Is

Figure 4. Percent change from baseline of extracellular DA from the nucleus accumbens over 30min samples. Using in vivo microdialysis, systemic LPS administration (100 jig) was found to increase DA release for about 1.5 hr (3 sampling periods). Exposure to mild air-puff presentations 4hr after LPS administration did not appreciably influence the response to LPS (from Borowski et al., 1997).

accumbal DA (Borowski et al., 1997). As will be seen shortly, this effect (as well as the behavioral actions of LPS) are distinct from those elicited by IL-ip.

In Summary, our findings suggest that in addition to promoting sickness, LPS may engender an anxiogenic-like reaction. Of course, it is still unclear whether such an outcome was a direct result of the central amine or peptide variations induced by the treatment or were secondary to the malaise engendered by the endotoxin. Moreover, it appeared that LPS effectively influenced responding for otherwise rewarding brain stimulation, but the characteristic pattern observed differed from that ordinarily evoked by stressors. In particular, at higher current intensities rats readily responded for rewarding stimulation, but as the rewarding value of stimulation diminished, the drop-off of responding was particularly precipitous. Once these animals ceased responding, the operant did not reappear during the ascending series despite the presence of high current intensities. In effect, in the presence of sickness or anhedonia engendered by the LPS, the cost of responding exceeded the benefits derived, and hence responding did not progress. It remains to be established whether a similar profile would be evident in a progressive ratio situation (Richardson & Roberts, 1996), where current was held constant but cost of responding was increased (by progressively increasing the number of responses needed to obtain a reward). In a different type of paradigm which has been used to assess anhedonia, Yirmiya (1996) found that LPS (like stressors) reduced consumption of sucrose, and this effect was attenuated by chronic pretreatment with an antidepressant agent (suggesting a parallel to depressive illness). We have, as yet, not assessed the effects of chronic antidepressant treatment on LPS-provoked disturbances of self stimulation responding.

5.2. Behavioral and Neurochemical Consequences of IL-2

As indicated earlier, the few behavioral analyses of patients undergoing immunotherapy that have been conducted indicated that chronic IL-2 administration markedly influenced cognitive processing, and promoted psychiatric disturbances.Thus, it was of interest to establish whether systemic IL-2 administration would likewise influence anxiety or affect responding for rewarding stimulation in rodent studies. At the outset, it must be emphasized that in most of our experiments the effects of acute IL-2 treatment were assessed, and only recently have we begun to evaluate the effects of chronic IL-2 treatment. As in other reports (Hanisch & Quirion, 1996; Hanisch, Rowe, Sharma, Meaney, & Quirion, 1994; Hanisch, Neuhaus, Rowe, van Rossum, Moller, Kettenmann, & Quirion, 1997), our studies revealed that the behavioral effects of IL-2, as well as central neurochemical changes induced by such treatments, were most notable after a chronic IL-2 regimen.

5.2.1. Anxiety Tests. The effects of acute IL-2 treatment could be distinguished from the actions of LPS, as well as those elicited by proinflammatory cytokines (IL-ip and TNFa). In CD-I mice acutely injected with IL-2 (0.05-1,6(xg; 550-17,600IU) there was no evidence of any change of exploratory patterns in an open field, including locomotor activity, rearing, grooming, sitting digging, or approach to a novel object. Likewise, when mice were permitted to freely explore a symmetrical Y-maze, IL-2 did not influence spontaneous alternation (i.e., mice tended to enter those arms of the maze least recently visited). Thus, these data suggest that IL-2 treated animals reacted normally to environmental cues, at least within a nonthreatening context. In addition to the lack of an effect in an exploratory situation, we observed that in tests of anxiety, such as the light-dark box, and in the elevated plus-maze, acute systemic IL-2 treatment was absolutely without effect on performance (Lacosta, Merali, & Anisman, 1998b). It was likewise reported that murine IL-2 did not influence elevated plus-maze performance in mice (Petitto et al., 1997), while we observed that in rats icv administration of IL-2 also failed to affect plus-maze performance (Connor, Song, Leonard, Merali, & Anisman, 1998). Although we have not yet assessed the effects of chronic IL-2 on performance in anxiety tests, we have observed that chronic IL-2 treatment over 7 days affected exploratory patterns. Specifically, while chronically treated mice did not display any signs of illness, they exhibited reduced levels of locomotor activity, and tended to make less frequent contact with a novel stimulus object (Lacosta, Merali, & Anisman, 1998b). Thus, it remains possible that chronic IL-2 (unlike acute treatment) impacts on anxiety.

