Reversal of chronic restraint-induced HPA axis dysregulation and depressive-like behaviour by chronic escitalopram treatment in rats: involvement of SERT.

Abstract

Chronic restraint stress (CRS) upregulates serotonin transporter (SERT) in adrenal glands and sensitizes restraint-induced corticosterone (CORT) secretion. We analysed the effect of chronic escitalopram (ECT) treatment on these CRS-induced changes. Rats were submitted to CRS or control conditions (CTRL) for 14 days; at day 8, animals received vehicle (VEH) or ECT treatment for 7 days. On day 15, SERT expression in adrenals was analysed by immunohistochemistry, Western blot, and RT-PCR; baseline and restraint-induced ACTH and CORT secretion was also determined. The effect of ECT on 5-HT turnover in adrenals and dorsal raphe nucleus (DRN), and on sucrose preference, was also investigated. SERT immunostaining (SERT-I) appeared in the adrenal medulla from CTRL animals and increased, apparently in the cortex, in adrenals from CRS-exposed animals; parallel increases of SERT protein and mRNA in adrenals were also observed. These CRS-induced changes were attenuated in ECT-treated animals. CRS exposure of VEH-treated animals blunted ACTH secretion at 10 min of restraint, and sensitized CORT responses at 30 min of restraint; these dysregulated responses were normalized by ECT treatment. CRS exposure increased 5-HT turnover in adrenal glands and decreased it in DRN; both effects were reversed by ECT. Finally, the depressogenic effect of CRS, as visualized by decreased sucrose preference, was reversed by ECT treatment. Data suggest that the antidepressant-like effects of ECT in CRS-exposed animals may be associated with: a) reversal of SERT expression and 5-HT turnover in the adrenals; b) reversal of decreased 5-HT turnover in DRN; and c) normalization of HPA axis activity.