The effect of LPS on emotions and social behavior.

LPS affects social interaction
LPS inducing fear and anxiety
LPS increases tendency for addiction.
LPS might might precipitate alcohol drinking behavior
Some of the physiological consequences of LPS are mediated by endogenous opioid peptides.

LPS affects social interaction

Mice injected with LPS showed a marked reduction in social behavior. Lurcher Mice who have a chronic inflammatory state show an even greater sensitivity to LPS. This decrease in social behavior was significantly more pronounced in Lurcher than in wild type mice. Children with ASD also have a chronic inflamation and this increases the effect from LPS. The good news is that the social inhibition produced by LPS is temporary. Once the gram negative bacteria leave the body, there will be a restoration of social behavior.

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1: Brain Behav Immun. 2004 Mar;18(2):149-57.

Alpha-tocopherol attenuates lipopolysaccharide-induced sickness behavior in mice.

Berg BM, Godbout JP, Kelley KW, Johnson RW.

Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801, USA.

Antioxidants protect cells from oxidative damage and reduce lipopolysaccharide (LPS)-induced expression of inflammatory cytokines. Because inflammatory cytokines induce sickness behavior, we hypothesized that antioxidants, namely alpha-tocopherol (alpha-T) and selenium would inhibit sickness behavior caused by LPS. In an initial study, mice were injected intraperitoneal (i.p.) with vehicle, 2, or 20mg alpha-T for 3 consecutive days and then challenged with vehicle, 1, 10, or 100 microg of LPS. Sickness behavior was quantified by measuring social exploratory behavior. Vehicle pretreated mice injected with LPS showed a marked reduction in social behavior at 4h (p < .01). However, sickness behavior induced by the lowest dose of LPS was partially or completely blocked by 2 or 20mg alpha-T, respectively. alpha-T did not prevent sickness from higher doses of LPS. In a second study, mice were fed AIN93-M modified diets containing 10, 75, and 500 mg alpha-T/kg and 0.05, 0.15, and 2mg selenium/kg for 8 weeks and then challenged with saline or LPS (1 microg). The highest concentration of dietary alpha-T and selenium tended (p = .1) to reduce LPS-induced sickness behavior. Mice fed diets low in antioxidants had reduced plasma alpha-T levels and glutathione peroxidase activity (p = .08 and p < .01, respectively) and elevated liver thiobarbituric acid reactive substances (p < .001) 24h post LPS. Collectively, these data indicate that alpha-T improved the oxidative status after exposure to LPS, which may explain its ability to ameliorate symptoms of sickness.

PMID: 14759592 [PubMed - indexed for MEDLINE]

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Hypersensitivity of lurcher mutant mice to the depressing effects of lipopolysaccharide and interleukin-1 on behaviour.

Neuroreport. 8(5):1119-1122, March 24, 1997.
Bluthe, Rose-Marie 1,3; Michaud, Bruno 1; Delhaye-Bouchaud, Nicole 2; Mariani, Jean 2; Dantzer, Robert 1

Abstract: LURCHER mutant mice are characterized by a fast and almost total loss of olivocerebellar neurones during the first postnatal month, associated with a chronic inflammatory state. To test their brain sensivity to proinflammatory cytokines, we assessed the behavioural responses of adult male Lurcher and wild type to an i.p. or i.c.v. injection of rat recombinant IL-1[beta], and lipopolysaccharide (LPS). IL-1[beta] (15 [mu]g kg-1, i.p. or 1 ng i.c.v.) decreased social exploration measured 2, 4 and 6 h later, and this decrease was significantly more pronounced in Lurcher than in wild type mice. LPS (60 [mu]g kg-1, i.p. or 5 ng i.c.v.) decreased social exploration measured 2 and 4 h later, and this effect was also significantly more marked in Lurcher than in wild type mice. These results suggest that the chronic inflammatory state which characterizes Lurcher mice renders these animals more sensitive to the effects of cytokines such as IL-1[beta] and LPS. This difference may be due to the higher reactivity of brain macrophages and glial cells to LPS and IL-1 in Lurcher mice than in wild type.

