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Bassliie Test Rscover^

Saseline Teal Recovery

Figure 9. Relative lohaiselineTal.es of chocolate milk consumption, mice (hat received intraperitoneal admin -istralion of 1L-I[i (left-hand panel) or TNFre (right-hand panel) exhibited dose-de pen den I reductions of consumption (measured over 2hr commencing 1 fir after treatment). Upon retesting 24 hr later, in the absence of further treatment, consumption levels returned to baseline values.

sumption (as did TNFcc), which returned to basal levels upon subsequent retesting 24hr later (Brebner, Hayley, Lacosta, Zacharko, Merali, & Anisman, 1998).

While IL-1{5 reliably reduced consumption, such an outcome may have been related to the illness induccd by the cytokine, or even a change in the perceived payability of the food substance, rather than an anhedonic effect. Indeed, several experiments conducted in rats provisionally suggested that IL-ip has limited cffects on reward processes. In rats with electrodes positioned within the medial fore brain bundle, treatment with IL-1(3 (1-0jig) did not alter responding for rewarding brain stimulation (Figure 10). To rule out the possibility that the lack of effects were attributable to the source of the cytokine, we assessed the cffects of IL-1 p obtained from R&D Systems and from the National Cancer Institute (Bethesda, Md). In both cases IL-lp was without effect on responding for brain stimulation reward. Moreover, this occurred irrespective of whether rats were initially tested 1 hr after cytokine administration (corresponding to peak ACTH and corticosterone changes) or at earjier times (15min post

Figure li). Following the establishment of stable rates of responding for rewarding stimulation from the lateral hypothalamus on a current titration schedule (baseline), rats received intraperitoneal injection of JL-l[i and then were repeatedlv tested for self-stimulation performance at various times afterward. 'Treatment with the cytokine did not influence responding in this paradigm. The left hand panel depicts the response/mitt (+SEM). while the right-hand panel shows the response thresholds (from Anisman et a!., 1998).

Figure li). Following the establishment of stable rates of responding for rewarding stimulation from the lateral hypothalamus on a current titration schedule (baseline), rats received intraperitoneal injection of JL-l[i and then were repeatedlv tested for self-stimulation performance at various times afterward. 'Treatment with the cytokine did not influence responding in this paradigm. The left hand panel depicts the response/mitt (+SEM). while the right-hand panel shows the response thresholds (from Anisman et a!., 1998).

D 0.25 hr 24 he i week 2 waaks Tinr-e

D 0.25 hr 24 he i week 2 waaks Tinr-e injection) (Anisman et al., 1996,1998). When animals were tested with a higher dose of IL-lp (2.0|ig/rat), a modest reduction of responding was observed. However, at this dose pronounced signs of illness were evident. As well, marked variability of performance was noted in response to the cytokine treatment. Two of the 7 rats tested ceased responding entirely, while the remaining rats were only modestly affected. Thus, while the overall response rate was not significantly different from baseline, responding during the ascending portion of the titration schedule was significantly impaired. This profile was somewhat similar to that elicited by LPS, and clearly distinguishable from that provoked by IL-2.Thus, it seems that the altered responding induced by IL-ip was more appropriately attributed to illness induced by the cytokine than direct effects on reward processes (Anisman et al., 1998).

5.3.4. Neurochemical Effects. As observed by other investigators (Dunn, 1995; Rivier, 1993), we have reliably found systemic IL-lp treatment to provoke marked increases of plasma ACTH and corticosterone, with the latter effects being evident at doses as low as 0.025 and 0.05pg. Systemic IL-lp also provoked region-specific alterations of biogenic amines in the brain (see Figure 11). Although NE levels and utilization were unaltered in the entire hypothalamus, NE levels were reduced in the PVN, while the utilization of NE (as reflected by MHPG accumulation) was increased in the arcuate plus median eminence. Furthermore, IL-lp increased NE utilization within the locus coeruleus, and induced somewhat less of an effect in the prefrontal cortex. Within nigrostriatal regions, as well as in the nucleus accumbens, there was no indication of any amine variations (Lacosta et al., 1998b).

