SN003, a CRF1 receptor antagonist, attenuates depressive-like behavior and detrusor overactivity symptoms induced by 13-cis-retinoic acid in rats

Abstract

Overactive bladder (OAB) often co-exists with depression in women. The corticotropin-releasing factor (CRF) system participates in the pathophysiology of both disorders. Therefore, we tested the effects of acute treatment with a reversible CRF receptor type-1 (CRF₁) antagonist, SN003 (1mg/kg, i.v.), representatives of first (solifenacin, 0.03mg/kg, i.v.) and second (mirabegron, 1mg/kg, i.v.) line treatments for OAB as well as an antidepressant imipramine (30mg/kg, i.p.) on changes in depressive-like behavior and detrusor overactivity (DO) symptoms induced by a 6-week administration of 13-cis-retinoic acid (13-cis-RA, 1mg/kg/day, i.p.) in female Wistar rats, using in vivo cystometric investigations, forced swim test (FST) and spontaneous locomotor activity test. Following cystometric and behavioral studies, tissue was harvested and CRF level was assessed in the hypothalamus, amygdala and plasma. 13-cis-RA-induced depressive-like behavior and DO symptoms were associated with increased CRF levels in the hypothalamus, amygdala and plasma. Solifenacin and mirabegron attenuated DO symptoms induced by 13-cis-RA, did not display antidepressant-like activity and did not influence CRF levels in brain tissues or plasma. Imipramine and SN003 displayed antidepressant-like activity and lowered increased levels of CRF in brain tissues and plasma. Imipramine attenuated changes in some of the cystometric parameters, which are associated with OAB dry (without urge incontinence), whereas SN003 attenuated changes in almost all cystometric parameters that were induced by 13-cis-RA. CRF₁ antagonist may be beneficial in case of OAB wet (with urge incontinence) or dry co-existing with depression. The possible mechanism may be related to the effects on central/peripheral CRF system.

Keywords: 13-cis-retinoic acid; 13-cis-retinoic acid (PubChem CID: 5282379), SN003 (PubChem CID: 10291750); CRF(1); Forced swim test; Overactive bladder; SN003; imipramine (PubChem CID: 44152164); mirabegron (PubChem CID: 9865528), solifenacin succinate (PubChem CID: 216457).