4.5 Article

Epigenetic Mediation of AKT1 rs1130233's Effect on Delta-9-Tetrahydrocannabinol-Induced Medial Temporal Function during Fear Processing

Journal

BRAIN SCIENCES
Volume 11, Issue 9, Pages -

Publisher

MDPI
DOI: 10.3390/brainsci11091240

Keywords

THC; cannabis; Marijuana; AKT1; Epigenetics; fMRI

Categories

Funding

  1. Medical Research Council, United Kingdom [G0501775]
  2. National Institute for Health Research (NIHR), UK through a Clinician Scientist award [NIHR-CS-11-001]
  3. NIHR Efficacy and Mechanism Evaluation scheme
  4. NIHR Biomedical Research Centre for Mental Health at the South London
  5. Maudsley NHS Foundation Trust
  6. Institute of Psychiatry, Psychology and Neuroscience, King's College London - Guy's and St Thomas' Trustees
  7. Institute of Psychiatry, Psychology and Neuroscience, King's College London - South London and Maudsley Trustees
  8. European Commission [FP7-PEOPLE-2013-CIG-631952]
  9. Bial Foundation Psychophysiology [292/16]
  10. Fundacao para a Ciencia e Tecnologia (FCT) [IF/00787/2014, LISBOA-01-0145-FEDER-030907, DSAIPA/DS/0065/2018]
  11. iMM Lisboa Director's Fund Breakthrough Idea Grant
  12. MRC [G0501775] Funding Source: UKRI
  13. Fundação para a Ciência e a Tecnologia [DSAIPA/DS/0065/2018] Funding Source: FCT

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High doses of THC have anxiogenic effects and their impact on brain function during fear processing can be modulated by genetic (AKT1 rs1130233) and epigenetic factors. Genetic variations at AKT1 rs1130233 and epigenetic methylation at specific CpG sites are associated with the effects of THC on brain activation during fear processing.
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 CpG(11-12) 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.

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