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0.78 (0.20)

0.56 (0.10)

Control

12.26 (0.22)

0.54 (0.07)

*For each immune challenge, animals were presented with two graduated tubes containing the sweet solution or water. Data represents the mean (+ S.E.M.) fluid consumption over a 24 hr period in non-deprived rats, following administration of LPS, IL-1(J, Mycoplasma fermentans or gpl20. Data for the acute immune challenges refcres to the consumption of a 10 mM saccharin solution by rats. Data for the EAE model refers to the consumption of a dilute sucrose solution by SJL mice over a period of 6 hr (averge of 2 sessions).

*For each immune challenge, animals were presented with two graduated tubes containing the sweet solution or water. Data represents the mean (+ S.E.M.) fluid consumption over a 24 hr period in non-deprived rats, following administration of LPS, IL-1(J, Mycoplasma fermentans or gpl20. Data for the acute immune challenges refcres to the consumption of a 10 mM saccharin solution by rats. Data for the EAE model refers to the consumption of a dilute sucrose solution by SJL mice over a period of 6 hr (averge of 2 sessions).

Interestingly, the decrease in sucrose preference preceded the appearance of clinical symptoms in this model, demonstrating the independence of anhedonia from the physical disease symptoms (unpublished observation). Studies in other laboratories corroborate these findings, demonstrating that immune challenges reduced the intake of sweetened milk (Swiergiel et al., 1996,1997), and abolished the reinforcing effect of cocaine (Suzuki, Funada, Sugano, Misawa, Okutomi, Soma, & Mizuno, 1994). Moreover, mice that spontaneously develop systemic autoimmune lupus-like disease, also show blunted sensitivity to sucrose, which can be reversed by an immunosuppressive treatment (Sakic, Denburg, Denburg, & Szechtman, 1996).

Several previous studies have used the consumption of sweet solutions as a model of anhedonia, describing a decrease in the consumption of and preference for sucrose and saccharin solutions in an animal model of depression (exposure to chronic mild unpredictable stress) (Willner, 1997). However, the use of consumption of sucrose or other calorie-rich highly palatable diets as a measure of cytokine-induced anhedonia is problematic, because of the marked anorexia and loss of body weight that accompany immune activation. Thus, a decrease in the total amount of sucrose or sweetened milk consumption may reflect either anhedonia and/or anorexia and reduced calorie intake. Because saccharin has a sweet taste but no calories, our findings that immune activation induced reduction in saccharin preference provide further support for the anhedonic effect of immune challenges.

It should be noted, however, that the validity of the saccharin preference test as a model of anhedonia is controversial. Previous research, demonstrated that although the major component of saccharin's taste is sweet, there is also an aversive, bitter-like component (Dess, 1993). Aubert & Dantzer (1998). have recently studied the effects of LPS on taste reactivity (TR) to saccharin, sucrose and quinine solutions. They showed that following LPS administration, TR to quinine and sucrose were unaltered, but the responses to saccharin or to a sucrose solution adulterated with quinine were changed, such that more aversive responses and less ingestive responses were exhibited by LPS-treated animals. These findings indicate that LPS accentuates the aversive component of the rewarding saccharin stimulus, suggesting that LPS produces increased finickiness rather than anhedonia. Nevertheless, it should be noted that changes in TR do not necessarily represent the overall hedonic response of the animal or its inclination to consume a palatable solution. TR responses are mediated by hedonic mechanisms in the lower brain stem taste centers, as evidenced by their preservation in decerebrate animals (Grill & Norgren, 1978). Hedonic evaluation assessed by the TR test can be at odds with consummatory or instrumental behavior. For example, in lines of rats that were genetically selected for high and low saccharin consumption, the high-consuming rats manifested more rejection responses to saccharin in the TR test (Badia-Elder, Kiefer, & Dess, 1996). Thus, it is possible that the effects of LPS and other immune challenges on saccharin preference is not solely explained by increased finickiness, but may be also related to their effects on incentive-motivational systems in brain centers higher than the brain stem. In conclusion, studies on the intake of and preference for palatable solutions as a model for anhedonia have some methodological problems, and therefore should employ both nutritive and non-nutritive solutions.

