Chronic social defeat up-regulates expression of norepinephrine transporter in rat brains

Abstract

Stress has been reported to activate the locus coeruleus (LC)–noradrenergic system. However, the molecular link between chronic stress and noradrenergic neurons remains to be elucidated. In the present study adult Fischer 344 rats were subjected to a regimen of chronic social defeat (CSD) for 4 weeks. Measurements by in situ hybridization and Western blotting showed that CSD significantly increased mRNA and protein levels of the norepinephrine transporter (NET) in the LC region and NET protein levels in the hippocampus, frontal cortex and amygdala. CSD-induced increases in NET expression were abolished by adrenalectomy or treatment with corticosteroid receptor antagonists, suggesting the involvement of corticosterone and corticosteroid receptors in this upregulation. Furthermore, protein levels of protein kinase A (PKA), protein kinase C (PKC), and phosphorylated cAMP-response element binding (pCREB) protein were significantly reduced in the LC and its terminal regions by the CSD paradigm. Similarly, these reduced protein levels caused by CSD were prevented by adrenalectomy. However, effects of corticosteroid receptor antagonists on CSD-induced down-regulation of PKA, PKC, and pCREB proteins were not consistent. While mifeprestone and spironolactone, either alone or in combination, totally abrogate CSD effects on these protein levels of PKA, PKC and pCREB in the LC and those in the hippocampus, frontal cortex and amygdala, their effects on PKA and PKC in the hippocampus, frontal cortex and amygdala were region-dependent. The present findings indicate a correlation between chronic stress and activation of the noradrenergic system. This correlation and CSD-induced alteration in signal transduction molecules may account for their critical effects on the development of symptoms of major depression.

Chronic social defeat up‐regulates expression of the serotonin transporter in rat dorsal raphe nucleus and projection regions in a glucocorticoid‐dependent manner

“…The care of ADX rats was the same as reported previously (Chen et al . ). Briefly, ADX rats were provided with 25 μg/mL CORT in the drinking water during whole experimental period.…”

Social defeat protocol and relevant biomarkers, implications for stress response physiology, drug abuse, mood disorders and individual stress vulnerability: a systematic review of the last decade

“…17 Corticosterone (CORT) secretion in animals under stress is mostly regulated by the activity of the HPAaxis and the negative feedback exerted by the levels of circulating glucocorticoids acting upon glucocorticoid receptors (GR). 18 This mechanism is triggered by a set of stress hormones, such as corticotropin releasing…”

“…51,57,62,85 They also had upregulation serotonin neurotransmitter metabolites and receptors in the cortex and thalamus. 78,82 Chronic exposure upregulates norepinephrine transporter (NET) expression in the LC and its terminal regions 18 and suppresses DA in the NAc and VTA. 37 As for neurotrophic factors, chronically stressed rats have lower bone morphogenetic protein 7 (BMP7) gene expression and suppression of BDNF in the LC, NAc and VTA.…”

“…Molecular markers of stress indicated that continuously socially defeated rats had markedly increased hormonal levels of CORT, 18,78,82 and decreased…”

Immediate post-defeat infusions of the noradrenergic receptor antagonist propranolol impair the consolidation of conditioned defeat in male Syrian hamsters

“…Noradrenergic activity plays a role in anxiety-like processes and is important for stress-related changes in behavior (Bremner et al, 1996; Chen et al, 2012; Morilak et al, 2005). Beta-adrenergic antagonists are widely prescribed, albeit “off-label”, in anxiety disorders such as social phobia (Brunello et al, 2000; Davidson, 2006), posttraumatic stress disorder (Giles, 2005; Kent et al, 2002; Vaiva et al, 2003), and panic disorder (Hirschmann et al, 2000; Sullivan et al, 1999).…”