytokines/adverse effects , Depression/etiology , Depression/immunology , Depressive Disorder/etiology , Depressive Disorder/immunology , Disease Models, Animal , Animals , Antidepressive Agents/therapeutic use , Behavior, Animal , Brain Chemistry , Cytokines/metabolism , Depression/drug therapy , Depression/metabolism , Depressive Disorder/drug therapy , Depressive Disorder/metabolism , Humans , Immune System Diseases/complications , Immune System Diseases/metabolism , Models, Immunological , Psychoneuroimmunology , Serotonin/metabolism
19.
Neurochem Int ; 46(2): 179-87, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15627518

ABSTRACT

We tested the hypothesis that beta2- and beta3-adrenergic receptor-mediated increases in brain tryptophan are due to the liberation of fatty acids, which in turn displace tryptophan from its albumin-binding site and thus facilitate its entry into the brain. Male CD-1 mice were injected with subtype-selective beta-adrenergic agonists 1h before brain samples were collected for analysis of tryptophan content by HPLC with electrochemical detection, and blood samples were collected for analysis of total and free tryptophan and nonesterified fatty acid (NEFA) concentrations. The beta2-selective agonist, clenbuterol (0.1 mg/kg), increased concentrations of tryptophan in all brain regions studied and decreased plasma total tryptophan, but had no effect on plasma free tryptophan or NEFAs. The beta3-selective agonists, BRL 37344 (0.2 mg/kg) or CL 316243 (0.01 mg/kg), increased brain tryptophan, plasma NEFAs and free tryptophan. Pretreatment with nicotinic acid (500 mg/kg), an inhibitor of lipolysis, almost completely prevented the increase in plasma free tryptophan and NEFAs, and attenuated the increase in brain tryptophan induced by CL 316243. These results suggest that beta2- and beta3-adrenergic agonists increase brain tryptophan by a mechanism other than the liberation of NEFAs. Nonetheless, beta3-adrenergic agonists appear to increase brain tryptophan by a mechanism that may depend partially on elevations of plasma NEFAs.


Subject(s)
Adrenergic beta-Agonists/pharmacology , Brain Chemistry/physiology , Fatty Acids, Nonesterified/metabolism , Receptors, Adrenergic, beta/physiology , Tryptophan/metabolism , Adrenergic beta-2 Receptor Agonists , Animals , Binding, Competitive/drug effects , Brain Chemistry/drug effects , Clenbuterol/pharmacology , Dioxoles/pharmacology , Ethanolamines/pharmacology , Hypolipidemic Agents/pharmacology , Male , Mice , Niacin/pharmacology , Oleic Acid/pharmacology , Serum Albumin/drug effects , Serum Albumin/metabolism , Tryptophan/blood
20.
Magn Reson Chem ; 43(2): 124-31, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15593356

ABSTRACT

A method of speeding up the acquisition of 1H-13C correlation data has been developed. It is applicable in situations where the experiment time is determined by the need to sample the second dimension adequately rather than by signal-to-noise ratio requirements. Two spectra with different, reduced, 13C sweep widths are measured, time being saved by reducing the number of increments in line with the reduction in the sweep width. Rules are presented for the selection of the two reduced sweep widths so that the correct 13C chemical shifts can be easily and unambiguously calculated. The benefits and limitations of this approach, in the context of the structure confirmation of small (MW < or = 450) organic compounds, is discussed. The use of a third spectrum to resolve problems that may be encountered when proton signals overlap is demonstrated.

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