Lipopolysaccharide‐Induced Sickness Behaviour Evaluated in Different Models of Anxiety and Innate Fear in Rats

Abstract

Abstract:The fact that there is a complex and bidirectional communication between the immune and nervous systems has been well demonstrated. Lipopolysaccharide (LPS), a component of gram-negative bacteria, is widely used to systematically stimulate the immune system and generate profound physiological and behavioural changes, also known as 'sickness behaviour' (e.g. anhedonia, lethargy, loss of appetite, anxiety, sleepiness). Different ethological tools have been used to analyse the behavioural modifications induced by LPS; however, many researchers analysed only individual tests, a single LPS dose or a unique ethological parameter, thus leading to disagreements regarding the data. In the present study, we investigated the effects of different doses of LPS (10, 50, 200 and 500 lg ⁄ kg, i.p.) in young male Wistar rats (weighing 180-200 g; 8-9 weeks old) on the ethological and spatiotemporal parameters of the elevated plus maze, light-dark box, elevated T maze, open-field tests and emission of ultrasound vocalizations. There was a dose-dependent increase in anxiety-like behaviours caused by LPS, forming an inverted U curve peaked at LPS 200 lg ⁄ kg dose. However, these anxiety-like behaviours were detected only by complementary ethological analysis (stretching, grooming, immobility responses and alarm calls), and these reactions seem to be a very sensitive tool in assessing the first signs of sickness behaviour. In summary, the present work clearly showed that there are resting and alertness reactions induced by opposite neuroimmune mechanisms (neuroimmune bias) that could lead to anxiety behaviours, suggesting that misunderstanding data could occur when only few ethological variables or single doses of LPS are analysed. Finally, it is hypothesized that this bias is an evolutionary tool that increases animals' security while the body recovers from a systemic infection.Several researches have yielded evidence that both humoral and neural pathways communicate the central nervous system about the presence of an invader [1]. During a systemic infection, the immune system conveys a message to the brain via vagus nerve and the circunventricular organs, and then neuronal cells respond producing cytokines that help the body to coordinate an adaptive behavioural response [1][2][3][4]. In fact, this behavioural response (or sickness behaviour -[5]) occurs because the organism needs to preserve energy during the response of the immune system to microorganism invasion [6]. Physiologically, these complex mechanisms are important to maintain homeostasis during an invasion of microorganisms. However, an excessive and prolonged production of proinflammatory cytokines in the body can damage tissues including the brain (producing severe behavioural deficits, such as depression and anxiety) [7]. For instance, recent studies have demonstrated anxiety-and depression-like behaviours in different animal models of inflammatory chronic diseases, such as systemic lupus erythematosus and rheumatoid arthritis respectively [8,9]. Curiously, i...

Lipopolysaccharide-Induced Behavioral Alterations Are Alleviated by Sodium Phenylbutyrate via Attenuation of Oxidative Stress and Neuroinflammatory Cascade

“…Depressive-like behavior in LPS-treated group revealed by marked reduction in the immobility time in FST and TST as compared to vehicle-treated control group. Our behavioral test results are in concordance with the previous experimental studies [3,23,34]. The observed anxiety and depressive-like behavior in behavioral paradigms may be accompanied by the elevation of oxidative stress and neuroinflammation in HC and PFC brain regions as well as by BDNF depletion in the HC region evoked by LPS administration.…”

“…Numerous experimental studies suggested the role of oxidative stress and inflammation in anxiety and depressive illness [3,32,33]. LPS is a very well-known endotoxin that can cause anxiety and depressive-like behavior in rodents after central or peripheral administration [3,34,35]. LPS elicits the production of proinflammatory cytokines (IL-β, IL-6, TNF-α) and reactive oxygen species (ROS) that eventually leads to peripheral as well as systemic inflammation.…”

Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone (6g) on lipopolysaccharide-induced anxiety models in mice

“…Treatment with compound 6g increased the ambulation scores but there was no significant effect observed on rearing scores. The results are in accordance with previous studies [27][28][29]. In addition to change in various behavioral parameters, the compound 6g also increased the levels of serotonin in LPStreated mice brain.…”

A central role for the mammalian target of rapamycin in LPS-induced anorexia in mice

“…injection of LPS 500 mg/kg BW was used to induce peripheral inflammation (Bassi et al 2012, Iwasa et al 2014. LPS administration induced anorexia, which is in line with previous studies (Gautron et al 2005, Ogimoto et al 2006.…”