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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.

SUBMITTER: Grillon C

PROVIDER: S-EPMC4367474 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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The CRH1 antagonist GSK561679 increases human fear but not anxiety as assessed by startle.

Grillon Christian C Hale Elizabeth E Lieberman Lynne L Davis Andrew A Pine Daniel S DS Ernst Monique M

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20150313 5

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 ...[more]

PMID: 25430779

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Project description:BackgroundMajor theories propose that perturbed threat learning is central to pathological anxiety, but empirical support is inconsistent. Failures to detect associations with anxiety may reflect limitations in quantifying conditioned responses to anticipated threat, and hinder translation of theory into empirical work. In prior work, we could not detect threat-specific anxiety effects on states of conditioned threat using psychophysiology in a large sample of patients and healthy comparisons. Here, we examine the utility of an alternative fear potentiated startle (FPS) scoring in revealing associations between anxiety and threat conditioning and extinction in this dataset. Secondary analyses further explored associations among conditioned threat responses, subcortical morphometry, and treatment outcomes.MethodsYouths and adults with anxiety disorders and healthy comparisons (n = 306; 178 female participants; 8-50 years) previously completed a well-validated differential threat learning paradigm. FPS and skin conductance response (SCR) quantified psychophysiological responses during threat conditioning and extinction. In this report, we examined normalizing raw FPS scores to intertrial intervals (ITI) to address challenges in more common approaches to FPS scoring which could mask group effects. Secondary analyses examined associations between FPS and subcortical morphometry and with response to exposure-based cognitive behavioral therapy in a subsample of patients.ResultsPatients and comparisons showed comparable differential threat conditioning using FPS and SCR. While SCR suggested comparable extinction between groups, FPS revealed stronger retention of threat contingency during extinction in individuals with anxiety disorders. Extinction indexed with FPS was not associated with age, morphometry, or anxiety treatment outcome.ConclusionITI-normalized FPS may have utility in detecting difficulties in extinguishing conditioned threat responses in anxiety. These findings provide support for extinction theories of anxiety and encourage continued research on aberrant extinction in pathological anxiety.

Dataset Information

The CRH1 antagonist GSK561679 increases human fear but not anxiety as assessed by startle.

Publications

The CRH1 antagonist GSK561679 increases human fear but not anxiety as assessed by startle.

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