Role of IL-1β and 5-HT2 receptors in midbrain periaqueductal gray (PAG) in potentiating defensive rage behavior in cat

Abstract

Feline defensive rage, a form of aggressive behavior that occurs in response to a threat can be elicited by electrical stimulation of the medial hypothalamus or midbrain periaqueductal gray (PAG). Our laboratory has recently begun a systematic examination of the role of cytokines in the regulation of rage and aggressive behavior. It was shown that the cytokine, interleukin-2 (IL-2), differentially modulates defensive rage when microinjected into the medial hypothalamus and PAG by acting through separate neurotransmitter systems. The present study sought to determine whether a similar relationship exists with respect to interleukin 1-β (IL-1β), whose receptor activation in the medial hypothalamus potentiates defensive rage. Thus, the present study identified the effects of administration of IL-1β into the PAG upon defensive rage elicited from the medial hypothalamus. Microinjections of IL-1β into the dorsal PAG significantly facilitated defensive rage behavior elicited from the medial hypothalamus in a dose and time dependent manner. In addition, the facilitative effects of IL-1β were blocked by pre-treatment with anti-IL-1β receptor antibody, while IL-1β administration into the PAG had no effect upon predatory attack elicited from the lateral hypothalamus. The findings further demonstrated that IL-1β's effects were mediated through 5-HT 2 receptors since pretreatment with a 5-HT 2C receptor antagonist blocked the facilitating effects of IL-1β. An extensive pattern of labeling of IL-1β and 5-HT 2C in the dorsal PAG supported these findings. The present study demonstrates that IL-1β in the dorsal PAG, similar to the medial hypothalamus, potentiates defensive rage behavior and is mediated through a 5-HT 2C receptor mechanism.

Tryptophan, kynurenine, and kynurenine metabolites: Relationship to lifetime aggression and inflammatory markers in human subjects

“…The same has been reported for interleukin-6 [IL-6; (Brummett et al, 2010; Coccaro et al, 2014; Marsland et al, 2008; Suarez, 2003)], and both CRP and IL-6 have been reported to be elevated in subjects with intermittent explosive disorder (Coccaro et al, 2014), a disorder of impulsive aggression (Coccaro, 2012). Moreover, animal studies demonstrate increased defensive aggression in cats when inflammatory cytokines, such as IL1-β and IL-2, were injected into the medial hypothalamus or periaqueductal grey (Bhatt et al, 2008; Patel et al, 2010; Zalcman and Siegel, 2006). …”

Reciprocal moderation by Toxoplasma gondii seropositivity and blood phenylalanine – tyrosine ratio of their associations with trait aggression

“…While elevated proinflammatory cytokines and glial cell abnormalities represent trait markers of major mental illnesses like major depressive disorder [4, 5], bipolar disorder [5, 6] and schizophrenia [5, 7], there also appears to be a state-mediated effect of suicidal behavior [8–10], acuity of mood episode or psychosis [6, 11, 12] and treatment [11–14] on cytokine levels, microglial activation and other indicators of central inflammation. Trait aggression [15–18] and impulsivity [19, 20], behaviors often present in these illnesses, are also associated with elevations of inflammatory biomarkers as suggested by human [21–25] and animal studies [26–29]. Higher rates of latent infection with neurotropic pathogens like Toxoplasma gondii ( T. gondii ) and Herpesvidae family viruses [30–34], may contribute to the low-grade immune activation observed in these conditions.…”

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

“…Addressing the second hypothesis, it should be noted that the principal inflammatory cytokines that are released following LPS injections that can potentially modulate defensive rage behavior include: IL-1β, IL-6 and TNFα (Bhatt et al 2008; Cartmell et al 2000; Givalois et al 1994; Hassanain et al 2003b; Hassanain et al 2005; Miller et al 1997). However, unpublished data in our laboratory suggested that IL-6 is not involved in the modulation of defensive rage behavior.…”

“…In particular, microinjections of IL-1 and IL-2 into the medial hypothalamus or PAG significantly modulated defensive rage behavior and their effects are mediated through classical neurotransmitters present in these regions (Bhatt et al 2005; Bhatt and Siegel 2006; Bhatt et al 2008; Hassanain et al 2003b; Hassanain et al 2005). IL-1β injected into PAG or medial hypothalamus significantly facilitated the defensive rage behavior through 5-HT receptors (Hassanain et al 2003b).…”