Corticosterone regulation of serotonin transporter and 5‐HT1A receptor expression in the aging brain

Abstract

Hypercortisolemia is often observed in patients suffering from major depression. As the serotonergic (5-hydroxytryptamine; 5-HT) system plays a major role in the etiology of depression, a loss of endocrine and neurotransmitter system interactions, including corticosterone regulation of 5-HT transporter (5-HTT) and 5-HT receptor expression, may underlie age-related deficits in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and correlate with an increased incidence of depression with advancing age. In this study, female Fischer 344 rats, ages 3, 13, and 18 months, were bilaterally adrenalectomized and supplemented for 3 weeks with corticosterone (0, 200, or 600 mg; LC, MC, or HC, respectively) containing 21 day sustained-release pellets implanted subcutaneously. Quantitative autoradiography of hippocampal and cortical regions using [3H]citalopram revealed a significant decrease in hippocampal 5-HTT binding in the 3-month HC treatment group compared to age-matched MC and LC groups; this loss was not present in the 13- or 18-month groups. Similarly, quantitative autoradiography using the radiolabeled 5-HT(1A) receptor agonist 8-hydroxy-2-(di-N-propylamino) tetralin demonstrated a significant decline in receptor density in 3- and 13-month MC and HC groups as compared to age-matched LC groups in the hippocampus. These hormone treatments (MC or HC), however, failed to alter hippocampal 5-HT(1A) binding site density in the 18-month groups as compared to the age-matched LC group. The 5-HT(2A) receptor was also evaluated using [3H]ketanserin and showed no age- or corticosterone-related changes in the cortex. Overall, an age-associated deficit in the regulation of the hippocampal serotonergic system by varied corticosterone treatment was revealed in the present study, which may underlie the increased incidence of depression and hypercortisolemia found with advancing age.

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

“…The binding of [ 3 H] paroxetine to cortical SERT was unaffected by current or previous corticosterone treatment. This is in agreement with two previous reports showing that neither infusion of a high level of corticosterone (600 mg corticosterone in a 21‐day implant) (37) nor dexamethasone (60 µg/kg/day for 26 days) (38) alter cortical SERT binding in 3‐month‐old rats. Furthermore, even in the hippocampus where there have been several studies, glucocorticoids only appear to affect SERT levels when administered to rats aged less than 3 months (43–47), which is consistent with the current observation.…”

The response of neurons in the bed nucleus of the stria terminalis to serotonin: Implications for anxiety

“…5-HT 1A receptors are also down-regulated in the DRN following uncontrollable shock (Short, 2000) and a repeated stress paradigm (Lanfumey et al, 1999). Consistent with these data, the chronic administration of the stress hormone corticosterone (Fernandes et al, 1997; Kuroda et al, 1992; Takao et al, 1997) or the synthetic glucocorticoid dexamethasone (Katagiri et al, 2001; Lanfumey et al, 1999) has been shown to increase the density and function of cortical 5-HT 2A receptors, while at the same time decreasing the density of 5-HT 1A receptors in frontal cortex (Crayton et al, 1996) and hippocampus (Fernandes et al, 1997; Maines et al, 1999; Takao et al, 1997). Together, these data suggest that chronic stress could shift the balance of BNST 5-HT responses to favor excitation, so that the stress-induced release of 5-HT would produce an anxiogenic response.…”

Subregion‐specific decreases in hippocampal serotonin transporter protein expression and function associated with endophenotypes of depression

“…Direct interactions between CORT and 5-HTT have not been studied extensively, and the available evidence is mixed. Three-weeks of CORT treatment were shown to decrease hippocampal 5-HTT binding in Fisher rats (Maines et al, 1999), but there was no evaluation of depression-related endophenotypes. One-week of CORT ingestion did not alter hippocampal 5-HT uptake in both Spontaneously Hypertensive rats and Wistar-Kyoto rats (Fernandez et al, 2001).…”

“…In addition, the rats used in these studies varied in their developmental stage, which could contribute to differences in sensitivity to the CORT treatment. Studies have shown that effects of CORT on hippocampal 5-HTT binding were age-dependent in rodents (Maines et al, 1999;Macri et al, 2009). Exposure to low levels of CORT in early developmental stages has been found to increase the production of auto-antibodies directed to 5-HTT in adulthood (Macri et al, 2009), which may subsequently decrease hippocampal 5-HT uptake.…”