COMT val158met genotype alters the effects of methamphetamine dependence on dopamine and dopamine-related executive function: preliminary findings

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 Metcarriers 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 *

A preliminary study on the association of single nucleotide polymorphisms and methylation of dopamine system‐related genes with psychotic symptoms in patients with methamphetamine use disorder

“…The COMT enzyme methylates and thereby inactivates catecholamine neurotransmitters, such as norepinephrine, epinephrine, and DA. COMTrs4818 is associated with cognitive processing (Gaysina et al, 2013; Ioannidis et al, 2020), executive function (Cherner et al, 2019; Saloner et al, 2020), psychological function (Madzarac et al, 2021; Vieira et al, 2022), pain modulation (Lisboa et al, 2022; Omair et al, 2015), and so forth. According to our data (shown in Table 3 and Figure 2), MAUD patients who were COMT rs4818 G carriers had higher motor‐impulsive scores.…”

Influence of age and cognitive performance on resting-state functional connectivity of dopaminergic and noradrenergic centres

“…Populations of dopaminergic neurons in the midbrain are implicated in reward processing by encoding incentive salience of the stimuli (Berridge and Kringelbach, 2015) and reward prediction error (Schultz, 2016). The research in animal models and humans supports the involvement of the dopaminergic system in cognitive functions such as sustained attention (Bellgrove et al, 2005), working memory (Bäckman and Lyberg, 2013), executive control (Saloner et al, 2020), as well as visuomotor search (Chen et al, 2020). Several resting-state studies have found the functional connectivity of VTA and SNc to be related to aspects of reward processing (Adrián-Ventura et al, 2019; Schmaal et al, 2012), impulsivity (Grimm et al, 2020), interoception (Chong et al, 2017) and gait speed (Karim et al, 2020).…”

“…Bellgrove et al, 2005), working memory(Bäckman and Lyberg, 2013), executive control(Saloner et al, 2020), as well as visuomotor search(Chen et al, 2020). Several resting-state studies have found the functional connectivity of VTA and SNc to be related to aspects of reward processing (Adrián-Ventura et al,2019;In individuals ranging from 18 to 49 years old, increased age was related to stronger coupling between VTA/SNc and lateral prefrontal cortex, superior temporal and parahippocampal gyri, as well as cerebellum(Manza et al, 2015;Peterson et al, 2017;Zhang et al, 2016).…”

Effect of Catechol-O-Methyltransferase Genotype Polymorphism on Neurological and Psychiatric Disorders: Progressing Towards Personalized Medicine

“…Among METH- men with Met/Met, the highest dopamine levels were seen, and these individuals performed EF better than Val/Met and Val/Val variants. It was concluded that slow clearance of dopamine worsens dopamine dysregulation associated with methamphetamine [ 25 ]. A similar study was done in 2019 with 149 subjects who performed three tests of EF.…”