Abstract
RationaleGiven the large number of patients that does not respond sufficiently to currently available treatment for anxiety disorders, there is a need for improved treatment. ObjectivesWe evaluated the anxiolytic effects of corticotropin releasing factor (CRF)1 receptor antagonists and glucocorticoid receptor (GR) antagonists in the separation-induced vocalization test in guinea pigs and transgenic mice with central CRF overexpression. Furthermore, we explored effects of these drugs when given in combination with a suboptimal dose of a selective serotonin re-uptake inhibitor (SSRI). MethodsIn guinea pig pups, the CRF1 receptor antagonists CP-154,526 and DMP695, and the GR antagonists mifepristone and Org34517 (all at 2.5, 10 and 40mg/kg intraperitoneally (IP)) were tested alone or in combination with 0.63mg/kg paroxetine IP. In CRF overexpressing mouse pups and wild type littermates, effects of CP-154,526 (10, 20 and 40mg/kg subcutaneously (SC)) and mifepristone (5, 15, 45mg/kg SC) were studied alone or in combination with 0.03mg/kg paroxetine SC. ResultsCRF1 but not GR antagonists reduced the number of calls relative to vehicle in guinea pigs and mice, independent of genotype. Treatment of CRF1 receptor or GR antagonists with paroxetine had no combined effect in guinea pigs, wild type or CRF overexpressing mice. ConclusionsCurrent results indicate robust anxiolytic properties of CRF1 receptor antagonists in guinea pigs and 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 antagonists with SSRIs following chronic drug administration.
Highlights
Serotonin re-uptake inhibitors (SSRIs) are among the most frequently described anxiolytics (Baldwin et al, 2014)
In the present study we found that CRF1 receptor antagonists, but not glucocorticoid receptor (GR) antagonists, showed anxiolytic-like effects in separation-induced distress vocalization tests in guinea pig pups and transgenic mouse pups overexpressing central corticotropin-releasing factor (CRF)
The CRF1 receptor antagonists CP-154,526 and DMP695 both reduced the number of distress calls across dose-ranges similar to those required for actions at CRF1 receptors in the brain
Summary
Serotonin re-uptake inhibitors (SSRIs) are among the most frequently described anxiolytics (Baldwin et al, 2014). Problems encountered with the existing anxiolytics include the large number of non-responders to drug treatment, the delayed onset of action and adverse effects (Stewart et al, 2015). There is a need for more effective pharmacotherapy. Such improved pharmacological treatment may be achieved by multi-target drug strategies (Hendriksen and Groenink, 2015; Millan, 2006). Anxiety disorders are complex disorders as many factors are involved in their pathogenesis. Persistent changes in corticotropin-releasing factor (CRF), a neuropeptide with central and peripheral effects on anxiety, may contribute to the development of anxiety disorders
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