3.7.2. Decreased Responding for Rewarding Intracranial Self Stimulation. Further evidence for the anhedonic effects of immune activation is provided by investigation of the effects of immune challenges and cytokines on rewarding intracranial self stimulation (ICSS). Suppression of ICSS is a very useful animal model to study anhedonia (Willner, 1994). Endotoxin-induced suppression of ICSS has been demonstrated more than 3 decades ago (Miller, 1964). This report was recently corroborated by the findings that exogenous administration of LPS (Borowski, Kokkinidis, Merali, & Anisman, 1997) or IL-2 (Anisman, Kokkinidis, Borowski, & Merali, 1998; Anisman, Kokkinidis, & Merali, 1996) produce a dramatic and long-lasting decrease in ICSS.

Antigenic challenge with sheep red blood cells also reduced ICSS from rat nucleus accumbens at times that approximated the peak of immune response (Zacharko, Zalcman, Macneil, Andrews, Mendella, & Anisman, 1997). As shown in the above studies, the effects of immune challenges on ICSS represent a specific motivational change, rather than motoric, soporific, attentional or cognitive deficit.

In contrast to the effects of LPS and IL-2, administration of IL-ip had no clear effect on ICSS: No effect of IL-ip on ICSS was detected following administration of a dose comparable to an effective dose of IL-2 (1 pg/rat), whereas a higher dose (2pg/rat), which induced overt signs of illness, attenuated ICSS (to a lesser extent than IL-2), with some of the animals ceasing responding almost completely and the others affected only slightly (Anisman et al., 1998). The authors conclude that whereas IL-2 reduce ICSS by producing anhedonia, the effects of IL-1 in this paradigm are secondary to illness. It should be noted, however, that these findings do not entirely rule out the possibility that IL-1 is involved in hedonic processes. It is possible that in contrast to the "pure" anhedonia produced by IL-2 (i.e., disruption of ICSS with no other signs of illness), illness and anhedonia are tightly coupled in IL-l-injected animals. The anhedonic effect of LPS is also coupled with sickness behavior; in fact, the dose of LPS (100 pg/kg), which was effective in decreasing ICSS, probably produced more illness than the ineffective dose of IL-1 (1 pg/rat). Thus, the possibility that IL-1 is at least partially involved in mediating the anhedonic effects of LPS can not be ruled out. Furthermore, several investigators have demonstrated that IL-1 acts synr-gistically with other cytokines in producing sickness behavior symptoms. Thus, in future research the possibility that IL-1 influences hedonic processes via interactions with other cytokines should be examined.

3.7.3. Reduced Libido and Impaired Sexual Activity. A significant reduction in sexual interest or desire, as well as difficulties in sexual functioning are commonly associated features of depression (DSM-IV, 1994; Mathew & Weinman, 1982). These features are viewed as manifestation of the general loss of interest and pleasure in activities that were previously considered pleasurable (DSM-IV, 1994). Indeed, in animal studies, sexual contact has been shown to act as a reinforcing stimulus (Meyerson & Lindstrom, 1973), i.e., its motivational effects are similar to those of other reinforcing stimuli such as ICSS or palatable food. To further explore this anhedonic aspect of immune activation, we have recently examined the effects of LPS and IL-1 P on sexual behavior in male and female rats, using various behavioral tests. Low doses of LPS, administered either peripherally or centrally, significantly reduced sexual motivation, preceptive (soliciting) behavior and receptivity in females. Higher doses of LPS completely abolished all aspects of female sexual behavior. In contrast, male sexual behavior was affected only by high doses of LPS (Avitsur, Pollak, & Yirmiya, 1997; Yirmiya, 1996) . Similarly, administration of IL-lp had no effect on any component of male sexual behavior, whereas even low doses of IL-ip, administered either peripherally or centrally, markedly decreased sexual motivation, preceptive behavior, receptivity, and attractivity in females (Avitsur et al., 1997; Avitsur, Cohen, & Yirmiya, 1998).

In conclusion, various immune challenges induce anhedonia as well as many behavioral alterations, which resemble the vegetative symptoms of depression. These findings suggest that immune activation produces a depression-like syndrome in animals.

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