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Figure 15, Mice received t.p. injection of either vehicle or subthreshold doses of 11.-1 [3 (0.05fig) or TNFa (1.0j.ig), or both cytokines. Plasma eort¡costero tie levels (Mean + S.E.M) (collected 1 hr after cytokine treatment) in mice that received both cytokines were greater than in mice that received vehicle or only one of (he cytokines.

Figure 16. Mean (+S.E.M) consumption of chocolate milk among mice that received either saline or TNFa ( 1,0,2.0 or 4.0 pg) and were then reexposed to cither saline or a low dose otTNFa (l.Oug) 2 weeks later. Consumption was assessed over a 2hr period beginning 1 hr after the second injection. The low dose reexposure treatment provoked a markedly greater reduction of consumption in animals that had previously received TNFct than in mice that had received saline. If the animals received the second injection 1 or 7 days following the initial TNFa treatment, then a sensitization effect was not evident (data not shown).

5.4.3. Sensitization Effects. In addition to it's immediate effects, systemic'IWot may engender the sensitization of central amine functioning, and may provoke protracted effects on behavior. Moreover, as in the case of IL-1|3 {Schmidt et al., 1995; Tiiders et al., 1993), the appearance of at least some of these consequences may be time-dependent. It was observed that in a test of chocolate milk consumption, marked alterations of behavior may be induced upon reexposure to TNFa in animals previously treated with the cytokine. However, this depended on the interval between the two cytokine treatments. If animals were treated with TNFa (4.0 pg) and then tested 2 weeks later behavior was hardly affected. However, in animals that were retested following treatment with a low dose of TNFa (1.0 pg), profound behavioral changes were observed (see Figure 16). These animals appeared much like animals that received a much higher dosage of TNFa (i.e., beyond that of 4.0 pg). In addition to reduced chocolate milk consumption, these animals exhibited clear signs of illness, including reduced motor activity, and marked soporific effects. In fact, reexposure to a somewhat higher dosage (2.0 pg), which in itself had modest effects, was lethal to about one-third of the mice. Precisely the same effects were evident irrespective of whether testing was undertaken 2 or 4 weeks after the initial TNFa treatment. Interestingly, if the second administration took place at a fairly short time following the initial treatment (1 or 7 days), then the second treatment was without behavioral effect. Thus, it appeared that treatment with TNFa induced a sensitization effect that was dependent on the passage of time.

Paralleling the behavioral sensitization, when mice were treated with TNFa (4,0pg) and then exposed to a low dose of this cytokine, a marked time-dependent sensitization effect was evident with respect to plasma corticosterone concentrations. At brief intervals following the initial treatment (1 day) reexposure to TNFa 0-0 pg) provoked a modest rise of corticosteronc levels (mean + SEM = 16,05 ± 2,30pg/dl) relative to control values (4.58 ± 0,81 pg/dl). The magnitude of this became progressively greater as the interval between the two TNFa tests increased (1,2 and 4 weeks equaled 22.11 ± 3.33,29.94 ± 1.97, and 30.46 ± 3.85 pg/dl, respectively). Sensitization effects were likewise apparent with respect to central neurotransmitter activity. Once more, the time-dependent nature of the sensitization was brain region-specific and also varied as a function of the particular neurotransmitter being assessed. As seen in Figure 17, in animals reexposed to the l.Opg dose of TNFa 4 weeks following initial treatment there

Reexposure Treatment M Saline □ TNT (1.0 ug)

Reexposure Treatment M Saline □ TNT (1.0 ug)

Saline 1 o 2.0 4,0 Initial TNI- I real men! (ug)
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