Peripheral and central mediators of lipopolysaccharide induced suppression of defensive rage behavior in the cat

Abstract

Based upon recent findings in our laboratory that cytokines microinjected into the medial hypothalamus or periaqueductal gray (PAG) powerfully modulate defensive rage behavior in cat, the present study determined the effects of peripherally released cytokines following lipopolysaccharide LPS challenge upon defensive rage. The study involved initial identification of the effects of peripheral administration of LPS upon defensive rage by electrical stimulation from PAG and subsequent determination of the peripheral and central mechanisms governing this process. The results revealed significant elevation in response latencies for defensive rage from 60-300 min, post LPS injection, with no detectable signs of sickness behavior present at 60 min. In contrast, head turning behavior elicited by stimulation of adjoining midbrain sites was not affected by LPS administration, suggesting a specificity of the effects of LPS upon defensive rage. Direct administration of LPS into the medial hypothalamus had no effect on defensive rage, suggesting that the effects of LPS were mediated by peripheral cytokines rather than by any direct actions upon hypothalamic neurons. Complete blockade of the suppressive effects of LPS by peripheral pretreatment with an anti-TNF-α antibody but not with an anti-IL-1 antibody demonstrated that the effects of LPS were mediated through TNF-α rather than through an IL-1 mechanism. A determination of the central mechanisms governing LPS suppression revealed that pretreatment of the medial hypothalamus with PGE 2 or 5-HT 1A receptor antagonists each completely blocked the suppressive effects of LPS, while microinjections of a TNF-α antibody into the medial hypothalamus were ineffective. Microinjections of p-MPPI into lateral hypothalamus (to test for anatomical specificity) had no effect upon LPS induced suppression of defensive rage. The results demonstrate that LPS suppresses defensive rage by acting through peripheral TNF-α in periphery and that central effects of LPS suppression of defensive rage are mediated through PGE 2 and 5-HT 1A receptors in the medial hypothalamus.

Pro‐inflammatory cytokines, IL‐1β and TNF‐α, produce persistent compromise in tonic immobility defensive behaviour in endotoxemia guinea‐pigs

“…Whereas the endotoxemic cats suppress the defensive range behaviour elicited by eletrical stimulation from the PAG, similar results were not observed when the LPS is microinjected in the medial hypothalamus (Bhatt et al . ). These effects may be mediated mainly by peripheral TNF‐ α , presenting the IL‐1 β minor participation in this type of behaviour.…”

“…Moreover, cytokines may change neuronal excitability and synaptic neurotransmission, for example by 5‐HT 1A receptors (Bhatt et al . ) or increasing the serotonin uptake in midbrain cells (Zhu et al . ).…”

A review of the neuro- and systemic inflammatory responses in post concussion symptoms: Introduction of the “post-inflammatory brain syndrome” PIBS

“…In a similar model Il-2 suppresses the defensive rage responses (Bhatt et al, 2005). However peripheral administration of LPS suppressed defensive rage, and this effect was blocked by administering TNF-a receptor blockers (Bhatt et al, 2009). This does raise some questions, as it is apparently contrary to the relationship we see in humans.…”

Lack of aggression and anxiolytic-like behavior in TNF receptor (TNF-R1 and TNF-R2) deficient mice

“…We recently extended these studies to identify cytokines that mediate the effects of LPS on aggression in cats. We found that LPS-induced modulation of defensive rage is mediated, in part, through peripheral TNF-α (Bhatt et al, 2009). Immunocytochemical studies further revealed that TNF receptors were present in abundant quantities throughout defensive rage sites in the medial hypothalamus (unpublished finding).…”