It will be recalled that a static measurement of amine levels or metabolites may not provide a sufficiently accurate index of amine activity, and thus experiments were conducted in rats to determine in vivo amine variations. These experiments revealed that IL-ip (l.Opg/rat) had little effect on DA release from the nucleus accumbens or the prefrontal cortex. Interestingly, as seen in Figure 12, IL-lp affected the release of accumbal 5-HT, as reflected by an accumulation of 5-HIAA, and these effects were exacerbated by the introduction of a stressor (air-puff) (Merali, Lacosta, & Anisman, 1997; Song et al., 1998). IL-ip was also found to influence 5-HT release at the hippocampus, but the interaction of the IL-1P and stressor effects were less profound. As in the case of IL-2, the amine variations were sustained for a protracted period of time, even though the half-life of IL-lp is fairly brief. Thus, it is possible that IL-lp sets into motion a series of peripheral and/or central effects that sustain the altered amine variations. Overall, it appears from these in vivo experiments that IL-lp influences 5-HT turnover, and that the neurochemical response associated with the cytokine may be influenced by the introduction of a relatively mild stressor. In effect, it may be important to consider that the behavior and neurochemical changes associated with cytokine and endotoxin challenge may be dependent on the stimulus context in which animals are tested. Essentially, as will be discussed shortly, following introduction of sickness-inducing agents the behavior of animals in their normal surroundings may be very different from that apparent in a novel, and thus somewhat threatening environment.

Although it has been suggested that systemic stressors (such as cytokine administration) would not affect HPA functioning via an amygdaloid mechanism, it ought to be noted that IL-ip may augment NE release from the central amygdala. In particular, in a recent experiment, we assessed the effects of IL-1 treatment in two strains of rats that had originally been bred for Fast or Slow development of generalized convulsive seizures elicited by amygdala stimulation (kindling) (Merali, Mclntyre,

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Figure II. Micc received intrape ri toncal Lnj ¿¡clioii of 1L-I|i and brain suctions taken I lir later, Ihc cytokine provoked dose-de pen dent changes of MHPG accumulation, indicating increased NE utilization, in the median eminence plus arcuate nucleus (ME/AreJ. lotus eoeruleus (EC), and the pre-fronial cortex (PFC), Levels ol NE within tticsc regions was unaltered (from Lacosta el ul„ I'J'JHb).

Figure 12. Percent change (+S.E.M) of extracellular 5-hydroxyindole acetic acid (5-HIAA) at the nucleus accumbens over 30min samples. After 4 samples rats received intraperitoneal IL-lfJ (l.Oug) or saline and 5 dialysate samples collected. Saline treated rats (open squares), and one group of rats that received IL-lfS (closed circlcs) then received a series of 5 air puff stressors, after which 5 further samples were collected. Rats that received IL-ip, but were not exposed to the air puff are represented by open triangles. Treatment with IL-1(5 increased accumbal 5-HIAA relative to baseline and relative to saline treated rats. While the airpuff hardly affected 5-HIAA in saline-treated rats, a marked increase of 5-HIAA was evident in rats that had received IL-lp (from Merali et al., 1997).

Figure 12. Percent change (+S.E.M) of extracellular 5-hydroxyindole acetic acid (5-HIAA) at the nucleus accumbens over 30min samples. After 4 samples rats received intraperitoneal IL-lfJ (l.Oug) or saline and 5 dialysate samples collected. Saline treated rats (open squares), and one group of rats that received IL-lfS (closed circlcs) then received a series of 5 air puff stressors, after which 5 further samples were collected. Rats that received IL-ip, but were not exposed to the air puff are represented by open triangles. Treatment with IL-1(5 increased accumbal 5-HIAA relative to baseline and relative to saline treated rats. While the airpuff hardly affected 5-HIAA in saline-treated rats, a marked increase of 5-HIAA was evident in rats that had received IL-lp (from Merali et al., 1997).

Michaud, & Anisman, unpublished report). However, it ought to be noted that these rats also differ in their response to stressors. The Fast rats tend to be more reactive (struggle more when restrained) and exhibit poorer inhibitory response tendencies in a passive avoidance test, habituation in an exploratory situation, as well as in a food-motivated delayed alternation test (Anisman, Lu, Song, Kent, Mclntyre, & Merali, 1997; Mohapel & Mclntyre, 1998). As shown in Figure 13, we observed that in the Fast kindling rats the release of NE at the central amygdala was not affected by the IL-ip (1.0 pg) treatment. In contrast, in the Slow kindling rats a marked rise of NE release was evident as early as 0.5 h following IL-1 administration, and persisted over the ensuing 2.5 hr test. Ordinarily, NE at the amygdala acts to inhibit kindling-induced seizure (Mclntyre, 1980), raising the possibility that the Slow strain is less prone to seizures owing to greater reactivity of amygdala NE neurons. Of course, at this juncture the relationship between amygdala NE and kindling in these strains is highly speculative. For the present purposes, the main point is that IL-lp may influence amygdala NE release, but organismic factors, possibly related to NE neuronal lability, may determine the central actions of IL-1 p. Inasmuch as the amygdala likely plays a prominent role in subserving anxiety (Lee & Davis, 1997), and CRH and NE may contribute in this

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Brain Blaster

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