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1: Physiol Behav. 2005 Jun 30;85(3):296-307.Click here to read Links Protracted increases in core body temperature and interleukin-1 following acute administration of lipopolysaccharide: implications for the stress response.

* Deak T, * Bellamy C, * Bordner KA.

Behavioral Neuroscience Program, Department of Psychology, State University of New York, SUNY-Binghamton, Vestal Parkway East, Binghamton, NY 13902-6000, USA.

Administration of lipopolysaccharide (LPS) produces a fever response often precipitated by the production of pro-inflammatory cytokines in the CNS. This pro-inflammatory cascade has traditionally been regarded as a transitory event that, with a non-replicating antigen such as LPS, would subside within a few hours. We present data showing that central and peripheral levels of IL-1 were substantially elevated as much as 48 h after LPS in some structures. In order to explore other aspects of the sickness response that might follow a similarly protracted time course, rats were implanted with telemetry probes and injected (i.p.) with 0, 10 or 100 mug/kg of LPS and left undisturbed for 96 h. Rats injected with LPS evinced a polyphasic fever with intermediate temperature peaks at approximately 5 and 8 h. Although the fever appeared to subside during the first night cycle, more detailed analysis confirmed that it was masked by the circadian rise in core temperature during the dark cycle and actually persisted for approximately 36 h following LPS. In contrast, LPS produced a transient suppression of social interaction that was no longer evident 24 h after LPS. Finally, we report that prior LPS produced a sensitized fever response to social conflict 48 h later. Taken together, these results suggest that acute administration of LPS results in a protracted fever response and increased IL-1 that persist for at least 24-48 h, and that LPS may render certain aspects of the stress response to a sensitized state.

LPS induces a depressive-like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior.[10]
All these symptoms are more common in autistic people than among neurotypical people.

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Illness, cytokines, and depression.

* Yirmiya R, * Pollak Y, * Morag M, * Reichenberg A, * Barak O, * Avitsur R, * Shavit Y, * Ovadia H, * Weidenfeld J, * Morag A, * Newman ME, * Pollmacher T.

Department of Psychology, Hebrew University, Hadassah Hospital, Jerusalem, Israel.

Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double-blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus-induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPS-induced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS-induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive-like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS-induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF-alpha mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness-associated depression.

PMID: 11268375 [PubMed - indexed for MEDLINE]

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* Hava G,
* Vered L,
* Yael M,
* Mordechai H,
* Mahoud H.

Department of Developmental Molecular Genetics and Zlotowski Center for Neuroscience Ben-Gurion University of the Negev Beer-Sheva, Israel.

Maternal intrauterine inflammation during pregnancy poses a major threat of neurodevelopmental brain damage in offspring and may cause poor cognitive and perceptual outcomes. In mice, we have previously shown that maternal inflammation induced by lipopolysaccharide (LPS) at gestation day 17th increased the levels of the pro-inflammatory cytokine IL-6 in the fetal brain. In this study, we used the same system and examined the effect of short, systemic maternal inflammation on anxiety and social behavior of the offspring. Adult offspring from the maternal inflammation group showed increased anxiety, as indicated by the elevated plus maze. Social interaction among offspring from the test groups was examined when two unfamiliar mice from different litters were introduced into a new home-cage. Offspring from the maternal inflammation group showed reduced activity, indicating increased fear. In addition, offspring from the maternal inflammation group were less aggressive towards their cagemates and they spent a significantly longer time trimming the whiskers of their cagemates during the first 30 min of their interaction, compared to offspring from the control group. Our data suggest that short systemic maternal inflammation have long-lasting consequences on the adult mouse stress and social behavior. (c) 2006 Wiley Periodicals, Inc. Dev Psychobiol 48: 162-168, 2006.

