Behavioral and Neurochemical Consequences of Iipopolysaccharide

5.1.1, Angiogenic Effects of Lipopolysacchuride. In a series of recent experiments (Lacosta, Kulczycki, Merali. & Anisman, 1996; Borowski, Kokkinidis. Merali, & Anisman, 199?). some conducted in mice and others in rats, we assessed the effects of lipopolysaccharide (LPS) on anxiety-like responses and on responding for rewarding brain stimulation. In mice, administration of low doses of LPS provoked classic signs of illness, including apparent soporific effects, reduced open-field exploration, reduced consumption of a palatable food (chocolate milk) and increased latency to approach a novel stimulus. As seen in Figure 1. in an elevated plus-maze, which has been used as a test of anxiety, animals treated with LPS reduced the frequency of open-arm visits, whereas visits to the closed arms of the ma/e were unaffected. When animals ventured onto the open arms they did not remain there long, supporting the view that the reduced visits were not secondary to motor disturbances. Paralleling the effects seen in the plus-maze, in a light-dark box test of anxiety, where high anxious animals tend to avoid the illuminated region, it was found lhat LPS increased the apparent reluctance of mice to remain in the brightly lit area. This effect was seen with doses as low as 0.5pg/mouse. As in the ease of the plus-maze, it was noted that when animals that had been treated with LPS entered the illuminated area of the light-dark box, they quickly left this area. Moreover, if LPS treated animals were placed directly into the illuminated region, like their vehicle-treated counterparts they left this area immediately (<2sec),

5.1.2. Anhedonic Effects of LPS. In addition to provoking anxiety-like effects, endotoxin treatment markedly affected responding for rewarding brain stimulation. Figure 2 shows the effects of LPS (HX)pg/rat) on responding for stimulation from the

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Figure I, LPS provokes a dose-dependent anxiogenic response in mice, as reflected by decreased visits to the open arms of an elevated plus-mw.e at 2hr following i.p. administration (left-hand panel). Entries into the closed arms was not affectcd by the endotoxin (right-hand panel) (f rom Lacosta el a).. 1996).

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Figure 2. In rats treated with LPS (100 p.g) responding for rewarding stimulation from the lateral hypothalamus was impaired. Responding at each current intensity is shown for vehicle and LPS-treated rats over the course of a descending, followed by an ascending series of current presentations (FromBorowski et al., 1997).

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Figure 2. In rats treated with LPS (100 p.g) responding for rewarding stimulation from the lateral hypothalamus was impaired. Responding at each current intensity is shown for vehicle and LPS-treated rats over the course of a descending, followed by an ascending series of current presentations (FromBorowski et al., 1997).

lateral hypothalamus in Wistar rats 2hr following LPS administration (Borowski et al., 1997). It is clear that the endotoxin provoked a marked reduction of responding for rewarding stimulation. However, the profile of results was not characteristic of that induced by a stressor. In particular, it seemed that during the initial portion of the test (descending series of current intensities) responding was only modestly reduced. At the higher current intensities LPS-treated animals generally displayed proficient performance. At the lower current intensities, which are ordinarily associated with lower rates of responding, LPS retarded performance. Interestingly, during the ascending portion of the titration function, responding remained depressed even when higher intensities were applied. At a lower dose (50pg), not shown in the figure, animals still emitted some responses, and hence had the opportunity to sample the rewarding value of the stimulation. Still, these animals showed depressed responding for rewarding stimulation during the ascending series of current presentations. Even at high doses, the animals displayed proficient discrimination ability (directing their responses to the + stimulus) suggesting that they could attend to the appropriate environmental cues. In effect, these data suggest that despite the malaise associated with the LPS treatment, given sufficient reward, rats will continue to emit responses, but as the benefit of responding wanes, the propensity to respond tails off precipitously. Moreover, once this occurs, it is less likely for animals to return to the operant readily.

5.1.3. Neurochemical Effects of LPS. Consistent with numerous earlier reports, LPS appreciably influenced HPA functioning, as reflected by increased plasma corti-costerone and ACTH at 2hr following treatment. As alluded to earlier, there have been several reports showing that LPS will profoundly affect biogenic amines within hypothalamic sites. Our findings in post-mortem tissue (in mice) and in vivo (among rats) have been consistent with these reports, and have also revealed that LPS markedly influenced NE, DA, and 5-HT at extrahypothalamic sites. In particular, as seen in Figure 3, in mice low doses of LPS (1.0-5.0 (ig) increased the utilization of NE within the PVN, as well as the hippocampus and prefrontal cortex (Lacosta et al., 1996). Given that DA variations within the nucleus accumbens are thought to play a pivotal role in subserving rewarding brain stimulation, we also assessed the effects of LPS (100 pg) on accum-bal DA release in vivo. As shown in Figure 4, LPS effectively increased the release of

Figure 3. Concentrations of the NE metabolite, 3-methoxy-4-hydroxyphenylenegIycol (MHPG), in the paraventricular nucleus of the hypothalamus (left-hand panel), prefrontal cortex (centcr panel), and hippocampus (right-hand panel) in post-mortem tissue of mice treated with varying doses of LPS 2lir earlier (from Lacnsta ct al., 19%).

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