O vehicle

Figure 3. Effects of i.c.v. administration of vehicle, IL-1(3 (100ng),TNF-<x (100 ng), or IL-2 (500ng) (A-C) on hippocampal extracellular levels of 5-HT. Intracerebroventricular pretreatment of the rats with the interleukin-1 receptor antagonist (IL-lra; 10ng) inhibits the i.c.v. IL-2- and attenuates the i.p. LPS-induced increase in hippocampal 5-HT (C, D). The time point of injection(s) is indicated by the arrow, "indicates the time period during which data from i.c.v. vehicle- and cytokine-treated (A, C) and from i.p. LPS- and i.c.v. IL-lra/i.p.LPS-treated animals (D) differ significantly (MANOVA with repeated measures). Data taken from Linthorst et al., 1995b and Pauli et al., 1998 by permission of the Journal of Neuroscience and the European Neuroscience Association, respectively.

serotonergic neurotransmission, and on the other hand i.c.v. IL-lra attenuates the LPS-induced effects on hippocampal 5-HT, it may be concluded that IL-lp released/produced locally in the hippocampus is involved in the activation of 5-HT in this brain structure during peripheral inflammation.

3.1.2. Serotonin and the Preoptic Area Peripheral immune stimulation and preoptic serotonergic neurotransmission. To compare the effects of LPS on serotonergic neurotransmission in the hippocampus with those in another brain structure, we have performed similar studies in the preoptic area. The preoptic area (often studied as an entity with the anterior hypothalamus) plays a key role in the regulation of autonomic and endocrine processes, such as body temperature, food intake, sleep, and sexual behaviour (Blatteis, 1990; Rivest & Rivier, 1993; Swanson, 1987). In contrast to the increase in hippocampal 5-HT, i.p. administration of LPS had no effects on preoptic extracellular levels of 5-HT (Figure 2C). However, about two hours after the injection of LPS a marginal rise in extracellular concentrations of 5-HIAA rise was observed (maximum about 120% of baseline; Figure 2D) (Linthorst et al., 1995a). Of interest in this respect is the finding of Wilkinson et al. (Wilkinson, Auerbach, & Jacobs, 1991), who have showed, using in vivo micro-dialysis in cats, that systemic administration of the pyrogen muramyl dipeptide had no effect on preoptic 5-HT. Other studies have focused on serotonergic neurotransmission in various other parts of the hypothalamus. The general picture arising from these studies is that systemic immune stimulation and administration of IL-1 increase the 5-HIAA/5-HT ratio (Dunn, 1992; Mefford & Heyes, 1990) and dialysate levels of 5-HIAA (Lavicky & Dunn, 1995). Central cytokines and preoptic serotonergic neurotransmission. Information in the literature on the effects of central administration of cytokines on preoptic serotonergic neurotransmission is too limited to deduct definite conclusions. Data from two reports, however, suggest that IL-1 may play a role in the effect of LPS on 5-HIAA as observed in our experiments. Intracerebroventricular and local application of IL-1 increased preoptic 5-HIAA levels as assessed by in vivo voltammetry and microdialysis, respectively (Gemma, Ghezzi, & De Simoni, 1991; Shintani, Kanba, Nakaki, Nibuya, Kinoshita, Suzuki, Yagi, Kato, & Asai, 1993).

Two reports have assessed the effects of central administration of cytokines on the hypothalamus. However, whereas one group, using an in vivo push-pull method, demonstrated that local application of IL-1 enhanced 5-HIAA levels (Mohankumar, Thyargarajan, & Quadri, 1993), i.c.v. injection of IL-1 and TNF-a was recently reported to decrease tissue levels of 5-HIAA in the hypothalamus (Connor et al., 1998).

