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 ?g/ml, 100 ?g/ml or 400 ?g/ml) or vehicle to adrenal-intact adult, male rats via the drinking water for 3 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 2h into the dark phase of a 12/12 h reversed light/dark cycle; the other half were killed 2h 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 concentrations 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.
