The fundamental question addressed in this application concerns the mechanisms that mediate bidirectional communication between the CNS and the immune system. The investigators focus on one potential mechanism, the interactions between neurotransmitters and cytokines, as they pertain to sleep. There is ample evidence that serotonin (5-HT) and interleukin-1 (IL-1) modulate sleep. 5-HT and IL-1 influence each other; IL-1 induces serotonergic activation, and 5-HT induces IL-1. Furthermore, the investigators' new data indicate that somnogenic responses to IL-1 are altered in animals in which 5-HT synthesis has been inhibited. Therefore, the somnogenic responses to IL-1 may be mediated, in part, by the serotonergic system. On the other hand, IL-1 may represent one of the sleep factors through which 5-HT has been proposed to influence sleep. The PI will investigate three specific aspects of these interactions: 1) Does 5-HT mediate, in part, IL-1-induced alterations in non-rapid eye movement sleep (NREMS)? 2) Do raphe nuclei mediate this effect? 3) Does IL-1 mediate, in part, the enhancement of NREMS induced by the 5-HT precursor L-tryptophan? They will investigate these questions by a) blocking 5-HT2 receptors prior to central administration of IL-1, b) microinjecting IL-1 into the raphe nuclei, and c) blocking central IL-1 actions with antibodies prior to inducing serotonergic activity with L-tryptophan. They will use rats chronically instrumented to allow administration of substances directly into the CNS with subsequent determination of sleep-wake behavior and serotonergic activity. Although there is evidence that IL-1 and 5-HT interact at multiple levels, the critical experiments necessary to determine the extent of interaction and specific effects on sleep have not been done. Direct evidence that interactions between these two systems may be a critical feature of the regulation of sleep would be obtained if blockade of serotonergic activity alters IL-1 induced enhancement of NREMS, and/or pretreatment with anti-IL-1 alters L-tryptophan-induced enhancement of NREMS. The proposed experiments will provide information useful for understanding the mechanisms whereby sleep is altered in response to an immune challenge. These experiments will also explore one possible brain site for the interactions between 5-HT and IL-1. The successful completion of these experiments will warrant the development of future, more extensive, studies of IL-1/5-HT interactions as they pertain to sleep-wake regulation.
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