CYP2D6, brain structure, and cognitive function in methamphetamine dependence

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DESCRIPTION (provided by applicant): Individuals who are methamphetamine (Meth) dependent tend to perform worse on cognitive tests than healthy comparison individuals. However, not all Meth-dependent individuals display cognitive deficits; while some have considerable cognitive problems, others perform comparably to healthy individuals who do not abuse drugs. One possible source of variability in cognitive function in Meth-dependent individuals may lie in the genetic susceptibility to the development of neurotoxicity from Meth use. With other factors held constant, individuals who are genetically vulnerable to Meth-induced neurotoxicity would be expected to perform worse on cognitive tests than those who are not genetically vulnerable. One possible genetic candidate which may moderate neurotoxicity in Meth abuse is the gene which codes for the enzyme Cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6). CYP2D6 is the primary enzyme to catalyze Meth metabolism by hydroxylation and demethylation. In a promising preliminary study, Cherner and colleagues (2010) found that Meth-dependent participants who were extensive metabolizers of Meth based on CYP2D6 genotype performed significantly worse on several cognitive tests than those who were intermediate or poor metabolizers. The authors reasoned that, because extensive metabolizers had the worst cognitive performance, neurotoxicity from Meth dependence may be preferentially related to the metabolic byproducts of Meth (e.g., 4- hydroxymethamphetamine), rather than the parent compound itself. However, this study did not measure any other correlates of neurotoxicity. To address this gap in the literature, we propose to measure the brain structure of Meth-dependent individuals who possess different functional variants of the CYP2D6 gene, using structural MRI. Assuming that CYP2D6 extensive metabolizers experience more neurotoxicity than intermediate or poor metabolizers, we hypothesize that extensive metabolizers will be more likely than intermediate/poor metabolizers to exhibit brain abnormalities which have been theorized to reflect Meth- neurotoxicity, including gray matter volume deficits and enlargement of striatal structures, as well as lower estimates of white-matter fiber organization. In addition, we will administer a battery of cognitive tests and attempt to replicate the findings of Cherner et al. (2010). We presently have a sample of Meth-dependent participants with CYP2D6 genotype (extensive metabolizers N = 30; intermediate/poor metabolizers N = 21; and 6 subjects yet to be genotyped) and structural MRI scans. The proposed work aims to add 24 participants to this dataset to test whether functional variants of CYP2D6 influence brain structure and cognitive performance. Successful completion of this research would identify a risk factor for cognitive dysfunction and brain abnormalities in Meth dependence, as well as a potential moderator of Meth-induced neurotoxicity.