Chronic non-invasive corticosterone administration abolishes the diurnal pattern of tph2 expression

Abstract

Both hypothalamic-pituitary-adrenal (HPA) axis activity and serotonergic systems are commonly dysregulated in stress-related psychiatric disorders. We describe here a non-invasive rat model for hypercortisolism, as observed in major depression, and its effects on physiology, behavior, and the expression of tph2, the gene encoding tryptophan hydroxylase 2, the rate-limiting enzyme for brain serotonin (5-hydroxytryptamine; 5-HT) synthesis. We delivered corticosterone (40 µg/ml, 100 µg/ml or 400 µg/ml) or vehicle to adrenal-intact adult, male rats via the drinking water for three weeks. On days 15, 16, 17 and 18, respectively, the rats’ emotionality was assessed in the open-field (OF), social interaction (SI), elevated plus-maze (EPM), and forced swim tests (FST). On day 21, half of the rats in each group were killed 2 h into the dark phase of a 12/12 h reversed light/dark cycle; the other half were killed 2 h into the light phase. We then measured indices of HPA axis activity, plasma glucose and interleukin-6 (IL-6) availability, and neuronal tph2 expression at each time point. Chronic corticosterone intake was sufficient to cause increased anxiety- and depressive-like behavior in a dose-dependent manner. It also disrupted the diurnal pattern of plasma adrenocorticotropin (ACTH), corticosterone, and glucose concentrations, caused adrenal atrophy, and prevented regular weight gain. No diurnal or treatment-dependent changes were found for plasma levels of IL-6. Remarkably, all doses of corticosterone treatment abolished the diurnal variation of tph2 mRNA expression in the brainstem dorsal raphe nucleus (DR) by elevating the gene’s expression during the animals’ inactive (light) phase. Our data demonstrate that chronic elevation of corticosterone creates a vulnerability to a depression-like syndrome that is associated with increased tph2 expression, similar to that observed in depressed patients.

The 5-HT7 receptor antagonist SB 269970 ameliorates corticosterone-induced alterations in 5-HT7 receptor-mediated modulation of GABAergic transmission in the rat dorsal raphe nucleus

“…Thus, corticosterone-induced decrease in the activity of the rat serotonergic system appears to develop only after prolonged exposure to corticosterone, while the early effects may include an increased excitability of DRN projection neurons primarily due to a reduction in the autoinhibitory function of 5-HT 1A somatodendritic receptors (Fairchild et al 2003; Laaris et al 1995; Rainer et al 2012) and a reduced GABAergic input from local DRN interneurons (this study). These effects may be accompanied by an elevation of the expression of gene encoding tryptophan hydroxylase 2 ( tph2 ), the rate-limiting enzyme for brain 5-HT synthesis in the DRN, reported to occur after 3 weeks of treatment of rats with corticosterone (Donner et al 2012). …”

Stress-induced alterations in estradiol sensitivity increase risk for obesity in women

“…While these studies do not subject animals to actual physical or emotional stressors, they mimic elevated levels of corticosterone that are associated with chronic exposure to stressors in rodents [31–33]. Chronic corticosterone administration via drinking water in male rats over three weeks disrupts endogenous adrenocorticotropic hormone (ACTH), corticosterone and glucose levels [34]. Administration of exogenous glucocorticoids in male rodents also results in augmented abdominal obesity under dietary conditions wherein only a prudent, low calorie chow diet (LCD) is available [13, 15], as well as when a CDD is offered exclusively [14].…”

CRTH2, a prostaglandin D2 receptor, mediates depression-related behavior in mice

“…Given that chronic CORT treatment increased depression-like behavior in the SIT [37], we first examined the effects of CRTH2 knockout on depression-like behavior in the SIT (Fig. 1A).…”