Invited Symposium: Cytokines, Monoamines and Behavior
Acute effects of systemic TNF-a treatment
Systemic TNF-a treatment dose dependently reduced consumption of the palatable chocolate milk solution and elevated plasma corticosterone levels. These results are in agreement with previous reports of the anorexic effects (Plata-Salaman et al., 1988) and enhanced glucocorticoid levels provoked by TNF-a(Benigni et al., 1996).
It was clear that TNF-a elicited amine variations at several hypothalamic and extrahypothalamic sites. Pronounced reductions of NE were evident in the dorsal hippocampus and locus coeruleus, but only modest reductions of the monoamine were found in the PVN. While 5-HT levels were reduced in the PVN, after the TNF-a treatment concentrations of the monoamine were elevated within the PFC and the metabolite, 5-HIAA, was increased at the central amygdala.Sensitization effects of TNF-a treatment
The general behavioral profile of the mice was altered upon reexposure to the cytokine such that time-dependent sensitization effects were evident. Those animals that received the second injection of the cytokine 14 or 28 days after the initial treatment displayed greater illness, reduced motor activity and a greater degree of isolation (i.e. reduced interaction with cagemates) relative to mice reexposed at other times (See Table 1). Moreover, mice reexposed to TNF-a after 14 days (other time interval were not assessed for this behavioral measure) displayed pronounced reductions of chocolate milk consumption.Table 1. Behavioral Scores as a function of the initial TNF-a(4.0 ug) or reexposure (1.0 ug) treatment.
sickness profile motor activity social isolation Sal/Sal 1.00 + 0 3.00 + 0 1.75 + 0.25 Sal/TNF 1.14 + 0.38 2.57 + 0.20 1.83 + 0.31 TNF/Sal 1.29 + 0.76 2.86 + 0.14 1.67 + 0.33 TNF/TNF (1 day) 1.80 + 0.20 2.00 + 0 1.40 + 0.40 TNF/TNF (7 days) 1.67 + 0.33 2.00 + 0.31 1.67 + 0.33 TNF/TNF (14 days) 2.83 + 0.17* 1.67 + 0.21* 2.83 + 0.40 TNF/TNF (28 days) 3.57 + 0.20** 1.00 + 0** 3.71 + 0.29** *P < 0.05 relative to Sal/Sal, **p < 0.05 relative to Sal/TNF
Reexposue to TNF-a after 7, 14 or 28 days elevated corticosterone levels above those seen in control mice, however, only upon reexposure to TNF-a 28 days after initial challenge did corticosterone levels exceed those observed in mice that received a single acute injection of the cytokine (i.e. a genuine sensitization effect) (See Table 2). Interestingly, in mice reexposed to TNF-a 24 h after the initial TNF-a treatment, corticoid levels were lower than those seen in animals that received the single acute cytokine administration, indicating a desensitization effect at this short reexposure interval.Table 2. Tim-dependent sensitization and desensitization effects for plasma corticosterone levels (ug/dl) as a function of the initial TNF-a(4.0 ug) or reexposure (1.0 ug) treatment.
Mean + S.E.M. Plasma Corticosterone (ug/dl) Sal/Sal 4.58 (0.81) Sal/TNF 24.87 (4.7)* TNF/Sal 5.83 (0.78) TNF/TNF (1 day) 16.05 (2.3) TNF/TNF (7 days) 22.11 (3.3)* TNF/TNF (14 days) 29.94 (1.97)* TNF/TNF (28 days) 30.46 (3.8)** *p < 0.05 relative to Sal/Sal, **p < 0.05 relative to Sal/TNF
Upon reexposure to TNF-a, marked time-dependent central neurochemical alterations were also evident (See Table 3). In particular, within the PVN and to a lesser extent in the dorsal hippocampus, levels of the NE metabolite, MHPG, were elevated upon reexposure to TNF-a 14 and 28 days after the initial administration of the cytokine relative to those of animals that received a single TNF-a administration. In contrast, within the PFC, MHPG levels and to a lesser extent 5-HIAA levels, were increased upon reexposure to TNF-a 24h after initial treatment compared to mice receiving saline or a single TNF-a injection.Table 3. Time-dependent variations of central NE and MHPG levels (ng/mg protein) within the PVN and PFC as a function of the initial TNF-a(4.0 ug) or reexposure (1.0 ug) treatment.
PVN PFC NE MHPG NE MHPG Sal/Sal 32.74 4.89 4.71 2.27 Sal/TNF 26.28 7.62* 6.69 3.14 TNF/Sal 24.42 5.45 5.39 2.67 TNF/TNF (1 day) 32.96 7.40 15.97** 11.6** TNF/TNF (7 days) 39.71 7.17 5.05 3.17 TNF/TNF (14 days) 34.61 8.07* 5.25 3.49 TNF/TNF (28 days) 24.28 9.56** 6.40 3.83 *p < 0.05 relative to Sal/Sal, **p < 0.05 relative to Sal/TNF
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|Hayley, S; Brebner, K; Merali, Z; Anisman, H; (1998). Sensitization Effects of TNF-alpha: Behavioral and Neurochemical Processes. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/anisman/hayley0615/index.html|
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