COMT val158met genotype alters the effects of methamphetamine dependence on dopamine and dopamine-related executive function: preliminary findings. (October 2020)

• Record Type: Journal Article
• Authors: Saloner, Rowan; Cherner, Mariana; Sundermann, Erin E.; Watson, Caitlin Wei-Ming; Iudicello, Jennifer E.; Letendre, Scott L.; Kumar, Adarsh; Ellis, Ronald J.
• Is Part Of: Psychiatry research. Volume 292(2020)
• Publication Date: 2020-10
• Subjects: Dopamine -- Homovanillic acid -- Catechol-o-methyltransferase -- Methamphetamine -- Executive function -- Prefrontal cortex; Psychiatry -- Periodicals; Psychiatry -- periodicals; Psychiatrie -- Périodiques; 616.89
• DOI: 10.1016/j.psychres.2020.113269
• Languages: English
• ISSNs: 0165-1781

Abstract

Highlights: Methamphetamine (METH) alters dopamine (DA) integrity and executive function (EF). METH-related EF deficits are greatest in Met/Met-carriers of COMT val158met gene. METH+ have lower CSF DA levels than METH- only in Met/Met, but not Val-carriers. CSF DA is highest in METH- Met/Met-and only correlates with better EF in this group. Slow DA clearance conferred by Met/Met-exacerbates METH-related DA injury. Abstract: The Met-allele of the COMT Val158Met polymorphism slows metabolism and increases bioavailability of dopamine (DA) in the prefrontal cortex compared to the Val-allele. Healthy Met-carriers outperform Val-carriers on executive function (EF) tests, yet this 'advantage' disappears in methamphetamine (METH) dependence. Met-carriers may be disproportionately vulnerable to METH-related perturbations of DA, yet it is unknown whether COMT modulates METH effects on CSF DA biomarkers. Participants were 75 METH+ and 47 METH- men who underwent neurocognitive testing, COMT genotyping, and lumbar puncture. CSF was assayed for DA and its metabolite, homovanillic acid (HVA). Separate linear models regressed DA, HVA, and HVA/DA ratios on COMT, METH and their interaction. Pearson correlations examined associations between DA and EF. Significant interactions indicated that METH+ had lower DA and higher HVA/DA ratios among Met/Met, but not Val/Met-or Val/Val. Met/Met-exhibited the highest DA levels among METH-, whereas DA levels were comparable between Met/Met-and Val-carriers among METH+. Higher DA correlated with better EF in METH- Met/Met, but did not predict EF in the entire sample. DA was expectedly higher in METH- Met/Met, yet a discordant genotype-phenotype profile emerged in METH+ Met/Met, consistent with the notion that slow DA clearance exacerbates METH-associated DA dysregulation.