Adverse effect of catechol-O-methyltransferase (COMT) Val158Met met/met genotype in methamphetamine-related executive dysfunction

Highlights

• Executive dysfunction in methamphetamine users varies by COMT Val158Met genotype.

• Methamphetamine effects on executive function are seen only in Met/Met carriers.

• Val carriers have similar executive function irrespective of methamphetamine use.

• Slower dopamine clearance conferred by Met is a liability in methamphetamine use.

• COMT-controlled prefrontal dopamine bioavailability impacts methamphetamine injury.

Abstract

Introduction

The Val allele of the Val158Met single-nucleotide polymorphism of the catechol-o-methyltransferase gene (COMT) confers greater catabolism of dopamine (DA) in the prefrontal cortex (PFC) than the Met allele. Met/Met homozygotes typically outperform Val-carriers on tests of executive function (EF), perhaps resulting from increased DA bioavailability. Methamphetamine (METH) causes large releases of DA, which is associated with neurotoxicity and executive dysfunction in chronic METH users. We hypothesized that, contrary to its effect in non-METH-using populations, slower DA clearance conferred by Met/Met will relate to worse EF in METH users.

Methods

149 non-Hispanic White men, stratified by METH dependence (METH+/−) and COMT (Val/Val, Val/Met, Met/Met), completed three tests of EF: Wisconsin Card Sorting Test (WCST), Stroop Color-Word Test (Stroop), and Trail Making Test Part B (Trails B). Demographically-adjusted test scores were averaged to create an EF composite T-score. We examined the interaction of METH and COMT on the EF composite and individual test T-scores, controlling for premorbid functioning and alcohol use.

Results

METH group differences in EF were evident only among Met/Met carriers (beta = −9.36, p < .001) but not among Val carriers: Val/Met (beta = −1.38, p = .44) and Val/Val (beta = −4.34, p = .10). These effects were most salient on the WCST.

Conclusions

In the pre-frontal hyperdopaminergic state triggered by methamphetamine, greater DA inactivation conferred by the Val allele may protect against METH-related executive dysfunction, suggesting genetically-driven differences in vulnerability to METH.

Introduction

Heavy, chronic methamphetamine (METH) exposure is associated with central nervous system (CNS) injury (Davidson, Gow, Lee, & Ellinwood, 2001) and neurocognitive deficits (Scott et al., 2007). Human studies in abstinent users have described deficits in executive function, attention, learning and memory, information processing speed, and motor skills (Dean, Groman, Morales, & London, 2013; Scott et al., 2007). Functions localized to the prefrontal cortex (PFC) and frontostriatal connections may be especially vulnerable to METH effects (Chang, Alicata, Ernst, & Volkow, 2007; Bernacer et al., 2013). The PFC plays a critical role in decision-making and inhibitory control (Sakagami, Pan, & Uttl, 2006), with DA as the major neurotransmitter implicated in the evaluation of rewards, maintenance of addictive behaviors, and differences cognitive function (Starr, Fox, Harris, Deary, & Whalley, 2007; Volkow, Fowler, Wang, & Goldstein, 2002).

Although METH-associated CNS injury is evident, METH exposure parameters (e.g., age at first use, total years of use, lifetime amount consumed, route of consumption, and post-acute length of abstinence) often do not inform the degree of impairment seen among people with a history of METH dependence (Cherner, Bousman et al., 2010; Cherner, Suarez et al., 2010; McCann et al., 2008). This suggests individual differences in vulnerability to the effects of METH, which may result from a combination of environmental and genetic factors. Examining genetic variability may offer insight as to how individual differences contribute to risk for cognitive dysfunction in chronic METH use.

Mechanisms of METH-related injury include alterations in dopamine (DA), serotonin, GABA and glutamate systems (Halpin, Collins, & Yamamoto, 2014; McCann et al., 2008). METH principally modulates DA neurotransmission and increases extracellular DA concentrations by a number of means, which include stimulating DA release and inhibiting reuptake via the DA transporter (Lin, Sambo, & Khoshbouei, 2016). In addition to dopaminergic activity in the synapse, an important mechanism of DA-related METH neurotoxicity may occur at the receptor level; for example, a recent study shows that phasic METH-induced DA release impacts D1 DA receptor availability which is negatively associated with cortical thickness (Okita et al., 2017). While DA is critical for cognitive function, overexposure to DA in the synapse caused by stimulant exposure likely plays a role in neural compromise, including damage to DA terminals, microvascular injury, and structural and functional abnormalities on neuroimaging (Dean, Morales, Helleman, & London, 2018; Nordahl, Salo, & Leamon, 2003; Schmidt, Ritter, Sonsalla, Hanson, & Gibb, 1985). Thus, regulatory mechanisms that assist in removing DA from the synapse, play an important role in DA homeostasis in the brain (Meyer-Lindenberg et al., 2006). Catechol-O-methyltransferase (COMT), COMT accounts for >60% of the metabolic degradation of released DA in the PFC (Carboni & Silvagni, 2004; Li et al., 2004; Westerink & Spaan, 1982).

