title: Sensitization to the neuroendocrine, central monoamine and behavioural effects of murine tumor necrosis factor-alpha: peripheral and central mechanisms.
abstract: Systemic administration of murine tumour necrosis factor-alpha (mTNF-alpha; 0.1-2.0 microg, 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-alpha 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-alpha reexposure at the 1- or 28-day intervals in the PFC and medial amygdala, respectively. Intracerebroventricular (i.c.v.; 1-500 ng) mTNF-alpha 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-alpha 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-alpha further enhanced the hypothalamic monoamine variations. Finally, systemic (i.p.) mTNF-alpha 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-alpha reflect the involvement of peripheral mechanisms. Moreover, it appears that mTNF-alpha promotes central neurochemical plasticity through independent central and peripheral mechanisms.
authors.affiliation: Institute of Neuroscience, Life Science Research Building, Carleton University, Ottawa, Ontario K1S 5B6, Canada. shayley@cs.carleton.ca
authors.forename: S
authors.initials: S
authors.lastname: Hayley
authors.forename: P
authors.initials: P
authors.lastname: Wall
authors.forename: H
authors.initials: H
authors.lastname: Anisman
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009490:Neurosecretory Systems / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D015306:Biogenic Monoamines; D014409:Tumor Necrosis Factor-alpha; D012701:Serotonin; D003345:Corticosterone; D009638:Norepinephrine