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Figure 2. Effects of i.p. administration of saline or LPS (lOOjig/kg body weight) on extracellular levels of 5-HT and 5-HIAA in the hippocampus (A, B) and the preoptic area (C, D) of the rat. The time point of injection is indicated by the arrow, "indicates the time period during which data from i.p. saline- and LPS-treated animals differ significantly (MANOVA with repeated measures). Data taken from Linthorst et al., 1995a and 1996 by permission of Oxford University Press and IBRO, respectively. O i.p. saline, A i.p. LPS.

activity of the animals together with other signs of sickness behaviour, such as a curled-up body posture and piloerection. Moreover, the activity of the HPA axis was stimulated as indicated by a marked and prolonged rise in free corticosterone concentrations (Linthorst, Flachskamm, Holsboer, & Reul, 1995a; Linthorst et al., 1995b). Extracellular levels of 5-HIAA represent an index of the amount of newly synthesized 5-HT, and do not reflect metabolism of released 5-HT (Auerbach, Minzenberg, & Wilkinson, 1989; Crespi, Garratt, Sleight, & Marsden, 1990; Kalen, Strecker, Rosengren, & Bjorklund, 1988; Linthorst, Flachskamm, Holsboer, & Reul, 1994). Hence, the rise in 5-HIAA concentrations shows that inflammation results in an enhanced synthesis of this indoleamine. This is of particular interest, because preliminary results from 5-HT1A receptor autoradiography experiments have shown that i.p. administration of LPS caused a long-term increase in the concentration of these receptors in the hippocampus (Reul et al., unpublished observations). Taken together, these results indicate that the rise in extracellular concentrations of the parent amine 5-HT together with the stimulation of its synthesis and the upregulation of 5-HT1A receptors may ensure a profound and extended activation of 5-HT-regulated postsynaptic events in the hippocampus.

Recent microdialysis studies carried out by Merali and colleagues (Merali, Lacosta, & Anisman, 1997) have shown that i.p. injection of IL-1 also increased extracellular levels of 5-HT and 5-HIAA in the hippocampus. Earlier studies on brain (tissue) neurotransmitter levels in rats and mice have demonstrated that systemic application of IL-1 (Kabiersch, Del Rey, Honegger, & Besedovsky, 1988; Zalcman, Green-Johnson, Murray, Nance, Dyck, Anisman, & Greenberg, 1994) and IL-6 (Zalcman et al., 1994) increased the turnover of 5-HT (as indicated by a rise in the ratio of 5-HIAA/5-HT) and/or increase 5-HIAA levels. These findings indicate that systemically produced IL-1 can affect 5-HT neurotransmission; a mechanism which may be involved in the effects of LPS on hippocampal serotonergic neurotransmission as found in our experiments.

Stimulatory effects of inflammation on higher brain structures are not confined to the hippocampus. Studies on brain neurotransmitter (tissue) levels have shown that peripheral injection of endotoxin, IL-1, and IL-6 enhanced 5-HT turnover in the frontal cortex (Dunn, 1992; Dunn & Welch, 1991; Zalcman et al., 1994). Moreover, Lavicky and Dunn (1995) reported increased levels of 5-HIAA in dialysates from the frontal cortex after i.p. administration of LPS. Unfortunately, no information on the parent amine was provided in this study.

It is now well accepted that arachidonic acid metabolites play an important role in the actions of cytokines released after an immune challenge (Gottschall, Komaki, & Arimura, 1992; Rothwell, 1991). Systemic administration of LPS induced the release of prostaglandin E2 in the hypothalamus (Sirko, Bishai, & Coceani, 1989; Smith, Hewson, Quarrie, Leonard, & Cuzner, 1994). Moreover, IL-lfJ increased levels of prostaglandin E2 in rat astrocyte cultures and rat brain (Katsuura, Gottschall, Dahl, & Arimura, 1989; Komaki, Arimura, & Koves, 1992). The cyclo-oxygenase inhibitor indomethacin suppressed the production of prostaglandins and inhibited the IL-1-induced release of ACTH (Katsuura, Gottschall, Dahl, & Arimura, 1988). Prostaglandins also play an important role in neurotransmission responses during inflammation. Pretreatment of rats with indomethacin (lOmg/kg body weight i.p.) largely but not completely blocked the LPS-induced increase in hippocampal extracellular levels of 5-HT and 5-HIAA (Linthorst et al., 1996). The indomethacin pretreatment, however, was able to prevent the fever, tachycardia and sickness behaviour responses entirely. The incomplete inhibition of hippocampal 5-HT by indomethacin suggests the involvement of other mediators. Nitric oxide might represent a candidate because results of various studies point to a role of nitric oxide in brain responses to inflammation (Karanth, Lyson, & McCann, 1993; Raber & Bloom, 1994; Rivier & Shen, 1994).

