Implantation of a Slow Release Corticosterone Pellet Induces Long‐Term Alterations in Serotonergic Neurochemistry in the Rat Brain

Abstract

Many studies point to an involvement of deficits in the serotonergic nervous system and hyperactivity of the hypothalamic‐pituitary‐adrenal (HPA) axis function with depression. Indeed early life stress, involving HPA axis activation, may predispose susceptible individuals to develop depression in later life. This study investigates the effects of elevating the neuroendocrine stress hormone, corticosterone, for 1 week in adolescent rats on markers of serotonergic neurone function at adulthood. Slow release corticosterone pellets were implanted for 7 days and various serotonergic parameters, as well as plasma corticosterone levels, were measured on day 7 or on day 28 (21 days following removal of the pellet). The corticosterone implant attenuated weight gain and reduced adrenal weights compared to that in control rats implanted with a cholesterol pellet. After 7 days, with the implant still in place, the diurnal variation in plasma corticosterone was reduced so that the level was approximately at that of the evening peak throughout the day. Twenty‐one days after removal of the implant, the diurnal variation in plasma corticosterone returned. Corticosterone treatment decreased [3H] 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin binding to the 5‐hydroxytryptamine1A receptor in the cortex but not in the hippocampus. Corticosterone treatment also enhanced the circadian rhythm observed in 5‐hydroxyindoleacetic acid level and the ratio of 5‐hydroxyindoleacetic acid to the 5‐hydroxytryptamine in the frontal cortex. Despite corticosterone pellet removal 21 days earlier, there was a persistent decrease in whole body and adrenal weight, cortical 5‐hydroxytryptamine1A receptor binding and an alteration in the diurnal variation in the 5‐hydroxytryptamine ‘turnover’ in the frontal cortex.

Sustained release of corticosterone in rats affects reactivity, but does not affect habituation to immobilization and acoustic stimuli

“…To minimize these risks we copied the design of previous studies where the levels of CORT were monitored (Meyer et al, 1979 see also the introduction). The decreased adrenal, thymus and body weights, as well as the decreased cfos expression in the PVN in the CORT exposed rats, observed here, indicate sustained effects on the endocrine regulation, which is still present at the time of termination (Akana et al, 1985;Akana et al, 1992;Bush et al, 2003;Stamp and Herbert, 2001;Umemoto et al, 1997).…”

“…Accordingly, nearly constant levels of corticosterone were obtained (that were about half maximal between normal and stress-induced levels in normal rats), the daily variations were virtually absent and all the HPA-responsiveness to stress was suppressed. Other consequences of the continuously elevated levels of corticosterone were decreased body weight, adrenal weight and thymus weight (Akana et al, 1985;Akana et al, 1992;Bush et al, 2003;Young et al, 1995). Using well documented designs (Akana et al, 1985;Akana et al, 1992;Meyer et al, 1979), together with the effects on the adrenals and thymus we could avoid additional and uncontrolled stress as caused by frequent blood sampling to control the corticosterone levels during the experiments.…”

A zebrafish model of glucocorticoid resistance shows serotonergic modulation of the stress response

“…CRH activates a subpopulation of serotonergic neurons in the raphe nuclei, and recruitment of this pathway mediates anxiety-like behavior in rats (Meloni et al, 2008). Chronic stress decreases serotonin receptor expression (Kieran et al, 2010) and serotonin binding in the limbic system and cortex, and lowers behavioral responses to serotonin (Bush et al, 2003). Serotonin also influences hypothalamic stress pathways (Locatelli et al, 2010).…”

Cholesterol and perhaps estradiol protect against corticosterone-induced hippocampal CA3 dendritic retraction in gonadectomized female and male rats

“…It is widely documented that GCs influence hippocampal neurochemistry (Luine et al 1993, Bush et al 2003, Schubert et al 2008), GC receptor expression (Kitraki et al, 2004, Wright et al, 2006), neuronal excitability (Pfaff et al, 1971; Kerr et al, 1989; Beck et al, 1994), and hippocampal-dependent behaviors such as spatial ability (Oitzl & de Kloet, 1992, de Quervain et al 1998, McLay et al 1998, Conrad et al 1999, Coburn-Litvak et al 2003, Dumas et al 2010, Schwabe et al 2010). Moreover, the hippocampus shows marked morphological alterations following chronic stress when GC elevations persist or when exogenous GCs are chronically administered.…”