Divergent Effects of Genetic Variation in Endocannabinoid Signaling on Human Threat- and Reward-Related Brain Function

Abstract

Background Fatty acid amide hydrolase (FAAH) is a key enzyme in regulating endocannabinoid (eCB) signaling. A common single nucleotide polymorphism (C385A) in the human FAAH gene has been associated with increased risk for addiction and obesity. Methods Using imaging genetics in 82 healthy adult volunteers, we examined the effects of FAAH C385A on threat- and reward-related human brain function. Results Carriers of FAAH 385A, associated with reduced enzyme and, possibly, increased eCB signaling, had decreased threat-related amygdala reactivity but increased reward-related ventral striatal reactivity in comparison to C385 homozygotes. Similar divergent effects of FAAH C385A genotype were manifest at the level of brain-behavior relationships. 385A carriers showed decreased correlation between amygdala reactivity and trait anxiety but increased correlation between ventral striatal reactivity and delay discounting, an index of impulsivity. Conclusions Our results parallel pharmacologic and genetic dissection of eCB signaling, are consistent with the psychotropic effects of Δ9-tetrahydrocannabinol and highlight specific neural mechanisms through which variability in eCB signaling impacts complex behavioral processes related to risk for addiction and obesity.

The Fatty Acid Amide Hydrolase C385A Variant Affects Brain Binding of the Positron Emission Tomography Tracer [11C]CURB

“…In this regard, a number of gene association studies have suggested that different frequencies of the FAAH variant may occur in certain neuropsychiatric conditions (including addictions and generalized anxiety disorder). [2][3][4]7,8 In our sample, the prevalence of FAAH variants (C/C, 58%; A/C, 38%; A/A, 4%) was similar to that in the literature for healthy controls. Another generic point to consider was the possibility that FAAH activity driven by racial differences in the impact of the gene variant has a race-specific effect.…”

“…3,6 Approximately 38% of individuals of European descent have one or more copies of the variant form of the enzyme (AC and AA genotypes). 4 Genetic association studies have thus far shown that the enzyme variant that leads to a reduced expression and functionality of FAAH; i.e., higher N-arachidonoylethanolamine (N-palmitoylethanolamine and N-oleoylethanolamine), is associated, in Caucasian individuals, with higher rates of cannabis sampling, higher reward reactivity (in functional magnetic resonance imaging task) 7 and trait impulsiveness, but lower risk of development of substance use disorder diagnosis (reduced drug-craving, withdrawal symptoms and self-reported drug liking in cannabis and methamphetamine users) as well as lower anxiety-relevant traits (lower amygdala reactivity to threat during functional magnetic resonance imaging task and self-reported anxiety). [1][2][3]8 We recently developed [ 11 C]CURB ([ 11 C-carbonyl]-6-hydroxy-[1,10-biphenyl]-3-yl cyclohexylcarbamate (URB694)) the first 1 available positron emission tomography (PET) radiotracer for imaging FAAH 9 and described kinetic analyses in which the composite parameter λk 3 (λ = K 1 /k 2 ) derived from a two-tissue compartment model with irreversible trapping was recommended as the preferred index for PET quantification of FAAH activity.…”

RETRACTED ARTICLE: Cannabinoid Type 1 Receptor Availability in the Amygdala Mediates Threat Processing in Trauma Survivors

“…Emerging evidence supports the potential utility of such targets, suggesting that variation in the FAAH gene is linked to reduced expression of FAAH that consequently results in elevations in circulating levels of anadamide (Chiang et al, 2004;Sipe et al, 2010), as well as decreased amygdala response to threat (Hariri et al, 2009) and more rapid habituation of the amygdala to repeated threat (Gunduz-Cinar et al, 2013b). Notably, elevating anandamide levels via FAAH inhibition appear to provide a more circumscribed spectrum of behavioral effects than blocking MAGL (Blankman and Cravatt, 2013) that could potentially result in a more beneficial side effect profile, as anandamide is less prone to CB 1 receptor desensitization and resultant behavioral tolerance (Lichtman et al, 2002;Schlosburg et al, 2010).…”

Endocannabinoids via CB1receptors act as neurogenic niche cues during cortical development

“…Likewise, mutations of ECB-metabolizing enzymes, including degrading (FAAH, ABHD6/12, MGL) or synthesizing enzymes (NAPE-PLD, DAGL), may result in less active enzymes that would increase or reduce ECB tone and signalling. In this regard, FAAH polymorphisms have been associated with drug abuse behaviours [90,91]. A recent proof of concept of this notion is the involvement of ABDH12 mutations that associate with the neurodegenerative disease polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract (PHARC) that occurs with concomitant demyelination and cerebellar ataxia [92].…”