PMID: 16489598 [PubMed - indexed for MEDLINE]

Experiment that shows LPS inducing fear and anxiety We know that children with ASD have more anxiety and fear.

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fear and anxiety.

* Spencer SJ,
* Heida JG,
* Pittman QJ.

Hotchkiss Brain Institute, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, 3330 Hospital Dr. N.W., Calgary, Alta., Canada T2N 4N1.

Neonatal exposure to an immune challenge has been shown to alter many facets of adult physiology including fever responses to a similar infection. However, there is a paucity of information regarding its effects on adult behaviours. Male Sprague-Dawley rats were administered a single injection of the bacterial endotoxin lipopolysaccharide (LPS) at 14 days old and were compared, when they reached adulthood, with neonatally saline-treated controls in several behavioural tests of unconditioned fear and anxiety. There was no effect of the neonatal treatment on performance in either the elevated plus maze, modified Porsolt's forced swim test or the open field test. However, neonatally LPS-treated rats did show significantly reduced exploration of novel objects introduced to the open field arena, indicating an effect of the neonatal immune challenge on behaviours relating to anxiety in the adult.

PMID: 16125259 [PubMed - indexed for MEDLINE]

Many children with ASD show signs of depression


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1: Biol Psychiatry. 2006 Oct 15;60(8):803-11. Epub 2006 Jun 30.Click here to read Links
Depressive behavior in mice due to immune stimulation is accompanied by reduced neural activity in brain regions involved in positively motivated behavior.

* Stone EA,
* Lehmann ML,
* Lin Y,
* Quartermain D.

Department of Psychiatry, New York University School of Medicine, New York, New York 10016, USA.

BACKGROUND: Immune stimulation inhibits positively motivated behavior and induces depressive illness. To help clarify the mechanism of these effects, neural activity in response to a positive stimulus was examined in brain regions associated with positively motivated activity defined on the basis of prior behavioral studies of central alpha1-adrenoceptor action. METHODS: Mice pretreated with either lipopolysaccharide or, for comparison, reserpine were exposed to a motivating stimulus (fresh cage) and subsequently assayed for fos expression and mitogen-activated protein kinase (MAPK) phosphorylation, two measures associated with alpha1-adrenoceptor-dependent neural activity, in several positive-activity-related (motor, piriform, cingulate cortex, nucleus accumbens, locus coeruleus) and stress-related brain regions (paraventricular hypothalamus, bed nucleus stria terminalis). RESULTS: Both lipopolysaccharide and reserpine pretreatment abolished fresh cage-induced fos expression and MAPK activation in the positive activity-related brain regions but enhanced these measures in the stress-related areas. CONCLUSIONS: The results support the hypothesis that immune activation reduces alpha1-adrenoceptor-related signaling and neural activity in brain regions associated with positive activity while it increases these functions in stress-associated areas. It is suggested that neural activities of these two types of brain regions are mutually antagonistic and that a reciprocal shift toward the stress regions is a factor in the loss of positively motivated behaviors in sickness behavior and depressive illness.

PMID: 16814258 [PubMed - indexed for MEDLINE]

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Comment in: Brain Behav Immun. 2006 Nov;20(6):515-6.

Immunity and emotions: lipopolysaccharide increases defensive behaviours and potentiates despair in mice.

* Renault J,
* Aubert A.

EA3248, Psychobiologie des Emotions, Faculte des Sciences, Parc de Grandmont, 37200 Tours, France.

