Epigenetic mediation of akt1 rs1130233′s effect on delta-9-tetrahydrocannabinol-induced medial temporal function during fear processing

Grace Blest-Hopley; Marco Colizzi; Diana Prata; Vincent Giampietro; Michael Brammer; Philip McGuire; Sagnik Bhattacharyya

doi:10.3390/brainsci11091240

Epigenetic mediation of akt1 rs1130233′s effect on delta-9-tetrahydrocannabinol-induced medial temporal function during fear processing

Grace Blest-Hopley, Marco Colizzi, Diana Prata, Vincent Giampietro, Michael Brammer, Philip McGuire, Sagnik Bhattacharyya^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

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, dou-ble-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 gy-rus/ amygdala activation. Number of A alleles at the AKT1 rs1130233 SNP, and percentage methyl-ation 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 parahippo-campal 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.

Original language	English
Article number	1240
Journal	Brain Sciences
Volume	11
Issue number	9
DOIs	https://doi.org/10.3390/brainsci11091240
Publication status	Published - 1 Sept 2021

Keywords

AKT1
Cannabis
Epigenetics
FMRI
Marijuana
THC

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@article{07079194dcd9493e8ae145335c6192a9,

title = "Epigenetic mediation of akt1 rs1130233′s effect on delta-9-tetrahydrocannabinol-induced medial temporal function during fear processing",

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, dou-ble-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 gy-rus/ amygdala activation. Number of A alleles at the AKT1 rs1130233 SNP, and percentage methyl-ation 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 parahippo-campal 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.",

keywords = "AKT1, Cannabis, Epigenetics, FMRI, Marijuana, THC",

author = "Grace Blest-Hopley and Marco Colizzi and Diana Prata and Vincent Giampietro and Michael Brammer and Philip McGuire and Sagnik Bhattacharyya",

note = "Funding Information: This work was supported by a Joint Medical Research Council/Priory Clinical research training fellowship (G0501775) from the Medical Research Council, United Kingdom, to SB. SB has also been supported during this work by the National Institute for Health Research (NIHR), UK through a Clinician Scientist award (NIHR-CS-11-001), a grant from the NIHR Efficacy and Mechanism Evaluation scheme and by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience, King?s College London jointly funded by the Guy?s and St Thomas? Trustees and the South London and Maudsley Trustees. DP was supported, during this work, by the European Com-mission Seventh Framework Programme Marie Curie Career Integration Grant FP7-PEOPLE-2013-CIG-631952, the 2016 Bial Foundation Psychophysiology Grant grant?Ref. 292/16, and the Funda??o para a Ci?ncia e Tecnologia (FCT) IF/00787/2014, LISBOA-01-0145-FEDER-030907 and DSAIPA/DS/0065/2018 grants, and the iMM Lisboa Director?s Fund Breakthrough Idea Grant 2016. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = sep,

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doi = "10.3390/brainsci11091240",

language = "English",

volume = "11",

journal = "Brain Sciences",

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T1 - Epigenetic mediation of akt1 rs1130233′s effect on delta-9-tetrahydrocannabinol-induced medial temporal function during fear processing

AU - Blest-Hopley, Grace

AU - Colizzi, Marco

AU - Prata, Diana

AU - Giampietro, Vincent

AU - Brammer, Michael

AU - McGuire, Philip

AU - Bhattacharyya, Sagnik

N1 - Funding Information: This work was supported by a Joint Medical Research Council/Priory Clinical research training fellowship (G0501775) from the Medical Research Council, United Kingdom, to SB. SB has also been supported during this work by the National Institute for Health Research (NIHR), UK through a Clinician Scientist award (NIHR-CS-11-001), a grant from the NIHR Efficacy and Mechanism Evaluation scheme and by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience, King?s College London jointly funded by the Guy?s and St Thomas? Trustees and the South London and Maudsley Trustees. DP was supported, during this work, by the European Com-mission Seventh Framework Programme Marie Curie Career Integration Grant FP7-PEOPLE-2013-CIG-631952, the 2016 Bial Foundation Psychophysiology Grant grant?Ref. 292/16, and the Funda??o para a Ci?ncia e Tecnologia (FCT) IF/00787/2014, LISBOA-01-0145-FEDER-030907 and DSAIPA/DS/0065/2018 grants, and the iMM Lisboa Director?s Fund Breakthrough Idea Grant 2016. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9/1

Y1 - 2021/9/1

N2 - 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, dou-ble-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 gy-rus/ amygdala activation. Number of A alleles at the AKT1 rs1130233 SNP, and percentage methyl-ation 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 parahippo-campal 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.

AB - 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, dou-ble-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 gy-rus/ amygdala activation. Number of A alleles at the AKT1 rs1130233 SNP, and percentage methyl-ation 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 parahippo-campal 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.

KW - AKT1

KW - Cannabis

KW - Epigenetics

KW - FMRI

KW - Marijuana

KW - THC

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U2 - 10.3390/brainsci11091240

DO - 10.3390/brainsci11091240

M3 - Article

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SN - 2076-3425

VL - 11

JO - Brain Sciences

JF - Brain Sciences

IS - 9

M1 - 1240

ER -

Epigenetic mediation of akt1 rs1130233′s effect on delta-9-tetrahydrocannabinol-induced medial temporal function during fear processing

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Keywords

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