Systemic administration of murine tumour necrosis factor-α (mTNF-α; 0.1-2.0 μg, i.p.) dose-dependently increased plasma corticosterone and augmented monoamine utilization within the paraventricular nucleus of the hypothalamus (PVN), locus coeruleus, medial prefrontal cortex (PFC), central and medial amygdala. A time-dependent sensitization was induced in mice, wherein reexposure to mTNF-α 28 days (but not 1 day) following the initial cytokine treatment provoked marked signs of illness (diminished activity, ptosis, piloerection) and increased plasma corticosterone levels. Serotonin (5-HT) activity was augmented upon mTNF-α reexposure at the 1- or 28-day intervals in the PFC and medial amygdala, respectively. Intracerebroventricular (i.c.v.; 1-500 ng) mTNF-α did not promote illness, but modestly increased plasma corticosterone levels. Neither the illness nor the corticosterone changes were subject to a sensitization upon i.c.v. cytokine reexposure. Acute i.c.v. mTNF-α increased norepinephrine (NE), 5-HT and dopamine (DA) activity within the PVN and median eminence/arcuate nucleus complex (ME/ARC), and NE utilization within the central amygdala. Subsequent i.c.v. mTNF-α further enhanced the hypothalamic monoamine variations. Finally, systemic (i.p.) mTNF-α pretreatment did not proactively influence sickness or corticosterone responses upon later i.c.v. cytokine challenge, but augmented locus coeruleus NE activity and 5-HT and DA utilization within the ME/ARC. It is suggested that the sensitization with respect to sickness and corticosterone activity in response to mTNF-α reflect the involvement of peripheral mechanisms. Moreover, it appears that mTNF-α promotes central neurochemical plasticity through independent central and peripheral mechanisms.

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European Journal of Neuroscience
Stress & Pathology Lab

Hayley, S, Wall, P., & Anisman, H. (2002). Sensitization to the neuroendocrine, central monoamine and behavioural effects of murine tumor necrosis factor-α: Peripheral and central mechanisms. European Journal of Neuroscience, 15(6), 1061–1076. doi:10.1046/j.1460-9568.2002.01936.x