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.

Figure 1

Schematic of the threat experiment. There were three conditions—no-shock (N), predictable shock (P), and unpredictable shock (U)—presented in two orders, each including three N, two P, and two U in each of the two orders (UNPNPNU as shown or PNUNUNP). Each N, P, and U condition contained four 8-s cues of different colors and geometric shapes (for illustration purposes, the cues are squares in N, circles in P, and triangles in U). In each P condition, a shock (indicated by ) was randomly associated with one of the four threat cues; it was administered 7.5 s after its onset. In each U condition, a shock was administered randomly in the absence of the cues. In the N condition, no shock was administered. Startle stimuli (indicated by ↑) were delivered in the presence and in the absence of the cue (ie, during intertrial intervals).

Figure 2

(Top) Fear-potentiated startle (difference startle magnitude between threat cue and ITI in the predictable (P) condition). (Bottom) Anxiety-potentiated startle (difference ITI startle magnitude between the unpredictable (U) and the predictable (P) condition). *p<0.05, **p<0.01, ***p<0.001.