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Volume 17, Number 11, Issue of June 1, 1997 pp. 4056-4065
Copyright ©1997 Society for Neuroscience

Dysregulation of Diurnal Rhythms of Serotonin 5-HT_2C and Corticosteroid Receptor Gene Expression in the Hippocampus with Food Restriction and Glucocorticoids

Received Dec. 4, 1996; revised Feb. 27, 1997; accepted March 12, 1997.

Megan C. Holmes, Karen L. French, and Jonathan R. Seckl

Molecular Endocrine Laboratory, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, Scotland, United Kingdom

Both serotonergic dysfunction and glucocorticoid hypersecretion are implicated in affective and eating disorders. The adverse effects of serotonergic (5-HT)_2C receptor activation on mood and food intake, the antidepressant efficacy of 5-HT₂ receptor antagonists, and the hyperphagia observed in 5-HT_2C receptor knockout mice all suggest a key role for increased 5-HT_2C receptor-mediated neurotransmission. Glucocorticoids, however, downregulate 5-HT_2C receptor mRNA in the hippocampus, and it is unclear how increased 5-HT_2C receptor sensitivity is achieved in the presence of elevated glucocorticoid levels in depression. Here we show a monophasic diurnal rhythm of 5-HT_2C receptor mRNA expression in the rat hippocampus that parallels time-dependent variations in 5-HT_2C receptor agonist-induced behaviors in open field tests. Rats entrained to chronic food restriction show marked but intermittent corticosterone hypersecretion and maintain an unaltered 5-HT_2C receptor mRNA rhythm. The 5-HT_2C receptor mRNA rhythm, however, is suppressed by even modest constant elevations of corticosterone (adrenalectomy + pellet) or with elevated corticosterone during the daytime (8 A.M.), whereas a normal rhythm exists in animals that have the same dose of corticosterone in the evening (6 P.M.). Thus, animals showing even a transient daytime corticosterone nadir exhibit normal hippocampal 5-HT_2C receptor mRNA rhythms, even in the presence of overt corticosterone hypersecretion. Chronic food restriction also abolishes the normal diurnal variation in hippocampal glucocorticoid receptor (GR) and mineralocorticoid receptor mRNAs and produces, unusually, both elevated corticosterone and increased GR. The mismatch between elevated glucocorticoids and maintained 5-HT_2C receptor and increased GR gene expression in the hippocampus provides a new model to dissect mechanisms that may underlie affective and eating disorders.

Key words: 5-HT_2C receptor; serotonin; corticosterone; diurnal rhythm; food restriction; depression; 5-HT_1A receptor; glucocorticoid receptor; mineralocorticoid receptor

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