Abstract
High doses of delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, have been shown to have anxiogenic effects. Additionally, THC effects have been shown to be modulated by genotype, including the single nucleotide polymorphism (SNP) rs1130233 at the protein kinase AKT1 gene, a key component of the dopamine signalling cascade. As such, it is likely that epigenetic methylation around this SNP may affect AKT gene expression, which may in turn impact on the acute effects of THC on brain function. We investigated the genetic (AKT1 rs1130233) and epigenetic modulation of brain function during fear processing in a 2-session, double-blind, cross-over, randomized placebo-controlled THC administration, in 36 healthy males. Fear processing was assessed using an emotion (fear processing) paradigm, under functional magnetic resonance imaging (fMRI). Complete genetic and fMRI data were available for 34 participants. THC caused an increase in anxiety and transient psychotomimetic symptoms and para-hippocampal gyrus/amygdala activation. Number of A alleles at the AKT1 rs1130233 SNP, and percentage methylation at the CpG11–12 site, were independently associated with a greater effect of THC on activation in a network of brain regions including left and right parahippocampal gyri, respectively. AKT1 rs1130233 moderation of the THC effect on left parahippocampal activation persisted after covarying for methylation percentage, and was partially mediated in sections of the left parahippocampal gyrus/hippocampus by methylation percentage. These results may offer an example of how genetic and epigenetic variations influence the psychotomimetic and neurofunctional effects of THC.
Highlights
We and others have provided evidence that sensitivity to the acute effects of THC on symptoms [15], cognition [18] and their neurophysiological underpinnings [15] as well as to the short-term psychotomimetic effects of cannabis [19], are moderated by a variation in the AKT1 gene. This gene codes for the protein kinase AKT, and its rs1130233 single nucleotide polymorphism (SNP) is a synonymous coding variation that has been linked to differential expression of the AKT protein, whereby the presence of an A allele is robustly associated with decreased expression of AKT [20,21,22,23]
We focused on the effects of THC on fear processing-related brain activation in-light-of previous evidence that a single dose of THC modulates normal functioning of limbic regions involved in the processing of fear, in particular the amygdala, which correlated directly with the severity of anxiety induced by THC acutely [9,13]
On brain activation during fear processing, while covarying for methylation percentage at the CpG site 11–12. These analysis examined the association between the median sum of squares (SSQ) ratio under each drug condition (THC and placebo) while processing fear with: (1) genotype (“number of A alleles +1”, at the AKT1 rs1130233 locus, coded as G/G = 1 G/A = 2 and A/A = 3); and (2) DNA methylation
Summary
We and others have provided evidence that sensitivity to the acute effects of THC on symptoms [15], cognition [18] and their neurophysiological underpinnings [15] as well as to the short-term psychotomimetic effects of cannabis [19], are moderated by a variation in the AKT1 gene (rs1130233). This gene codes for the protein kinase AKT, and its rs1130233 single nucleotide polymorphism (SNP) is a synonymous coding variation that has been linked to differential expression of the AKT protein, whereby the presence of an A allele is robustly associated with decreased expression of AKT [20,21,22,23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
