Abstract
Hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA) and impairment of the central corticotropin-releasing factor (CRF) system are factors in the pathogenesis of depression. Though several antagonists of the CRF1 receptor were effective in the recognized behavioral tests for antidepressant activity, there is still little information on the potential interactions between CRF1 receptor inhibitors and conventional antidepressant therapy. The aim of our study was to assess the influence of SN003, a CRF1 receptor blocker, on the activity of imipramine and fluoxetine in the forced swim test (FST) in rats which presented some signs of depression. The experiments were carried out on female Wistar rats subjected to 14-day subcutaneous corticosterone (CORT) administration (20 mg/kg/day). The antidepressant-like effect was determined by the FST and the CRF levels in the hypothalamus, amygdala, and peripheral blood were measured by a high-sensitivity immunoenzymatic test. SN003 (0.5 mg/kg) potentiated the antidepressant-like effect of imipramine (15 mg/kg) and fluoxetine (7.5 mg/kg). Moreover, the co-administration of the tested agents abolished CORT-induced increase in CRF levels in the examined biological material more profoundly than monotherapy. Our present findings give further evidence that the blockage of CRF action may be useful in the treatment of mood disorders. The concurrent use of well-known antidepressants with CRF1 receptor antagonists could be beneficial in terms of safety, since it requires lower doses of the applied agents.
Highlights
Literature data indicate that stressful life events may predispose to the development of depression
corticotropin-releasing factor (CRF) produced in the parvocellular neurons of the paraventricular nucleus in the hypothalamus serves as a hormone, whereas CRF produced in other brain regions serves as a neurotransmitter (Chappell et al 1986)
We demonstrated that a high-affinity non-peptidic CRF1 receptor blocker which displays >1000-fold selectivity over CRF2 receptors—SN003—possesses antidepressant-like activity comparable to that obtained with typical antidepressant drugs (Wrobel et al 2016)
Summary
Literature data indicate that stressful life events may predispose to the development of depression. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis (the stress axis) has been observed in depressed patients, and it is regarded as an important factor in the pathogenesis of this disease. While HPA axis is crucial for the endocrine response to a stressor, the corticotropin-releasing factor (CRF), known as the corticotropin-releasing hormone, plays an important role in regulating this neuroendocrine reaction. In a stressful situation, increased synthesis and release of CRF is observed, which in turn triggers the release of the adrenocorticotropic hormone (ACTH), followed by the higher synthesis and release of glucocorticoids—cortisol (in primates) or corticosterone (in rodents). Glucocorticoids send a negative feedback which causes a decrease in the synthesis and release of CRF, ACTH, and cortisol/corticosterone. The HPA negative feedback loop may be impaired (Galard et al 2002).
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