Inhibition of the CRF1 receptor influences the activity of antidepressant drugs in the forced swim test in rats

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.

Keywords: CRF1 receptor antagonist; Corticotropin-releasing factor level; Fluoxetine; Forced swim test; Imipramine; Rats.

Fig. 1

Effect of an acute administration of imipramine (IMI, 15 or 30 mg/kg), fluoxetine (FLX, 7.5 or 15 mg/kg), and SN003(0.5 or 1 mg/kg) on the behavior of rats subjected to 14-day corticosterone treatment (CORT, 20 mg/kg/day) in the forced swim test. The values represent the mean + SEM (n = 13–15 animals per group) after a single (a) or combined (b) injection. ***p < 0.001 versus saline; ^^^p < 0.001 versus CORT; ⁺⁺⁺ p < 0.001, ⁺⁺ p < 0.01versus CORT plus SN003; ^˅˅˅ p < 0.001, ^˅˅ p < 0.01 versus CORT plus respective antidepressant drug (Dunnett’s or Newman-Keuls Multiple Comparison post hoc test)

Fig. 2

Influence of an acute administration of imipramine (IMI, 15 or 30 mg/kg), fluoxetine (FLX, 7.5 or 15 mg/kg), and SN003 (0.5 or 1 mg/kg) on the locomotor activity of rats subjected to 14-day corticosterone treatment (CORT, 20 mg/kg/day). The values represent the mean + SEM (n = 13–15 animals per group)

Fig. 3

Effect of an acute administration of imipramine (IMI, 15 or 30 mg/kg), fluoxetine (FLX, 7.5 or 15 mg/kg), and SN003(0.5 or 1 mg/kg) given as a single injection or in combination on the CRF levels in hypothalamus (a), amygdala (b), and peripheral blood (c) of rats subjected to 14-day corticosterone treatment (CORT, 20 mg/kg/day). The values represent the mean + SEM (n = 13–15 animals per group). ***p < 0.001 versus saline; ^^^p < 0.001, ^^p < 0.01, ^p < 0.05 versus CORT; ⁺⁺⁺ p < 0.001, ⁺⁺ p < 0.01, ⁺ p < 0.05 versus CORT plus SN003; ^˅˅˅ p < 0.001, ^˅ p < 0.05 versus CORT plus respective antidepressant drug (Dunnett’s or Newman-Keuls Multiple Comparison post hoc test)