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Easei-ne 0.25 Hr 24 hr

2 weeks region. Together, these data provisionally suggest that (a) IL-2 may induce an anhe-donic effect, as reflected by altered responding from both the dorsal VTA and the lateral hypothalamus, (b) these effects likely reflect the central actions of the cytokine, and (c) the effects engendered by IL-2 are reminiscent of those induced by stressors in terms of the protracted behavioral changes observed, and the region-specific effects noted.

5.2.4. Neurochemical alterations. In evaluating the neuroendocrine effects of IL-2, it became clear that the effects of this cytokine were readily distinguishable from the effects of stressors. For instance, while stress potently activates HPA activity, we observed across a range of doses that acute i.p. administration of IL-2 did not influence plasma corticosterone or ACTH levels (Lacosta et al., 1998a). Moreover, we observed that even after 7 days of IL-2 treatment, which it will be recalled influences exploration and Morris water-maze performance, plasma corticosterone levels were unaltered.

Across a series of doses IL-2 (0.1-1.6[ig; 1.1 x 104IU/pg) did not appreciably influence NE, DA, 5-HT or their respective metabolites in several mouse brain regions, including the hypothalamus, locus coeruleus, hippocampus, prefrontal cortex, nucleus accumbens, substantia nigra, and caudate (Lacosta et al., 1998). Of course, static measurements of amines and metabolites in post mortem tissues may not provide a clear picture of transmitter utilization, and thus we also evaluated in vivo variations of amine release in response to 1.0 pg of systemically administered IL-2 (Anisman et al., 1996; Song, Merali, & Anisman, 1998). In this experiment we assessed DA released from the nucleus accumbens, since this region was thought to be essential in subserving the rewarding value of electrical brain stimulation. In contrast to the effects of stressors which ordinarily enhanced DA release from the shell of the nucleus accumbens (Kalivas & Duffy, 1995), DA release was greatly inhibited by IL-2 treatment, and this effect was further exacerbated by application of a stressor (mild air-puff) (see Figure 7). It ought to be underscored, however, that IL-2 may have dose-dependent biphasic effects on DA and ACh activity (Araujo et al., 1989; Lapchak, 1992). Thus, while IL-2 inhibited DA release from the accumbens, it is essential to conduct more detailed dose-response analyses in order to understand the actions of acute IL-2 treatment on motivational systems. As well, as stressors differentially influence DA release from the core and the shell of the nucleus accumbens, it may be important to distinguish the effects of IL-2 from both these regions.

We have recently observed that the differential effects of acute and chronic IL-2 noted in several behavioral paradigms, are also evident with respect to brain amine variations. In particular, contrary to the lack of effect seen after acute treatment, repeated administration of IL-2 (l.Opg over each of 7 days) resulted in marked region-specific biogenic amine variations. In mice that had received chronic IL-2 (l.Opg; 1.1 x 104IU), the level and/or utilization of NE was elevated in the median eminence (although not in the PVN), hippocampus and prefrontal cortex. Hippocampal 5-HT utilization was likewise elevated, while in the prefrontal cortex 5-HT levels declined. It is still premature to ascribe specific cognitive impairments associated with IL-2 immunotherapy in humans to such neurochemical changes in the rodent brain, but it is significant that the spatial disturbances seen in human patients is paralleled by spatial disturbances in the Morris water-maze test. It is conceivable that the behavioral changes described earlier, as well as the cognitive disturbances in humans, may represent the extrahypothalamic amine changes associated with a chronic IL-2 regimen.

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Figure 7. Following 4 baseline dialysate samples (_>Omiti/satnple) being laken, rats received either IL-2 (I.Optg; 1.1 x 10'HJ) or saline treatment Release of DA from the nucleus about 2.5lir following treatment declined by approximately 25%. Upon presentation of an air-puff the decline was more pronounced, reaching 50% of baseline (from Anismati el aL 1 ''96).

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Figure 7. Following 4 baseline dialysate samples (_>Omiti/satnple) being laken, rats received either IL-2 (I.Optg; 1.1 x 10'HJ) or saline treatment Release of DA from the nucleus about 2.5lir following treatment declined by approximately 25%. Upon presentation of an air-puff the decline was more pronounced, reaching 50% of baseline (from Anismati el aL 1 ''96).

