The neurobiology of aggression and rage: role of cytokines.

Recent studies have suggested an important relationship linking cytokines, immunity and aggressive behavior. Clinical reports describe increasing levels of hostility, anger, and irritability in patients who receive cytokine immunotherapy, and there are reports of a positive correlation between cytokine levels and aggressive behavior in non-patient populations. On the basis of these reports and others describing the presence or actions of different cytokines in regions of the brain associated with aggressive behavior, our laboratory embarked upon a program of research designed to identify and characterize the role of IL-1 and IL-2 in the hypothalamus and midbrain periaqueductal gray (PAG)--two regions functionally linked through reciprocal anatomical connections--in the regulation of feline defensive rage. A paradigm involved cytokine microinjections into either medial hypothalamus and elicitation of defensive rage behavior from the PAG or vice versa. These studies have revealed that both cytokines have potent effects in modulating defensive rage behavior. With respect to IL-1, this cytokine facilitates defensive rage when microinjected into either the medial hypothalamus or PAG and these potentiating effects are mediated through 5-HT2 receptors. In contrast, the effects of IL-2 are dependent upon the anatomical locus. IL-2 microinjected into the medial hypothalamus suppresses defensive rage and this suppression is mediated through GABA(A) receptors, while microinjections of IL-2 in the PAG potentiate defensive rage, in which these effects are mediated through NK-1 receptors. Present research is designed to further delineate the roles of cytokines in aggressive behavior and to begin to unravel the possible signaling pathways involved this process.