3.1.1.2. Central cytokines and hippocampal serotonergic neurotransmission. As described above, LPS causes profound rises in extracellular concentrations of 5-HT and 5-HIAA, and in the levels of 5-HT,A receptors in various regions of the hippocampus. Although LPS induces the synthesis and release of many (proinflammatory) cytokines, which cytokines are involved in the LPS-induced brain-mediated responses needs to be clarified. Therefore, a series of studies was designed to delineate the role of cytokines in hippocampal serotonergic neurotransmission. First, it was examined to what extent singly administered cytokines would be able to mimic the effects of i.p. injected LPS. Two proinflammatory cytokines were tested, i.e. TNF-a and IL-lp, and compared with the actions of the non-inflammatory cytokine IL-2. Biotelemetry measurements showed that i.e.v. administration of these cytokines increased body temperature and free corticosterone levels (Kluger, 1991;Linthorst et al., 1995b; Pauli, Linthorst, & Reul, 1998). However, whereas IL-lp and IL-2 induced sickness behaviour and profound rises in hippocampal levels of 5-HT and 5-HIAA, TNF-a had no effects on these parameters (using doses effective in inducing fever and HPA axis activation; Figure 3A-C) (Linthorst et al., 1995b; Pauli et al., 1998). A recent study on brain neurotransmitter (tissue) levels showed that i.c.v. administration of IL-lp increased hippocampal 5-HIAA levels in rats, whereas IL-2, IL-6, and TNF-a were ineffective (Connor, Song, Leonard, Merali, & Anisman, 1998). The discrepancy between the latter report and our observation that i.c.v. IL-2 stimulates hippocampal 5-HT and 5-HIAA, may not only be explained by methodological differences (brain tissue levels vs. micro-dialysis), but also by the early time point of killing of the rats (45min after administration of IL-2) in the study of Connor et al. Hence, it may be concluded that both central IL-ip and IL-2, but not TNF-a, are able to stimulate hippocampal serotonergic neurotransmission.

IL-2 is an important cytokine within the immune system where it acts as the main T-cell growth factor. IL-2 stimulates the release of various cytokines from immune cells, among which IL-1 (Janssen, Mulder, The, & Deleij, 1994). Therefore, we were interested to determine whether IL-2 exerts its effects on the level of the brain also via the induction of IL-1. For this purpose, rats were pretreated i.c.v. with the IL-1 receptor antagonist (IL-lra). Pretreatment with IL-lra completely blocked the i.c.v. IL-2-induced increases in hippocampal 5-HT and 5-HIAA (Figure 3C), but only attenuated the rise in free corticosterone (Pauli et al., 1998).These results clearly demonstrate that the effects of IL-2 on hippocampal serotonin are caused via the release of IL-1, whereas IL-1 plays only a minor role in the IL-2-induced activation of the HPA axis.

The finding that central administration of IL-ip has marked effects on hippocampal 5-HT has fed the notion that IL-1 may be involved in the LPS-induced changes in the levels of this neurotransmitter. Indeed, i.c.v. pretreatment of rats with IL-lra (lOjig) resulted in a 50% reduction of the LPS-induced activation of hippocampal 5-HT release (Figure 3D), pointing to a role of brain IL-1 in the effects of LPS on 5-HT in the hippocampus (Linthorst et al., 1995b). Moreover, we have demonstrated that local infusion of IL-1 [3 into the hippocampus also resulted in elevations of extracellular 5-HT (Linthorst et al., 1994). Based on the observations that on the one hand i.c.v. and intrahippocampal IL-ip mimic the effects of LPS on hippocampal

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