Prefrontal white matter impairment in substance users depends upon the catechol-o-methyl transferase (COMT) val158met polymorphism

Individuals addicted to most chemical substances present with hypoactive dopaminergic systems as well as altered prefrontal white matter structure. Prefrontal dopaminergic tone is under genetic control and is influenced by and modulates descending cortico-striatal glutamatergic pathways that in turn, regulate striatal dopamine release. The catechol-O-methyltransferase (COMT) gene contains an evolutionarily recent and common functional variant at codon 108/158 (rs4680) that plays an important role in modulating prefrontal dopaminergic tone. To determine if the COMT val158met genotype influences white matter integrity (i.e., fractional anisotropy (FA)) in substance users, 126 healthy controls and 146 substance users underwent genotyping and magnetic resonance imaging. A general linear model with two between-subjects factors (COMT genotype and addiction status) was performed using whole brain diffusion tensor imaging (DTI) to assess FA. A significant Genotype × Drug Use status interaction was found in the left prefrontal cortex. Post-hoc analysis showed reduced prefrontal FA only in Met/Met homozygotes who were also drug users. These data suggest that Met/Met homozygous individuals, in the context of addiction, have increased susceptibility to white matter structural alterations, which might contribute to previously identified structural and functional prefrontal cortical deficits in addiction.

[1]  A. Grace,et al.  The Catechol-O-Methyltransferase Polymorphism: Relations to the Tonic–Phasic Dopamine Hypothesis and Neuropsychiatric Phenotypes , 2004, Neuropsychopharmacology.

[2]  R. A. Zimmerman,et al.  Changes in brain water diffusion during childhood , 1999, Neuroradiology.

[3]  P. Basser.  Inferring microstructural features and the physiological state of tissues from diffusion‐weighted images , 1995, NMR in biomedicine.

[4]  Alexander Leemans,et al.  Microstructural maturation of the human brain from childhood to adulthood , 2008, NeuroImage.

[5]  S. Mori,et al.  Principles of Diffusion Tensor Imaging and Its Applications to Basic Neuroscience Research , 2006, Neuron.

[6]  Yu-Shin Ding,et al.  Behavioral / Systems / Cognitive Activation of Orbital and Medial Prefrontal Cortex by Methylphenidate in Cocaine-Addicted Subjects But Not in Controls : Relevance to Addiction , 2005 .

[7]  Ming D. Li.  Identifying susceptibility loci for nicotine dependence: 2008 update based on recent genome-wide linkage analyses , 2008, Human Genetics.

[8]  Iroise Dumontheil,et al.  Influence of the COMT Genotype on Working Memory and Brain Activity Changes During Development , 2011, Biological Psychiatry.

[9]  Mark W. Woolrich,et al.  Advances in functional and structural MR image analysis and implementation as FSL , 2004, NeuroImage.

[10]  E. Bongarzone,et al.  Identification of the Dopamine D3 Receptor in Oligodendrocyte Precursors: Potential Role in Regulating Differentiation and Myelin Formation , 1998, The Journal of Neuroscience.

[11]  Daniel Rueckert,et al.  Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data , 2006, NeuroImage.

[12]  Takashi Hanakawa,et al.  Functional activity related to risk anticipation during performance of the Iowa gambling task , 2005, NeuroImage.

[13]  P. Garris,et al.  Different kinetics govern dopaminergic transmission in the amygdala, prefrontal cortex, and striatum: an in vivo voltammetric study , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  G. Di Chiara,et al.  Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[15]  K O Lim,et al.  In vivo detection and functional correlates of white matter microstructural disruption in chronic alcoholism. , 2000, Alcoholism, clinical and experimental research.

[16]  Clare E. Mackay,et al.  Corpus callosum damage in heavy marijuana use: Preliminary evidence from diffusion tensor tractography and tract-based spatial statistics , 2008, NeuroImage.

[17]  J S Fowler,et al.  Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. , 2001, The American journal of psychiatry.

[18]  Jean-Lud Cadet,et al.  Frontal cortical tissue composition in abstinent cocaine abusers: a magnetic resonance imaging study , 2003, NeuroImage.

[19]  K. A. Il’yasov,et al.  Fast quantitative diffusion-tensor imaging of cerebral white matter from the neonatal period to adolescence , 2004, Neuroradiology.

[20]  N. Volkow,et al.  Imaging dopamine's role in drug abuse and addiction , 2009, Neuropharmacology.

[21]  R. Weinshilboum,et al.  Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. , 1996, Pharmacogenetics.

[22]  M C Neale,et al.  A population-based twin study in women of smoking initiation and nicotine dependence , 1999, Psychological Medicine.

[23]  Dana Quade,et al.  Nonparametric Partial Correlation , 1967 .

[24]  P. Thompson,et al.  Diffusion imaging, white matter, and psychopathology. , 2011, Annual review of clinical psychology.

[25]  Gary H. Glover,et al.  COMT genotype affects prefrontal white matter pathways in children and adolescents , 2010, NeuroImage.

[26]  N. Volkow,et al.  Decreased dopamine activity predicts relapse in methamphetamine abusers , 2011, Molecular Psychiatry.

[27]  Alex Fornito,et al.  White matter microstructure in opiate addiction , 2012, Addiction biology.