5.3. Behavioral and Neurochemical Consequences of IL-3fi

The majority of studies assessing the behavioral effects of IL-1 (J have focused on sickness behavior (including sleep and anorexia) and the processes subserving these effects; however, assessments have also been made of IL-ip effects on other behaviors, including exploration, and acquisition of learned appetitive responses (Bluthe et a!., 1997; Dantzer et al„ 1996; Linthorst et at., 1995; Moldofsky, 1995; Plata-Salaman, 1998). In the main, these studies have shown that IL-ip readily disrupted behavioral outputs. Given the profound illness induced by IL-1fi, it is difficult to discern to what extent (he behavioral effects of the cytokine reflect changes of motivational or anxiety processes. Yet, as indicated earlier, IL-1 ra has been shown to attenuate the central amine and neuroendocrine changes induced by stressors (Shintani et al„ 1995a, b), and to antagonize the shut tle-escapc performance disturbances otherwise provoked by prior exposure to inescapable shock (Maicr & Watkins, 1995). Thus, there is reason to suppose that the effects of IL-1 (3 might reflect the stress-like actions, rather than sickness induced by the cytokine. Accordingly, we conducted several experiments to assess ihe actions of IL-1(3, alone or in conjunction with either TNFot or IL-6, on behavioral outputs and on central neurochemical processes.

5.3./. Palatable Food Intake. Behaviorally. IL-1 produced a dose dependent disruption in the consumption of a highly palatable substance (chocolate milk), and in an open field situation this cytokine reduced active responding and reduced exploratory tendencies (Lacosta. Merali, & Anisman, 1998b). Interestingly, although lL-ip (0.2-1.6fig) substantially reduced locomotor activity (and accompanying exploration), at low doses IL-ip (0.2 and 0.4 p.g) induced a transient increase of exploratory tendencies directed towards a novel object. When animals were tested in a free-running spontaneous alternation task, they exhibited high levels of alternation, comparable to that seen in saline treated mice. Indeed, this was the case even if mice received 7 days of treatment (0.5 jig/m o us e/d ay). As spontaneous alternation performance is thought to reflect habituation of exploratory tendencies (Kokkinidis & Anisman, 1980), these data, like those involving LPS, suggest that IL-lp treated mice are able to attend and respond appropriately to the environmental cues, at least when placed in a novel situation (Lacosta et al., 1998b).

5.3.2. Anxiogenic Effects. The behavioral profile of mice in anxiety-related situations differed from that seen in following IL-2 treatment. Systemic administration of IL-lp (at low doses) provoked a decline in the number of entries into the open arms of an elevated plus maze, without an appreciable change of closed-arm entries. Figure 8 shows that while IL-ip induced an anxiogenic-like effect (reduced open arm entries in a plus maze), IL-2 did not provoke such an effect. We have observed that the anxiogenic effect of IL-lp tended to appear at low doses, and was less remarkable at doses above 0.8 pg, possibly owing to the masking of anxiety by the sickness (Lacosta et al., 1996). In addition to the effects of systemic IL-ip, central IL-ip administration also decreased entries into the open arms of a plus maze (Connor et al., 1998). Thus, these data suggest that IL-ip induces anxiogenic-like effects, stemming from the central actions of this cytokine. However, a note of caution must be introduced at this juncture. We have observed that the plus-maze test is generally associated with a high degree of between-animal variability, and we have not uniformly found IL-ip to induce anxiogenic-like effects in this paradigm. In one study, for instance, we observed that the cytokine did not promote a statistically significant decline in open-arm entries. However, in this study animals engaged in a great increase of risk-assessment (i.e., the animal sits at the choice point, and extends its forelimbs and body onto the open arm, but without fully entering on to this arm). Thus, while there is reason to suppose that IL-ip induces an anxiogenic-like action, such a conclusion cannot be considered as being unequivocal.

5.3.3. Anhedonic Effects. With respect to the potential anhedonic effects of IL-ip, we assessed the effects of this cytokine (as well as that of other cytokines) on the consumption of a highly palatable food substance (chocolate milk). After stable consumption was established (less than 10% between days variability) mice were injected with IL-ip and lhr later their consumption was monitored over a lhr period. As seen in Figure 9, the cytokine provoked a dose dependent reduction of chocolate milk con-

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