title: Protein kinase B (AKT1) genotype mediates sensitivity to cannabis-induced impairments in psychomotor control.
abstract: BACKGROUND
  What determines inter-individual variability to impairments in behavioural control that may underlie road-traffic accidents, and impulsive and violent behaviours occurring under the influence of cannabis, the most widely used illicit drug worldwide?
  
  
  METHODS
  Employing a double-blind, repeated-measures design, we investigated the genetic and neural basis of variable sensitivity to cannabis-induced behavioural dyscontrol in healthy occasional cannabis users. Acute oral challenge with placebo or Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, was combined with functional magnetic resonance imaging, while participants performed a response inhibition task that involved inhibiting a pre-potent motor response. They were genotyped for rs1130233 single nucleotide polymorphisms (SNPs) of the protein kinase B (AKT1) gene.
  
  
  RESULTS
  Errors of inhibition were significantly (p = 0.008) increased following administration of THC in carriers of the A allele, but not in G allele homozygotes of the AKT1 rs1130233 SNP. The A allele carriers also displayed attenuation of left inferior frontal response with THC evident in the sample as a whole, while there was a modest enhancement of inferior frontal activation in the G homozygotes. There was a direct relationship (r = -0.327, p = 0.045) between the behavioural effect of THC and its physiological effect in the inferior frontal gyrus, where AKT1 genotype modulated the effect of THC.
  
  
  CONCLUSIONS
  These results require independent replication and show that differing vulnerability to acute psychomotor impairments induced by cannabis depends on variation in a gene that influences dopamine function, and is mediated through modulation of the effect of cannabis on the inferior frontal cortex, that is rich in dopaminergic innervation and critical for psychomotor control.
authors: Department of Psychosis Studies,King's College London,Institute of Psychiatry, De Crespigny Park, London,UK.
authors: S
authors: S
authors: Bhattacharyya
authors: Social, Genetic and Developmental Psychiatry Centre,King's College London,Institute of Psychiatry, De Crespigny Park, London,UK.
authors: C
authors: C
authors: Iyegbe
authors: Department of Psychosis Studies,King's College London,Institute of Psychiatry, De Crespigny Park, London,UK.
authors: Z
authors: Z
authors: Atakan
authors: Pharmacology Research Unit, IMIM-Hospital del Mar and Psychiatric Department,ICN,Hospital Clinico, Barcelona,Spain.
authors: R
authors: R
authors: Martin-Santos
authors: Department of Neurology, Psychiatry and Medical Psychology, Faculty of Medicine of Ribeirão Preto,University of São Paulo,Brazil.
authors: J A
authors: JA
authors: Crippa
authors: Social, Genetic and Developmental Psychiatry Centre,King's College London,Institute of Psychiatry, De Crespigny Park, London,UK.
authors: X
authors: X
authors: Xu
authors: Department of Neuroimaging, Centre for Neuroimaging Sciences,King's College London,Institute of Psychiatry, De Crespigny Park, London,UK.
authors: S
authors: S
authors: Williams
authors: Department of Neuroimaging, Centre for Neuroimaging Sciences,King's College London,Institute of Psychiatry, De Crespigny Park, London,UK.
authors: M
authors: M
authors: Brammer
authors: Department of Child and Adolescent Psychiatry,King's College London,Institute of Psychiatry, De Crespigny Park, London,UK.
authors: K
authors: K
authors: Rubia
authors: Department of Psychosis Studies,King's College London,Institute of Psychiatry, De Crespigny Park, London,UK.
authors: D
authors: D
authors: Prata
authors: Social, Genetic and Developmental Psychiatry Centre,King's College London,Institute of Psychiatry, De Crespigny Park, London,UK.
authors: D A
authors: DA
authors: Collier
authors: Department of Psychosis Studies,King's College London,Institute of Psychiatry, De Crespigny Park, London,UK.
authors: P K
authors: PK
authors: McGuire
mesh_terms: D000328:Adult; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D013759:Dronabinol / Q000008:administration & dosage / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D007266:Inhibition, Psychological; D008279:Magnetic Resonance Imaging; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D011597:Psychomotor Performance / Q000187:drug effects* / Q000502:physiology; D055815:Young Adult
chemical_list: D063386:Cannabinoid Receptor Agonists; D013759:Dronabinol; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt