Research reportDifferential effects of interleukin (IL)-1β, IL-2 and IL-6 on responding for rewarding lateral hypothalamic stimulation
Introduction
Exogenous or endogenous threats to homeostasis, which include injury, bacterial infection and inflammation, give rise to a cascade of immunological alterations. These are coupled with metabolic and neuroendocrine changes, collectively referred to as the acute phase response, and may be associated with a profile of behavioral changes described as sickness behavior 20, 29. The sickness behavior, which can be provoked by endotoxins, such as lipopolysaccharide (LPS), or cytokines, such as interleukin-1 (IL-1) is characterized by increased body temperature, curled body posture, piloerection, increased sleep, reduced social exploration, lethargy, anorexia, and possibly anhedonia, as well [29].
While sickness behaviors may stem from the peripheral physiological changes associated with the acute phase response, it seems likely that the source for at least some of the behaviors may involve the central nervous system. Indeed, it is well established that immune activation may affect endocrine and neurotransmitter functioning 3, 6, 7, 15, 22, 60, just as manipulations of endocrine or central neurochemical activity may influence immune functioning 3, 12, 59. For instance, systemically administered IL-1 has been shown to increase the turnover and reduce the levels of norepinephrine (NE) and serotonin (5-HT) in the hypothalamus, as well as limbic brain regions 17, 24, 33, 39, 72. Moreover, when applied directly to the brain, IL-1 affected the release of NE, dopamine (DA) and 5-HT from the hypothalamus 36, 44, 45, 62. As well, it seems that central administration of the IL-1 receptor antagonist (IL-1ra) prevented the neuroendocrine effects of systemically administered LPS 15, 25and has also been shown to partially antagonize the decline of operant responding for food reinforcement otherwise provoked by IL-1 treatment [28].
Interleukin-6 (IL-6), like IL-1, is a proinflammatory cytokine released from activated macrophages. The data concerning the effects of this cytokine on endocrine, neurotransmitter functioning and on behavior are less extensive than those involving IL-1. It has been reported that IL-6 administered systemically or intracerebroventricularly did not affect hypothalamic NE turnover [65], although enhanced pituitary ACTH activity has been observed [37]. Interestingly, IL-1 and IL-6 have been reported to act synergistically with respect to HPA functioning [73], and an IL-6 antagonist was shown to attenuate the LPS-induced ACTH response [54].
Administration of interleukin-2 (IL-2), a cytokine released by activated T-helper cells, has been shown to have endocrine effects 23, 26, 27, 42and to increase the turnover of hypothalamic NE [72]. In contrast to IL-1, which was shown to promote CRH release from both the central amygdala and the hypothalamus [58]and increase POMC mRNA levels [19], IL-2 did not influence CRH mRNA within the paraventricular nucleus [19]and did not affect plasma corticosterone or ACTH concentrations 32, 72. Interestingly, IL-2 receptors have been identified within the brain [4], and application of IL-2 to striatal slices enhanced DA release under basal conditions and during potassium-evoked neuronal depolarization 34, 35. Moreover, it has been reported that systemic IL-2 administration reduced the in vivo release of DA from the nucleus accumbens [2]. As well, when applied directly to the locus coeruleus, IL-2 influenced arousal/sleep 49, 50and its application to the caudate or substantia nigra provoked ipsilateral turning, suggesting action within nigrostriatal regions [34]. Taken together, these data suggest a possible role for IL-2 in subserving some of the central neurochemical and behavioral effects associated with antigenic challenge.
Although there is reason to believe that the sickness behavior may be influenced by CNS processes, and cytokines contribute to such effects, it is difficult to disentangle the various components of the sickness response from one another. For instance, the diminished food intake associated with LPS or IL-1 treatment may reflect the anorexic or feeding suppressant effects of the treatments, independent of any anhedonic effects (i.e. diminution of the rewarding aspects of otherwise reinforcing stimuli). Alternatively, endotoxin or cytokine challenge may induce anhedonia, but in an appetitive paradigm it is difficult to discern the relative contributions of anorexia vs. that of anhedonia. Yet, it has been demonstrated that IL-2 elicited disturbances in responding for rewarding hypothalamic self-stimulation [2], just as stressors were previously found to have such effects [70]. These effects could not be attributed to either motoric factors or general malaise, and were more likely related to an anhedonia stemming from disturbances of mesolimbic DA activity.
In light of the findings that IL-1 and IL-6 both influence endocrine and central neurotransmitter processes, and IL-1 also induced sickness behaviors, it was of interest to determine whether systemic administration of proinflammatory cytokines would lead to impairments of responding for rewarding hypothalamic stimulation, just as stressors and IL-2 administration provoked such effects. It might be noted that following systemic IL-2 administration, the effects on ICSS were relatively modest, but became progressively more pronounced when animals were tested over a 1-week period thereafter [2]. Accordingly, in the present investigation, we assessed the immediate and longer term effects of IL-1, IL-6 and IL-2 on responding for rewarding brain stimulation from the lateral hypothalamus.
Section snippets
Subjects
Male Wistar rats (250–300 g) were group housed in a temperature-controlled environment with continuous access to food and water, and were maintained on a 12:12-h light–dark schedule. Behavioral testing was conducted during the light portion of the schedule. Following arrival from the supplier (Charles River, Que.) rats were acclimated to the laboratory for 2 weeks before serving as experimental subjects.
Apparatus
The ICSS apparatus comprised 4 black Plexiglas boxes (60×50×35 cm). Two holes, 4 cm in
Acute effects of IL-2 on self-stimulation
The number of reinforced and the number of non-reinforced responses emitted were analyzed by analysis of variance with repeated measures for the cytokine and current variables. Newman–Keuls multiple comparisons (α=0.05) were used to compare treatment differences or variations of responding as a function of the current intensity. Since not all animals reached asymptotic levels of responding, the reward thresholds were calculated for each animal's rate–intensity function using the a priori
Discussion
Commensurate with our previous findings [2], systemic administration of IL-2 provoked a disturbance of responding for rewarding brain stimulation from the lateral hypothalamus. As previously observed, when animals were tested soon after IL-2 treatment, the response impairment was relatively modest; however, a significant rightward shift in the rate–intensity function and an increase of the reward threshold was observed among animals retested 24 and 168 h later. In our previous studies, we had
Acknowledgements
This research was supported by a grant in aid of research from the Medical Research Council of Canada.
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