title: Cannabis and cocaine decrease cognitive impulse control and functional corticostriatal connectivity in drug users with low activity DBH genotypes.
abstract: The dopamine β-hydroxylase (DβH) enzyme transforms dopamine into noradrenaline. We hypothesized that individuals with low activity DBH genotypes (rs1611115 CT/TT) are more sensitive to the influence of cannabis and cocaine on cognitive impulse control and functional connectivity in the limbic 'reward' circuit because they experience a drug induced hyperdopaminergic state compared to individuals with high activity DBH genotypes (rs1611115 CC). Regular drug users (N = 122) received acute doses of cannabis (450 μg/kg THC), cocaine HCl 300 mg and placebo. Cognitive impulse control was assessed by means of the Matching Familiar Figures Test (MFFT). Resting state fMRI was measured in a subset of participants to determine functional connectivity between the nucleus accumbens (NAc) and (sub)cortical areas. The influence of cannabis and cocaine on impulsivity and functional connectivity significantly interacted with DBH genotype. Both drugs increased cognitive impulsivity in participants with CT/TT genotypes but not in CC participants. Both drugs also reduced functional connectivity between the NAc and the limbic lobe, prefrontal cortex, striatum and thalamus and primarily in individuals with CT/TT genotypes. Correlational analysis indicated a significant negative association between cognitive impulsivity and functional connectivity in subcortical areas of the brain. It is concluded that interference of cannabis and cocaine with cognitive impulse control and functional corticostriatal connectivity depends on DBH genotype. The present data provide a neural substrate and behavioral mechanism by which drug users can progress to drug seeking and may also offer a rationale for targeted pharmacotherapy in chronic drug users with high risk DBH genotypes.
authors.affiliation: Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands. j.ramaekers@maastrichtuniversity.nl.
authors.forename: J G
authors.initials: JG
authors.lastname: Ramaekers
authors.affiliation: Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: van Wel
authors.affiliation: Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Spronk
authors.affiliation: Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Franke
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Kenis
authors.affiliation: Department of Forensic Toxicology, Institute of Legal Medicine, Goethe University of Frankfurt, Frankfurt, Germany.
authors.forename: S W
authors.initials: SW
authors.lastname: Toennes
authors.affiliation: Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: K P C
authors.initials: KP
authors.lastname: Kuypers
authors.affiliation: Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: E L
authors.initials: EL
authors.lastname: Theunissen
authors.affiliation: Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Stiers
authors.affiliation: Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.|The Netherlands Forensic Psychiatric Centre Pompestichting, Nijmegen, The Netherlands.
authors.forename: R J
authors.initials: RJ
authors.lastname: Verkes
mesh_terms: D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D001931:Brain Mapping; D002188:Cannabis; D003042:Cocaine / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D019970:Cocaine-Related Disorders / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D018592:Cross-Over Studies; D004299:Dopamine beta-Hydroxylase / Q000235:genetics*; D004311:Double-Blind Method; D013759:Dronabinol / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D056344:Executive Function / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D007175:Impulsive Behavior; D008279:Magnetic Resonance Imaging; D008297:Male; D002189:Marijuana Abuse / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D009483:Neuropsychological Tests; D011619:Psychotropic Drugs / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D012146:Rest; D055815:Young Adult
chemical_list: D011619:Psychotropic Drugs; D013759:Dronabinol; D004299:Dopamine beta-Hydroxylase; D003042:Cocaine
keywords: Cannabis; Cocaine; DBH genotype; Fuctional connectivity; Impulse control