Dysregulation of Diurnal Rhythms of Serotonin 5-HT_2Cand Corticosteroid Receptor Gene Expression in the Hippocampus with Food Restriction and Glucocorticoids

Abstract

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-HT 2 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 ϩ 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.

Effect of circadian phase on context and cued fear conditioning in C57BL/6J mice

“…The expression of glucocorticoidand mineralcorticoid receptor mRNA (Holmes et al, 1995), as well as 5-HT2C receptor mRNA expression (Holmes, French, & Seckl, 1997), shows diurnal rhythms. The hippocampus also expresses rhythmicity in Jun-B and c-fos mRNA (Menegazzi et al, 1994) and in Fos protein levels (Kononen et al, 1990).…”

Calorie restriction attenuates LPS-induced sickness behavior and shifts hypothalamic signaling pathways to an anti-inflammatory bias

“…However, others have found that POMC is reduced after a period of CR (9,49). Although circulating corticosterone (CORT) levels are often increased after CR (27,33,47,64), earlier components of the hypothalmic-pituitary-adrenal axis (HPA) axis are often unaffected, such as ACTH, which is synthesized from POMC (1). This highlights that HPA axis alterations after CR have yet to be fully understood.…”

“…One possible mechanism by which CR exerts its antiinflammatory effect are glucocorticoids, which are increased after CR (33,47) and act to increase the transcription of anti-inflammatory cytokines and decrease the transcription of proinflammatory cytokines (4). Indeed, CR reduces both basal and LPS-stimulated levels of TNF-␣ and IL-6 mRNA in alveolar macrophages in rats (18).…”

Treatment Enhances Ultradian Rhythms of CSF Monoamine Metabolites in Patients with Major Depressive Episodes

“…Expression of the 5-HT transporter fluctuates over time and affects citalopram binding, sleep behaviors, brain 5-HT levels, 5-HT 1A receptors, and 5-HIAA levels (Fabre et al 2000). Both citalopram binding at the serotonin transporter (Kulikov et al, 1997) and 5-HT 2C receptor RNA expression (Holmes et al, 1997) increase significantly during morning hours. Monoamine function varies diurnally in rodent hypothalamus slices (Blier et al, 1989) and 5-HIAA rhythms vary regionally in rodent microdialysis studies (Nakayama, 2002).…”