Many studies have pointed out the relationships between immunity and depression, supporting a neuroimmune hypothesis of depressive disorders. However, despite the growing interest for such a hypothesis and the amount of clinical and experimental data available, the precise nature of this relationship between immunity and depression remains unclear. The present study aimed to investigate further the link between depression and immunity in mice using the modified version of the forced-swimming test. Based on a two-session test, results from our first experiment showed that endotoxin enhanced active defensive behaviours in mice during the first exposure to water, but was associated with increased immobility (i.e., 'behavioural despair') in the subsequent session. In our second experiment, we showed that these effects were blocked by a chronic antidepressant treatment with imipramine. Finally, we suggest a link between immunity and depression, based on the behavioural context in which immune activation takes place. We hypothesize that immune activation, by enhancing reactivity to the negative features of a given situation, increases defensive motivation of subjects, but therefore makes them more vulnerable to the deleterious emotional consequences of failure in defensive strategies.

LPS and the opioid effect.

For many people in the autism community, the opioid effect is at the heart of the explanation of ASD. Research indicates that LPS induces an opioid effect: analgesia(a lack of pain. ) This resembles the effects from morphine
Definition of Analgesic and its relation to morphine and other opiates.
View an article about analgesia and its relation to morphine

Research showing that LPS induces an opioid effect:
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1: Brain Res. 1994 Jun 13;648(1):80-6.
Behavioral effects of lipopolysaccharide in rats: involvement of endogenous opioids.

* Yirmiya R, * Rosen H, * Donchin O, * Ovadia H.

Department of Psychology, Hebrew University of Jerusalem, Mount Scopus, Israel.

Activation of the immune system in response to either infection or lipopolysaccharide (LPS) produces neurophysiological, neuroendocrine and behavioral changes. Some of the physiological consequences of LPS are mediated by endogenous opioid peptides. The following studies were designed to characterize the effects of LPS in several behavioral paradigms, and to determine the role of opioids in mediating these effects. The effects of LPS on locomotor and self-care activity were assessed in the open field test. Rats were injected with either saline or a dose of LPS (25, 50, 100, or 1000 micrograms/kg). 4 h later, the animals were placed in an open field and the numbers of line crossings, rearings and grooming episodes were counted. LPS significantly suppressed the three open field behaviors in a dose-related manner. The effect of LPS on sensitivity to pain was determined using the hot-plate and tail-flick tests. Administration of LPS (200 micrograms/kg) increased pain sensitivity in the hot plate test 30 min after drug administration, but produced a significant analgesic response 4 h after drug administration in both tests. Further characterization of LPS-induced analgesia demonstrated that it began about 2 h after and disappeared 30 h after the administration of LPS. Administration of naltrexone completely blocked the analgesic effects of LPS 4 h after its administration, but had no effect on LPS-induced suppression of activity in the open field. The effect of LPS on body temperature was biphasic, producing hypothermia at 2 h and hyperthermia at 8-30 h after its administration. Naltrexone had no effect on the body temperature changes induced by LPS.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 7922530 [PubMed - indexed for MEDLINE]

LPS increases tendency for addiction and might might precipitate alcohol drinking behavior.
We know that many kids with ASD tend to have food addiction.

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Endotoxin exposure in utero increases ethanol consumption in adult male offspring.

* Liu X, * Lee JG, * Yee SK, * Bresee CJ, * Poland RE, * Pechnick RN.

Department of Psychiatry, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Epidemiological studies have suggested that adverse experiences in utero predispose individuals to neurobehavioral disorders including drug abuse in adulthood. The present study was designed to examine the hypothesis that maternal endotoxin exposure during pregnancy increases ethanol consumption in adult offspring. Pregnant Sprague-Dawley rats were subjected to lippopolysaccharide (LPS, 1.0 mg/kg, s.c.) treatment on alternate days throughout pregnancy. Adult male offspring were tested for ethanol consumption by using a free-access and two bottle choice paradigm. The animals exposed to LPS showed increased ethanol intake and preference as well as decreased rearing activity in the open field test. These data suggest that maternal infection during pregnancy might precipitate alcohol drinking behavior in adult offspring and this effect might be due, at least in part, to elevated levels of anxiety.

PMID: 15106858 [PubMed - indexed for MEDLINE]