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.