title: The CRH1 antagonist GSK561679 increases human fear but not anxiety as assessed by startle.
abstract: Fear to predictable threat and anxiety to unpredictable threat reflect distinct processes mediated by different brain structures, the central nucleus of the amygdala and the bed nucleus of the stria terminalis (BNST), respectively. This study tested the hypothesis that the corticotropin-releasing factor (CRF1) antagonist GSK561679 differentially reduces anxiety but increases fear in humans. A total of 31 healthy females received each of four treatments: placebo, 50 mg GSK561679 (low-GSK), 400 mg GSK561679 (high-GSK), and 1 mg alprazolam in a crossover design. Participants were exposed to three conditions during each of the four treatments. The three conditions included one in which predictable aversive shocks were signaled by a cue, a second during which shocks were administered unpredictably, and a third condition without shock. Fear and anxiety were assessed using the acoustic startle reflex. High-GSK had no effect on startle potentiation during unpredictable threat (anxiety) but increased startle potentiation during the predictable condition (fear). Low-GSK did not affect startle potentiation across conditions. Consistent with previous findings, alprazolam reduced startle potentiation during unpredictable threat but not during predictable threat. The increased fear by high-GSK replicates animal findings and suggests a lift of the inhibitory effect of the BNST on the amygdala by the CRF1 antagonist.
authors.affiliation: Section of the Neurobiology of Fear and Anxiety, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Grillon
authors.affiliation: Section of the Neurobiology of Fear and Anxiety, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hale
authors.affiliation: Section of the Neurobiology of Fear and Anxiety, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Lieberman
authors.affiliation: Section of the Neurobiology of Fear and Anxiety, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Davis
authors.affiliation: Section of the Neurobiology of Fear and Anxiety, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pine
authors.affiliation: Section of the Neurobiology of Fear and Anxiety, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: Monique
authors.initials: M
authors.lastname: Ernst
mesh_terms: D000161:Acoustic Stimulation; D000328:Adult; D000525:Alprazolam / Q000494:pharmacology; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D059031:Anticipation, Psychological / Q000502:physiology; D001007:Anxiety / Q000139:chemically induced* / Q000503:physiopathology; D053961:Azabicyclo Compounds / Q000009:adverse effects / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004597:Electroshock; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D009483:Neuropsychological Tests; D010069:Oxadiazoles / Q000009:adverse effects / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000009:adverse effects / Q000494:pharmacology*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology; D011795:Surveys and Questionnaires; D035501:Uncertainty; D000099052:CRF Receptor, Type 1
chemical_list: D014151:Anti-Anxiety Agents; D053961:Azabicyclo Compounds; C556497:NBI 77860; D010069:Oxadiazoles; D011619:Psychotropic Drugs; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000525:Alprazolam