CRF1 but not glucocorticoid receptor antagonists reduce separation-induced distress vocalizations in guinea pig pups and CRF overexpressing mouse pups. A combination study with paroxetine

Abstract Rationale Given the large number of patients that does not respond sufficiently to currently available treatment for anxiety disorders, there is a need for improved treatment. Objectives We evaluated the anxiolyticeffects of corticotropin releasing factor( CRF) 1 receptor antagonistsand glucocorticoid receptor (GR) antagonistsin the separation-induced vocalization test in guinea pigsand transgenic mice with central CRFoverexpression. Furthermore, we explored effects of these drugs when given in combination with a suboptimal dose of a selective serotonin re-uptake inhibitor(SSRI). Methods In guinea pigpups, the CRF1 receptor antagonists CP-154,526and DMP695, and the GR antagonists mifepristoneand Org34517 (all at 2.5, 10 and 40 mg/kg intraperitoneally (IP)) were tested alone or in combination with 0.63 mg/kg paroxetineIP. In CRFoverexpressing mouse pups and wild type littermates, effects of CP-154,526(10, 20 and 40 mg/kg subcutaneously (SC)) and mifepristone(5, 15, 45 mg/kg SC) were studied alone or in combination with 0.03 mg/kg paroxetineSC. Results CRF1 but not GR antagonistsreduced the number of calls relative to vehicle in guinea pigsand mice, independent of genotype. Treatment of CRF1 receptor or GR antagonistswith paroxetinehad no combined effect in guinea pigs, wild type or CRFoverexpressing mice. Conclusions Current results indicate robust anxiolyticproperties of CRF1 receptor antagonistsin guinea pigsand mice overexpressing CRF, and lack thereof of GR antagonists. Although no combined treatment effects were observed, it would be interesting to study combined treatment of CRF1 receptor antagonistswith SSRIs following chronic drug administration.