Escitalopram alters gene expression and HPA axis reactivity in rats following chronic overexpression of corticotropin-releasing factor from the central amygdala

Abstract

Summary We have previously demonstrated that viral-mediated overexpression of corticotropin-releasing factor (CRF) within the central nucleus of the amygdala (CeA) reproduces many of the behavioral and endocrine consequences of chronic stress. The present experiment sought to determine whether administration of the selective serotonin reuptake inhibitor (SSRI) escitalopram reverses the adverse effects of CeA CRF overexpression. In a 2 × 2 design, adult male rats received bilateral infusions of a control lentivirus or a lentivirus in which a portion of the CRF promoter is used to drive increased expression of CRF peptide. Four weeks later, rats were then implanted with an Alzet minipump to deliver vehicle or 10 mg/kg/day escitalopram for a 4-week period of time. The defensive withdrawal (DW) test of anxiety and the sucrose-preference test (SPT) of anhedonia were performed both before and after pump implantation. Additional post-implant behavioral tests included the elevated plus maze (EPM) and social interaction (SI) test. Following completion of behavioral testing, the dexamethasone/CRF test was performed to assess HPA axis reactivity. Brains were collected and expression of HPA axis-relevant transcripts were measured using in situ hybridization. Amygdalar CRF overexpression increased anxiety-like behavior in the DW test at week eight, which was only partially prevented by escitalopram. In both CRF-overexpressing and control groups, escitalopram decreased hippocampal CRF expression while increasing hypothalamic and hippocampal expression of the glucocorticoid receptor (GR). These gene expression changes were associated with a significant decrease in HPA axis reactivity in rats treated with escitalopram. Interestingly, escitalopram increased the rate of weight gain only in rats overexpressing CRF. Overall these data support our hypothesis that amygdalar CRF is critical in anxiety-like behavior; because the antidepressant was unable to reverse behavioral manifestations of CeA CRF-OE. This may be a potential animal model to study treatment-resistant psychopathologies.

A shift toward T helper 2 responses and an increase in modulators of innate immunity in depressed patients treated with escitalopram

“…It is possible that the mechanisms through which escitalopram improves depressive symptoms are related to its ability to enhance serotonin neurotransmission, modulate some cytokine levels, and affect the neuroendocrine system. This view is supported by several previous studies where escitalopram improved hyperactivity of the hypothalamicpituitary-adrenal axis in patients with depression (Sarubin et al, 2014), in healthy first-degree relatives of patients with depression , and in an animal model (Flandreau et al, 2013).…”

Anhedonia but not passive floating is an indicator of depressive‑like behavior in two chronic stress paradigms

“…Thus, chronic administration of CORT to mice resulted in a decrease in sucrose preference (Sturm et al 2015), while Bowens and colleagues (2012) did not find anhedonia in mice with high CORT after social defeat but mice with low CORT exhibited decreased sucrose preference. Direct injection of CRF into the nucleus accumbens shell induced depressive-like behavior including anhedonia in rats (Chen et al 2012), though viral vector-mediated CRF over-expression in the central nucleus of amygdala did not modify sucrose preference during first weeks after administration of CRF vector, and later on sucrose preference even increased (Flandreau et al 2013).…”

Escitalopram affects spexin expression in the rat hypothalamus, hippocampus and striatum

“…There are many suggestions that SSRI treatment may affect the hypothalamic corticotropin-releasing factor (CRF) pathway [19,20] and hypothalamo-pituitary adrenal (HPA) axis [21]. Interestingly, 2 hours after escitalopram administration the level of TRH-like peptides was increased in the rat nucleus accumbens, striatum, cerebellum and medulla oblongata, while TRH concentration was decreased in the nucleus accumbens.…”

“…The dose used at the experiment were taken from the publications where authors examine the influence of the escitalopram on the neuropeptide expression in the rat brain [19,23]. 24 hours after the last drug administration, animals were anaesthetized with isoflurane and quickly sacrificed.…”