Functional Genetic Variation of the Cannabinoid Receptor 1 and Cannabis Use Interact on Prefrontal Connectivity and Related Working Memory Behavior

Abstract

Cannabinoid signaling is involved in different brain functions and it is mediated by the cannabinoid receptor 1 (CNR1), which is encoded by the CNR1 gene. Previous evidence suggests an association between cognition and cannabis use. The logical interaction between genetically determined cannabinoid signaling and cannabis use has not been determined. Therefore, we investigated whether CNR1 variation predicts CNR1 prefrontal mRNA expression in postmortem prefrontal human tissue. Then, we studied whether functional variation in CNR1 and cannabis exposure interact in modulating prefrontal function and related behavior during working memory processing. Thus, 208 healthy subjects (113 males) were genotyped for the relevant functional SNP and were evaluated for cannabis use by the Cannabis Experience Questionnaire. All individuals performed the 2-back working memory task during functional magnetic resonance imaging. CNR1 rs1406977 was associated with prefrontal mRNA and individuals carrying a G allele had reduced CNR1 prefrontal mRNA levels compared with AA subjects. Moreover, functional connectivity MRI demonstrated that G carriers who were also cannabis users had greater functional connectivity in the left ventrolateral prefrontal cortex and reduced working memory behavioral accuracy during the 2-back task compared with the other groups. Overall, our results indicate that the deleterious effects of cannabis use are more evident on a specific genetic background related to its receptor expression.

Neural Correlates of Social Influence Among Cannabis Users

“…This reaction time slowing was associated with increased inferior frontal gyrus (IFG) activation, raising the hypothesis that cannabis users compared to controls expended more effortful processing when they opposed group influence. Cognitive variables such as attention and working memory contribute to decision speed, [51, 52] and cannabis use is often associated with these domain-specific deficits [53–55]. The longer reaction time during the trials in which the cannabis users disagreed with the group may have indicated that the cannabis users had less ability to identify and/or resolve information conflicts (though this interpretation is one among many, and should be verified in future studies).…”

Because difficulty is not the same for everyone: the impact of complexity in working memory is associated with cannabinoid 1 receptor genetic variation in young adults

“…Bertolino's group reported an association of the rs1406977, another SNP of gene CNR1, with higher mRNA expression in post-mortem dorsolateral prefrontal cortex for AA subjects than for G carriers. And in an in vivo study, they reported better performance for AA subjects than for G-carriers of the rs1406977 for healthy controls and for cannabis-users; however, they only tested a 2-back task for rs1406977 (Colizzi et al, 2015). For the rs2180619, Heitland's group documented a trend to reducing the power in the theta frequency band in the spectrum at resting state for G-carriers compared to AA homozygous (Heitland et al, 2014).…”

“…Other groups have tested the association of other SNPs of the CNR1 gene with WM (Colizzi et al, 2015) and the electroencephalographic response at rest (Heitland, Kenemans, Böcker, & Baas, 2014). Bertolino's group reported an association of the rs1406977, another SNP of gene CNR1, with higher mRNA expression in post-mortem dorsolateral prefrontal cortex for AA subjects than for G carriers.…”

Neural mechanisms of sensitivity to peer information in young adult cannabis users

“…This is the first study to our knowledge to investigate this effect in humans with social influence and in the context of MJ use. Decision speed is modulated by cognitive variables such as attention and working memory (Ester, Ho, Brown, & Serences, 2014; Nunez, Srinivasan, & Vandekerckhove, 2015; Whitney, Rinehart, & Hinson, 2008) and it has been widely demonstrated that MJ use is associated with these domain-specific deficits (Colizzi et al, 2015; Jacobus et al, 2015; Price et al, 2015). An alternative explanation is that longer reaction time during the incongruent trials could indicate that the MJ users experience impaired cognition associated with identifying and/or resolving information conflicts.…”