title: CRF1but not glucocorticoid receptor antagonists reduce separation-induced distress vocalizations in guinea pig pups and CRF overexpressing mouse pups. A combination study with paroxetine.
abstract: 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.
  
  
  
  We evaluated the anxiolytic effects of corticotropin releasing factor (CRF)1receptor 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).
  
  
  
  In guinea pig pups, the CRF1receptor 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.
  
  
  
  CRF1but not GR antagonists reduced the number of calls relative to vehicle in guinea pigs and mice, independent of genotype. Treatment of CRF1receptor or GR antagonists with paroxetine had no combined effect in guinea pigs, wild type or CRF overexpressing mice.
  
  
  
  Current results indicate robust anxiolytic properties of CRF1receptor 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 CRF1receptor antagonists with SSRIs following chronic drug administration.
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Brain Center Rudolf Magnus (BCRM), P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: P Monika
authors.initials: PM
authors.lastname: Verdouw
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Brain Center Rudolf Magnus (BCRM), P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: Joantine C J
authors.initials: JC
authors.lastname: van Esterik
authors.affiliation: Department of Anatomy, Radboud University Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Bernard W M M
authors.initials: BW
authors.lastname: Peeters
authors.affiliation: Institut de Recherches Servier, Croissy-sur-Seine, France.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Brain Center Rudolf Magnus (BCRM), P.O. Box 80082, 3508 TB Utrecht, The Netherlands. Electronic address: l.groenink@uu.nl.
authors.forename: Lucianne
authors.initials: L
authors.lastname: Groenink
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006168:Guinea Pigs; D008426:Maternal Deprivation; D051379:Mice; D008822:Mice, Transgenic; D015735:Mifepristone / Q000494:pharmacology; D017374:Paroxetine / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D013256:Steroids / Q000494:pharmacology; D014828:Vocalization, Animal / Q000187:drug effects*; D000099052:CRF Receptor, Type 1
chemical_list: C437952:(N-(2-chloro-4,6-dimethylphenyl)-1-(1-methoxymethyl)-(2-methoxymethyl)-6-methyl-1H-1,2,3-triazolo(4,5-c)pyridin-4-amine) mesylate; D014151:Anti-Anxiety Agents; D052117:Benzodioxoles; C101628:CP 154526; C526064:Org 34517; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; D013256:Steroids; D015735:Mifepristone; D017374:Paroxetine; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone
keywords: Anxiety; CP-154,526; CRF overexpressing mice; CRH; DMP695; Distress calls; Mifepristone; Org34517; SSRI; Serotonin re-uptake inhibitor