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Derangement of the interaction between the immune and neuroendocrine systems represent one of the major mechanisms in the development of chronic fatigue syndrome. Induction of chronic fatigue syndrome by i.p. administration of the synthetic double-stranded RNA poly I:C provides a suitable experimental model for studying these mechanisms. We report here our studies of changes in the intensity of the cytotoxic and proliferative activities of splenocytes, changes in the intensity of immunomodulatory cytokine signal transduction via the sphingomyelin pathway in the P2 membrane fraction of the cerebral cortex, and changes in the activity of the hypothalamo-hypophyseal-adrenocortical system (HHACS) during development of chronic fatigue syndrome in rats. Suppression of both cytotoxic and proliferative activity was demonstrated in rat splenocytes during the formation of experimental chronic fatigue syndrome. Important data showing suppression of the activity of neutral sphingomyelinase (N-SMase) activity were obtained, this being a key enzyme in the sphingomyelin cascade, in cerebral cortex cells three days after animals were given Poly I:C. Injections of poly I:C were followed by impairment of HHACS function in rats, with decreases in corticosterone concentrations in standard functional tests in which animals were given ACTH and hydrocortisone. The results lead to the conclusion that impairments to the interaction between the immune and neuroendocrine systems during development of chronic fatigue, including changes in HHACS activity, are mediated both at the level of changes in the activity of immunocompetent cells and directly on brain cell membranes.