[28]  Yihong Yang,et al.  Implicit reference-based group-wise image registration and its application to structural and functional MRI , 2009, NeuroImage.

[29]  David W Brook,et al.  Adolescent Academic Adjustment Factors and the Trajectories of Cigarette Smoking from Adolescence to the Mid-30s , 2011, International journal of mental health.

[30]  Thomas E. Nichols,et al.  Nonparametric permutation tests for functional neuroimaging: A primer with examples , 2002, Human brain mapping.

[31]  Melissa T. Buelow,et al.  Construct Validity of the Iowa Gambling Task , 2009, Neuropsychology Review.

[32]  P. Basser,et al.  Diffusion tensor MR imaging of the human brain. , 1996, Radiology.

[33]  Nunzio Pomara,et al.  Reduced frontal white matter integrity in cocaine dependence: a controlled diffusion tensor imaging study , 2002, Biological Psychiatry.

[34]  Stefan Gazdzinski,et al.  Tract-based spatial statistics (TBSS) of diffusion tensor imaging data in alcohol dependence: Abnormalities of the motivational neurocircuitry , 2009, Psychiatry Research: Neuroimaging.

[35]  I. Ulmanen,et al.  Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. , 1995, Biochemistry.

[36]  Joseph A Maldjian,et al.  Decreased gray matter concentration in the insular, orbitofrontal, cingulate, and temporal cortices of cocaine patients , 2002, Biological Psychiatry.

[37]  J. Provenzale,et al.  Evaluation of normal age-related changes in anisotropy during infancy and childhood as shown by diffusion tensor imaging. , 2002, AJR. American journal of roentgenology.

[38]  Baoci Shan,et al.  Disrupted White Matter Integrity in Heroin Dependence: A Controlled Study Utilizing Diffusion Tensor Imaging , 2008, The American journal of drug and alcohol abuse.

[39]  P. Bhide,et al.  Dopamine, cocaine and the development of cerebral cortical cytoarchitecture: a review of current concepts. , 2009, Seminars in cell & developmental biology.

[40]  Mark Slifstein,et al.  Altered prefrontal dopaminergic function in chronic recreational ketamine users. , 2005, The American journal of psychiatry.

[41]  Yihong Yang,et al.  Factors underlying prefrontal and insula structural alterations in smokers , 2011, NeuroImage.

[42]  Larry A. Kramer,et al.  Diffusion Tensor Imaging and Decision Making in Cocaine Dependence , 2010, PloS one.

[43]  P. Buckley,et al.  Association of Low Striatal Dopamine D2 Receptor Availability With Nicotine Dependence Similar to That Seen With Other Drugs of Abuse , 2009 .

[44]  Paul J. Harrison,et al.  Catechol-O-Methyltransferase Inhibition Improves Set-Shifting Performance and Elevates Stimulated Dopamine Release in the Rat Prefrontal Cortex , 2004, The Journal of Neuroscience.

[45]  M. Egan,et al.  Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. , 2004, American journal of human genetics.

[46]  Gonneke Willemsen,et al.  Heritability of Smoking Initiation and Nicotine Dependence , 2005, Behavior genetics.

[47]  John J. Foxe,et al.  Assessing white matter integrity as a function of abstinence duration in former cocaine-dependent individuals. , 2010, Drug and alcohol dependence.

[48]  D. Attwell,et al.  Neurotransmitter receptors in the life and death of oligodendrocytes , 2007, Neuroscience.

[49]  Daniel H. Mathalon,et al.  Frontally mediated inhibitory processing and white matter microstructure: age and alcoholism effects , 2010, Psychopharmacology.

[50]  George Fein,et al.  Prefrontal cortical volume reduction associated with frontal cortex function deficit in 6-week abstinent crack-cocaine dependent men. , 2002, Drug and alcohol dependence.

[51]  P. Worhunsky,et al.  White Matter Integrity is Associated with Treatment Outcome Measures in Cocaine Dependence , 2010, Neuropsychopharmacology.

[52]  Nora D. Volkow,et al.  Profound Decreases in Dopamine Release in Striatum in Detoxified Alcoholics: Possible Orbitofrontal Involvement , 2007, The Journal of Neuroscience.

[53]  Y Tamagawa,et al.  Adult and neonatal human brain: diffusional anisotropy and myelination with diffusion-weighted MR imaging. , 1991, Radiology.

[54]  V. Menon,et al.  White matter development during childhood and adolescence: a cross-sectional diffusion tensor imaging study. , 2005, Cerebral cortex.

[55]  R W Cox,et al.  AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. , 1996, Computers and biomedical research, an international journal.

[56]  Tianhua Niu,et al.  A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men. , 2004, American journal of human genetics.

[57]  Khader M Hasan,et al.  Quantitative diffusion tensor tractography of association and projection fibers in normally developing children and adolescents. , 2007, Cerebral cortex.

[58]  In Chan Song,et al.  Decreased frontal white-matter integrity in abstinent methamphetamine abusers. , 2007, The international journal of neuropsychopharmacology.

[59]  Christian Beaulieu,et al.  Diffusion tensor imaging of neurodevelopment in children and young adults , 2005, NeuroImage.

[60]  David Goldman,et al.  Addictions biology: haplotype-based analysis for 130 candidate genes on a single array. , 2008, Alcohol and alcoholism.