3.2. Noradrenaline

3.2.1. Noradrenaline and the Hippocampus. Intraperitoneal injection of LPS (100 pg/kg) moderately increased hippocampal extracellular levels of NA (maximum about 150% of baseline; Figure 4A) and its major metabolite MHPG (maximum about 170% of baseline; Figure 4B) (Linthorst et al., 1996). Pretreatment of the animals with indomethacin almost completely blocked the LPS-induced increases in NA and MHPG (Linthorst et al., 1996), pointing to an important role of prostaglandins. The incomplete inhibition, however, shows that, apart from prostaglandins, other mediators released during inflammation are involved in the stimulation of hippocampal noradrenergic neurotransmission (see Studies of Zalcman et al. suggest that IL-1, released peripherally during inflammation, may play a key role in the LPS-induced effects on hippocampal NA. Intraperitoneal administration of IL-1 (5, but not of IL-2 or IL-6, increased the ratio MHPG/NA in hippocampal tissue of mice (Zalcman et al., 1994). Unfortunately, there is hardly any information available on the effects of centrally administered cytokines on noradrenergic neurotransmission in the hippocampus. Recently, it has been described that i.e.v. injection of IL-1, IL-2, IL-6, and TNF-a exerts no effects on NA in this brain structure (Connor et al., 1998).

Interestingly, changes in noradrenergic neurotransmission during inflammation have also been found in the prefrontal cortex. Using brain tissue samples of mice and in vivo microdialysis in rats, Dunn and colleagues showed that peripheral administration of LPS enhanced the ratio of MHPG/NA and extracellular levels of NA and MHPG in the prefrontal cortex, respectively (Dunn, 1992; Lavicky & Dunn, 1995). An involvement of IL-1 released into the circulation during inflammation is still controversial, since increases in the ratio MHPG/NA (Dunn, 1992) as well as no effects (Zalcman et al., 1994) after i.p. injection of IL-1 have been reported in the literature.

3.2.2. Noradrenaline and the Preoptic Area. Whereas peripherally administered LPS has a moderate effect on hippocampal NA, this treatment resulted in dramatic increases in extracellular NA (about 500% of baseline; Figure 4C) and MHPG (about 400% of baseline; Figure 4D) in the preoptic area (Linthorst et al., 1995a). NA and MHPG concentrations remained elevated for at least 6 hours. Prostaglandins serve as important mediators in these effects, because pretreatment with indomethacin largely prevented LPS-induced rises in preoptic extracellular concentrations of NA and MHPG. Similar as found for NA and 5-HT in the hippocampus, the incomplete inhibition of preoptic NA by indomethacin suggests an involvement of additional mediators.

Unfortunately, only one other research group has studied the effects of peripheral inflammation on NA in the preoptic area.Terao and colleagues showed that i.p. administration of IL-1 increased the turnover of NA in this brain area (Terao, Oikawa, & Saito, 1993). Shintani and colleagues (1993) have shown, using a microdialysis method, that local perfusion of the preoptic area with IL-1 resulted in marked and sustained elevations of extracellular NA and MHPG.

Because NA plays a key role in the regulation of HPA axis activity during stress, several research groups have extensively studied the effects of immune stimulation on noradrenergic neurotransmission in the hypothalamus and paraventricular nucleus (PVN). The general picture arising from these studies is that peripheral inflammation results in elevations in the turnover and extracellular levels of hypothalamic NA (Dunn, 1992; Lavicky & Dunn, 1995; Mefford & Heyes, 1990). Peripheral induction of IL-1 may be responsible for the effects of LPS on NA in the hypothalamus and PVN, because i.p. injection of IL-1, but not of IL-6, increased the ratio of MHPG/NA in the hypothalamus of mice (Dunn, 1988; Mefford & Heyes, 1990; Zalcman et al., 1994). Moreover, systemic administration of IL-1 increased the extracellular levels of NA in the PVN (Mohankumar & Quadri, 1993; Smagin, Swiergiel, & Dunn, 1996). The role of central cytokines is not conclusive yet. Intracerebroventricular administration of IL-1 enhanced the turnover of NA in the hypothalamus (Terao et al., 1993), although one study showed no effect of IL-1 in this brain structure (Connor et al., 1998). No effects of i.c.v. injection of TNF-a, IL-6, and IL-2 were reported (Connor et al., 1998; Terao et al., 1993). In the PVN, i.c.v. treatment with IL-1 enhanced the levels of extracellular NA (Terrazzino, Perego, & De Simoni, 1995).

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