Genetic variation in endocannabinoid signaling: Anxiety, depression, and threat- and reward-related brain functioning during the transition into adolescence

• Published in: Behavioural brain research 2024-04, Vol.463, p.114925, Article 114925
• Main Authors: Desai, Shreya, Zundel, Clara G., Evanski, Julia M., Gowatch, Leah C., Bhogal, Amanpreet, Ely, Samantha, Carpenter, Carmen, Shampine, MacKenna, O’Mara, Emilie, Rabinak, Christine A., Marusak, Hilary A.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Amidohydrolases - genetics; Amidohydrolases - metabolism; Amygdala; Anxiety - genetics; Brain - diagnostic imaging; Brain - metabolism; Depression - genetics; Endocannabinoid System; Endocannabinoids - genetics; FAAH C385A; Female; Genetic Variation - genetics; Humans; Male; Mental Health; Nucleus Accumbens; Reward; Youth
• ISSN: 0166-4328; 1872-7549; 1872-7549
• DOI: 10.1016/j.bbr.2024.114925

The endocannabinoid system modulates neural activity throughout the lifespan. In adults, neuroimaging studies link a common genetic variant in fatty acid amide hydrolase (FAAH C385A)—an enzyme that regulates endocannabinoid signaling—to reduced risk of anxiety and depression, and altered threat- and reward-related neural activity. However, limited research has investigated these associations during the transition into adolescence, a period of substantial neurodevelopment and increased psychopathology risk. This study included FAAH genotype and longitudinal neuroimaging and neurobehavioral data from 4811 youth (46% female; 9–11 years at Baseline, 11–13 years at Year 2) from the Adolescent Brain Cognitive DevelopmentSM Study. Linear mixed models examined the effects of FAAH and the FAAH x time interaction on anxiety and depressive symptoms, amygdala reactivity to threatening faces, and nucleus accumbens (NAcc) response to happy faces during the emotional n-back task. A significant main effect of FAAH on depressive symptoms was observed, such that depressive symptoms were lower across both timepoints in those with the AA genotype compared to both AC and CC genotypes (p’s0.05). Additionally, there were no main effects of FAAH on anxiety or neural responses (p’s>0.05). Our findings add to emerging evidence linking the FAAH C385A variant to lower risk of psychopathology, and extend these findings to a developmental sample. In particular, we found lower depressive symptoms in FAAH AA genotypes compared to AC and CC genotypes. Future research is needed to characterize the role of the FAAH variant and the eCB system more broadly in neurodevelopment and psychiatric risk.