Abstract
Failure to extinguish fear can lead to persevering anxiety and has been postulated as an important mechanism in the pathogenesis of human anxiety disorders. In animals, it is well documented that the endogenous cannabinoid system has a pivotal role in the successful extinction of fear, most importantly through the cannabinoid receptor 1. However, no human studies have reported a translation of this preclinical evidence yet. Healthy medication-free human subjects (N=150) underwent a fear conditioning and extinction procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex was measured to assess fear-conditioned responding, and subjective fear ratings were collected. Participants were genotyped for two polymorphisms located within the promoter region (rs2180619) and the coding region (rs1049353) of cannabinoid receptor 1. As predicted from the preclinical literature, acquisition and expression of conditioned fear did not differ between genotypes. Crucially, whereas both homozygote (G/G, N=23) and heterozygote (A/G, N=68) G-allele carriers of rs2180619 displayed robust extinction of fear, extinction of fear-potentiated startle was absent in A/A homozygotes (N=51). Additionally, this resistance to extinguish fear left A/A carriers of rs2180619 with significantly higher levels of fear-potentiated startle at the end of the extinction training. No effects of rs1049353 genotype were observed regarding fear acquisition and extinction. These results suggest for the first time involvement of the human endocannabinoid system in fear extinction. Implications are that genetic variability in this system may underlie individual differences in anxiety, rendering cannabinoid receptor 1 a potential target for novel pharmacological treatments of anxiety disorders.
Highlights
From an evolutionary perspective, the acquisition of fear responses enables organisms to respond appropriately to predictors of aversive events.[1,2] Yet, it is important to extinguish fear when cues that previously predicted danger are no longer followed by an aversive event.[3]
We tested if genetic variability in the human cannabinoid receptor 1 is associated with the extinction of fear
This hypothesis was directly derived from preclinical studies,[11,20] where converging evidence demonstrates cannabinoid receptor 1 (CB1) as a major determinant of fear extinction
Summary
The acquisition of fear responses enables organisms to respond appropriately to predictors of aversive events.[1,2] Yet, it is important to extinguish fear when cues that previously predicted danger are no longer followed by an aversive event.[3]. Given the vast amount of preclinical evidence, cannabinoidbased pharmacotherapy in humans has been proposed frequently as a promising avenue for the development of new treatments for anxiety.[6,23,24,25,26] there is as of yet a great paucity in research regarding mechanisms through which the ECS may regulate fear states in humans, such as through fear extinction. This impedes utilization of the ECS in development of novel human treatments.
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