5.2.2. Spatial Learning. Our initial experiments suggested that acute administration of hIL-2 did not provoke anxiety, nor did it affect several other behaviors in exploratory or habituation tests. Yet, it was reported that IL-2 administered repeatedly directly into brain disrupted Morris-water maze performance (Hanisch & Quirion, 1996), a finding commensurate with data indicating that IL-2 altered hippocampal ACh activity (Araujo et al., 1989; Hanisch, Seto, & Quirion, 1993) which is presumably involved in spatial learning. As well, humans undergoing IL-2 immunotherapy also exhibited disturbances in tests involving spatial learning or performance (Capuron, Ravaud, Radat, Dantzer, & Goodall, 1998). Accordingly, we conducted several experiments in which we assessed the effects of acute and chronic systemically administered IL-2 on Morris water-maze performance.

In the Morris water-maze, animals are placed in a water-filled pool (often with milk powder added to make the water opaque), and required to learn the position of a platform submerged just beneath the surface. As each trial begins from a different location, animals need to use extraneous cues to localize and to find the platform. There

Trials

Figure 5. Mice received 7 days of systemic IL-2 (l.Oug/mouse; 1.1 x 10"IU) or vehicle and then tested in a Morris water-maze where the location of the safe platform varied over days. Mice received 8 trials a day over 8 days, and continued to receive the IL-2 or vehicle treatments 1 hr before test on each test day. The left hand panel shows that performance in IL-2 treated mice over days was disrupted by the chronic IL-2 treatment. The right hand panel indicates that on the first trial of each day vehicle and IL-2 mice exhibited comparable performance. However, while rapid improvement was seen over trials in vehicle animals, the between-trial improvement was limited in IL-2 treated mice (from Lacosta et al., 1998a).

are several variants of this procedure: in some paradigms the location of the platform is always the same (e.g., N.E. quadrant), while in other paradigms a new location is used on each day. In the latter paradigm, on the first trial of each day the animal is unaware of the location of the platform, although the animal will have learned the concept that there is, in fact, a platform located within the pool (reference memory), and hence latencies decline over days. Having found the platform on any given day, subsequent trials evaluate the animal's ability to recall the position of the platform (working memory) (Whishaw, 1985). When animals were tested in a simple Morris water-maze (fixed location of the platform) animals acutely treated with hIL-2 (1.0 pg; 1.1 x 104IU, 1 hr before test on each of 5 successive days), exhibited proficient performance. In subsequent studies we assessed the effects of chronic IL-2 on performance. However, as the fixed location paradigm is so quickly acquired, the potential effects of IL-2 may be obfuscated. Accordingly, mice were tested in the more complex Morris water-maze in which the position of the platform varied over days. Mice received 7 days of i.p. IL-2 treatment (1.0 ng; 1.1 x 104IU) or saline administration, after which training commenced. On each of the ensuing 8 days mice received i.p IL-2 treatment and tested lhr afterward (8 trials/day). As seen in Figure 5, performance in the spatial learning test was impaired following chronic IL-2 treatment. This disruption was evident as early as the first test day. Importantly, when the data were assessed over the 8 daily trials, it was noted that on the first trial of each session the groups did not differ, suggesting that they were equally capable of swimming and employing a search strategy to find the platform. However, while saline-treated mice gained from the first trial experience, showing marked between-trial improvements, the IL-2 treated mice seemed less disposed to gaining from the experience of the first trial. Thus, it seems that the animal's working spatial memory was impaired by the chronic IL-2 treatment.

5.2.3. Anhedonia. Acute, systemic IL-2 treatment influenced responding for rewarding brain stimulation in both rats and mice. In the initial experiments rats had electrodes implanted within the lateral hypothalamus (medial forebrain bundle) and trained to respond on the discriminated titration paradigm until stable responding was achieved (<10% between days variation, coupled with >95% choice accuracy in the dis-

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