Divergent effects of genetic variation in endocannabinoid signaling on human threat- and reward-related brain function.
Biol Psychiatry. 2009 Jul 1; 66(1):9-16
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This study shows that a common functional polymorphism believed to affect endocannabinoid (eCB) signaling is associated with processing of threatening and rewarding stimuli. Individuals with the variant linked with higher synaptic eCB levels showed blunted neural response to threat and enhanced response to reward. These findings may have important implications regarding the role of eCB signaling in both anxiety and substance-use disorders.
The eCB system appears to be implicated in several psychiatric conditions including anxiety and substance-use disorders. Sources of individual variability in eCB signaling, and behaviors thought to be modulated by this system, are poorly understood. This study employed an imaging genetics approach to investigate associations between genes involved in eCB function and behavioral and neural responses to emotionally-salient stimuli. The authors studied a common polymorphism of the gene encoding fatty acid amide hydrolase (FAAH). FAAH degrades synaptic eCBs, and affects eCB signaling. One variant of the polymorphism (385A) is associated with reduced FAAH expression, and is, hence, believed to increase synaptic eCB levels compared with the non-mutated allele (385C). The authors examined threat processing, which is central to anxiety, and reward processing, which is associated with disorders of impulse control and substance abuse. They found that individuals with the 385A allele had blunted amygdala responses to threatening stimuli, and enhanced ventral striatum responses to a reward probe, compared to those who were homozygous for the 385C allele. These findings are consistent with the hypothesis that elevated eCB levels reduce anxiety and may also be involved in reward-related pathology, commonly found in addictive disorders. The study uses a powerful combination of genetic and imaging tools to investigate the mechanisms underlying anxiety and substance-use disorders, and supports the notion that the eCB system plays an important role. These findings may lead to potential pharmacotherapies targeting this system, and provide important information about genetic sources of individual variability that may contribute to cannabis use and other substance-use disorders.
de Wit H and Bedi G: F1000Prime Recommendation of [Hariri AR et al., Biol Psychiatry 2009, 66(1):9-16]. In F1000Prime, 20 May 2009; DOI: 10.3410/f.1160596.621969. F1000Prime.com/1160596#eval621969
F1000Prime Recommendations, Dissents and Comments for [Hariri AR et al., Biol Psychiatry 2009, 66(1):9-16]. In F1000Prime, 27 Mar 2015; F1000Prime.com/1160596
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