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Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1.
Transl Psychiatry. 2012 Sep 25; 2:e162.TP

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.

Authors+Show Affiliations

Department of Experimental Psychology & Psychopharmacology, Faculty of Social Sciences, Utrecht University, Utrecht, The Netherlands. i.heitland@uu.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23010766

Citation

Heitland, I, et al. "Failure to Extinguish Fear and Genetic Variability in the Human Cannabinoid Receptor 1." Translational Psychiatry, vol. 2, 2012, pp. e162.
Heitland I, Klumpers F, Oosting RS, et al. Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1. Transl Psychiatry. 2012;2:e162.
Heitland, I., Klumpers, F., Oosting, R. S., Evers, D. J., Leon Kenemans, J., & Baas, J. M. (2012). Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1. Translational Psychiatry, 2, e162. https://doi.org/10.1038/tp.2012.90
Heitland I, et al. Failure to Extinguish Fear and Genetic Variability in the Human Cannabinoid Receptor 1. Transl Psychiatry. 2012 Sep 25;2:e162. PubMed PMID: 23010766.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1. AU - Heitland,I, AU - Klumpers,F, AU - Oosting,R S, AU - Evers,D J J, AU - Leon Kenemans,J, AU - Baas,J M P, Y1 - 2012/09/25/ PY - 2012/9/27/entrez PY - 2012/9/27/pubmed PY - 2013/2/21/medline SP - e162 EP - e162 JF - Translational psychiatry JO - Transl Psychiatry VL - 2 N2 - 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. SN - 2158-3188 UR - https://www.unboundmedicine.com/medline/citation/23010766/Failure_to_extinguish_fear_and_genetic_variability_in_the_human_cannabinoid_receptor_1_ L2 - http://dx.doi.org/10.1038/tp.2012.90 DB - PRIME DP - Unbound Medicine ER -