Sal TNF Sal TNF-1 TNF-7 TNF-14TNF-28

Days Between TNF Reexposure

Figure 17. Mean (+S.E.M) concentrations of MHPG within the PVN (upper panel) and prefrontal cortex (lower panel) as a function of TNFa treatments. Mice received 2 intraperitoneal injections. The 3 groups at the left received either vehicle treatment only, vehicle followed two weeks later by a low dose of TNFa (1.11 jig) orTNFu (4.fJ fig) followed by vehicle. Til e four groups on the right received two injections of TNFa; the first was a 4.0 Jig time, while I he second was 1.0 pg. Tie two injections were administered either 1.7,14 or 28 days apart. Note that a sensitization effect was evident with respect to PVN MHPG in mice that received the second TNFa treatment 28 days after initial exposure, but not at shorter intervals. In contrast, within the prefrontal cortex (as well as several other limbic sites not shown) the sensitization was only evident 1 day following initial treatment (from Hayley et al., 1WS).

was an increase of NE utilization in the PVN relative to that seen in animals that received only a single TNFa injection. A comparable amine change was not evident at earlier intervals following the initial TNFa treatment. Inasmuch as the plasma corti-costerone changes also increased over time, these two changes may be related to one another.

In contrast to the PVN NE variations, an entirely different profile of changes was seen in other brain regions. In particular, both NE and 5-HT utilization in the hippocampus, amygdala, and PFC were very much increased in animals re exposed to TNFa 1 day following the initial treatment. At the longer intervals (7,14, and 28 days), however, there was no indication of a sensitization effect (see Figure 17). Finally, as in the case of the aforementioned amine changes, accumbal DA utilization was evident upon reexposure to TNFa 1 day after initial treatment, but not at longer intervals. We have, as yet, not had the opportunity to assess peptide changes in detail in animals treated with TNFa. However, in some recent experiments (Hayley, Staines, Mclntyre,

Merali, & Anisman, unpublished report) we observed that 14 days after TNFa treatment there was a marked increase of cFOS expression in the PVN, preoptic nucleus, central amygdala, and the PVN of the thalamus. Moreover, at this time CRH and AVP coexpression was increased within CRH neurons in the external zone of the median eminence. The latter finding, it will be recognized, is commensurate with reports concerning the effects of IL-1 and stressors (Bartanusz et al., 1993; Schmidt et al., 1995; Tilders et al., 1993), although it remains to be determined whether this apparent sensitization increases with time following initial treatment.

It is important to underscore at this juncture that the nature of the sensitization effects associated with TNFa lead to the suggestion that independent circuits seem to be involved in the augmented HPA functioning, and those involved in limbic activity. Although it is often assumed that hippocampal 5-HT or NE activity may be involved in PVN activation, it is clear that effects on the hippocampus (as well as the amygdala and PFC) are not necessarily translated as either PVN NE or corticosterone variations. Conversely, PVN NE and plasma corticosterone changes are not necessarily linked to variations of limbic amines. Furthermore, it is abundantly clear that the amine sensitization effects seen 1 day after initial TNFa treatment are independent of any malaise animals suffered from the treatment, which did not occur until 2 weeks after initial treatment. Of course, it is possible that the elevated PVN NE activity, as well as the increases of plasma corticosterone observed at the longer intervals were, in fact, secondary to illness associated with the reexposure treatment.

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