A single nucleotide polymorphism (SNP) of COMT involves a Val to Met amino acid substitution at codon 158 in the membrane-bound COMT (COMT Val158Met). Due to 40% higher enzymatic activity of the Val compared to Met allele (Chen et al., 2004), homozygote carriers of the Val allele (Val/Val genotype) metabolize PFC DA at a more efficient rate, resulting in lower levels of DA in the synapse, whereas those with Met/Met genotype have the lowest rate of DA clearance, resulting in higher level of DA at the synapse. As METH substantially augments the concentration of extracellular DA, we hypothesized that COMT genotype would be a relevant predictor of brain consequences of METH exposure.

COMT Val158Met has been examined in many contexts relevant to catecholamine function. With regard to cognition, it has been linked most consistently to differences in executive function (Bruder et al., 2005; Wishart et al., 2011), although some controversy remains about the replicability of findings (Barnett, Scoriels, & Munafo, 2008; Goldman, Weinberger, Malhotra, & Goldberg, 2009). In healthy adults, the Val allele has been linked to executive dysfunction (Barnett, Jones, Robbins, & Muller, 2007), whereas the Met allele is associated with enhanced executive function (Barnett et al., 2007; Egan et al., 2001). Some evidence suggests this effect may be specific to men (Egan et al., 2001; Solis-Ortiz, Perez-Luque, Morado-Crespo, & Gutierrez-Munoz, 2010). The Met-associated cognitive advantage is likely due to higher DA bioavailability in the PFC resulting from slower clearance coded by Met. Other findings point to an inverted U-shape relationship between DA activity in the PFC and cognitive performance (Mattay et al., 2003; Tunbridge, Harrison, & Weinberger, 2006) such that the relationship between COMT and PFC function is likely to be context dependent and more complex than a simple dichotomy in which a Val allele is harmful and a Met allele is protective. For example, under conditions of DA excess, such as after METH administration, the greater metabolic activity conferred by Val alleles may be more advantageous in restoring the brain to homeostasis. In an earlier study of COMT Val158Met and executive dysfunction in the context of HIV disease and METH dependence, we found that, regardless of HIV status, individuals with Met/Met genotype had better executive function compared (Wallace, Gudelsky, & Vorhees, 1999) to Val carriers, except if they were METH users, and this effect did not generalize to other cognitive domains (Bousman et al., 2010). Although increased bioavailability of cortical DA associated with the Met/Met genotype is thought to enhance executive function under physiologically normal conditions, in the hyperdopaminergic state induced by METH, slow DA clearance could result in neurotoxicity, possibly via DA auto-oxidation (Moszczynska & Callan, 2017; Riddle, Fleckenstein, & Hanson, 2006; Wallace et al., 1999), thus attenuating any advantage, or posing a liability for executive function in METH-using Met/Met individuals.

Here, we aim to examine whether variability in COMT Val158Met contributes to individual differences in executive deficits reported after heavy chronic METH exposure, with the goal to potentially identify genotype groups that are at higher risk of METH-associated executive dysfunction. In this investigation, we are focusing on a more homogenous sample than in our prior work, reducing variability associated with sex and racial background, as well as HIV status, since HIV can also affect dopaminergic circuitry. Our analyses will examine the main and interactive effects of COMT genotype and METH dependence on a three-test composite of executive function (Wisconsin Card Sorting Test, Stroop Color-Word Test, and Trail Making Test Part B). Follow-up analyses will examine the effects of COMT genotype and METH dependence on each test of executive function. We hypothesize that, contrary to its effect in the general population, among individuals with METH dependence, slower DA clearance in the PFC conferred by the Met/Met genotype, in conjunction with METH-induced dopaminergic excess, will be associated with worse executive function, while Val carriers will show comparatively better executive function.