title: Preliminary evidence of anxiolytic effects of the CRF(1) receptor antagonist R317573 in the 7.5% CO(2) proof-of-concept experimental model of human anxiety.
abstract: We have validated the use of prolonged inhalation of 7.5% carbon dioxide (CO(2)) as a human model of anxiety and have shown that drugs from two prototypical classes of anxiolytics, benzodiazepines and a serotonin reuptake inhibitor, attenuate CO(2)-induced symptoms (Bailey et al., 2007a). Preclinical evidence suggests that drugs acting at the corticotropin-releasing factor (CRF) system may be useful for the treatment of depression, anxiety, and other stress-related disorders (Valdez, 2006), hence we have now examined the effects of a CRF(1) receptor antagonist in the 7.5% CO(2) model. In a randomized double-blind, placebo-controlled, study in 32 healthy participants we examined the effects of 7 days of treatment with the CRF(1) receptor antagonist, R317573, at a dose that shows a favourable safety profile and is comparable with those effective in preclinical models (40 mg). On day 8, eight of the placebo-treated group received lorazepam (LZP) 2 mg as a positive control. All participants underwent 20 min inhalation of 7.5% CO(2)-enriched air. Subjective reports of peak gas effects were assessed using visual analogue scales and questionnaires. The mean age of participants was 26 years, and 13 were male. The peak effects of CO(2) were expressed as a difference from baseline scores obtained while breathing air alone. Compared with placebo (PLAC), both drug groups showed a decrease in all subjective symptoms, total score on the panic symptom inventory (CRF 11 [2.6], PLAC 16.4 [3.1], LZP 2.9 [3.0]) and a generalized anxiety disorder symptom scale (CRF 2.2 [1.5], PLAC 8.2 [2.2], LZP 1.1 [1.5]). We have shown that a drug that acts to inhibit the CRF(1) receptor shows efficacy in the 7.5% CO(2) model of anxiety in healthy participants.
authors.affiliation: Severnside Alliance for Translational Research, University of Bristol, Bristol, UK. jayne.bailey@bristol.ac.uk
authors.forename: Jayne E
authors.initials: JE
authors.lastname: Bailey
authors.forename: Andreas
authors.initials: A
authors.lastname: Papadopoulos
authors.forename: Alison
authors.initials: A
authors.lastname: Diaper
authors.forename: Suzanne
authors.initials: S
authors.lastname: Phillips
authors.forename: Me
authors.initials: M
authors.lastname: Schmidt
authors.forename: P
authors.initials: P
authors.lastname: van der Ark
authors.forename: Colin T
authors.initials: CT
authors.lastname: Dourish
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
authors.forename: David J
authors.initials: DJ
authors.lastname: Nutt
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000494:pharmacology*; D001007:Anxiety / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002245:Carbon Dioxide / Q000008:administration & dosage*; D004311:Double-Blind Method; D005260:Female; D006805:Human Experimentation; D006801:Humans; D008140:Lorazepam / Q000494:pharmacology; D008297:Male; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D011795:Surveys and Questionnaires; D055815:Young Adult; D000099052:CRF Receptor, Type 1
chemical_list: D014151:Anti-Anxiety Agents; D018019:Receptors, Corticotropin-Releasing Hormone; D002245:Carbon Dioxide; D000099052:CRF Receptor, Type 1; D008140:Lorazepam