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Orexin Expression and Function: Glucocorticoid Manipulation, Stress, and Feeding Studies

Henry Wellcome Laboratory for Integrative Neuroscience and Endocrinology (G.K.F., M.S.H., D.S.J.), University of Bristol, Bristol BS1 3NY, United Kingdom; Department of Biology (D.N.C.J.), Psychiatry Centre of Excellence for Drug Discovery (CEDD) and Discovery Research (S.W.), GlaxoSmithKline, Harlow Essex CM19 5AW, United Kingdom; Metabolic Diseases (K.A.A.-B.), Metabolic and Viral Diseases CEDD, GlaxoSmithKline, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Dr. M. Harbuz, Henry Wellcome Laboratory for Integrative Neuroscience and Endocrinology, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, United Kingdom. E-mail: m.s.harbuz{at}bris.ac.uk.

We investigated the effects of glucocorticoid manipulation on orexin-A-induced feeding and prepro-orexin mRNA levels in the lateral hypothalamic area (LHA) of the rat brain. Adrenalectomy (ADX) reduced orexin-A-induced feeding over 4 h by about 60%, compared with shams, an effect that was reversed by corticosterone (CORT) replacement. ADX had no effect on prepro-orexin mRNA levels in the LHA in either the morning or the evening; however, message was up-regulated by CORT in the morning but not the evening. An increased number of emulsion grains per cell in the LHA suggests that this is a specific increase in prepro-orexin mRNA and is not due to an increased number of cells expressing message. Prepro-orexin mRNA levels in the LHA were elevated 4 h after injection of lipopolysaccharide, compared with saline-injected controls. Partial but not complete abolition of orexin-A-induced feeding by ADX suggests that orexin-A-induced feeding may be mediated through glucocorticoid-dependent and glucocorticoid-independent pathways. In the morning increased prepro-orexin mRNA after CORT replacement demonstrates that orexin expression is sensitive to increased concentrations of glucocorticoids. However, the lack of effect of ADX on prepro-orexin mRNA levels suggests that endogenous glucocorticoids are not involved in tonic regulation of basal prepro-orexin expression. Overall our data constitute a body of evidence for an integrated relationship between central orexin expression, stress, glucocorticoid manipulation, and feeding patterns in the rat.