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RationaleIndividuals suffering from alcohol use disorder (AUD) demonstrate difficulty with decision-making and impulsivity that may be associated with impaired frontal cortical function. Therapeutics that enhance frontal dopamine tone could decrease impulsivity and in turn reduce alcohol consumption in individuals with AUD.ObjectivesTo determine if the catechol-O-methyltransferase (COMT) inhibitor tolcapone can attenuate alcohol consumption in individuals with AUD and whether this attenuation correlates with tolcapone-induced changes in laboratory-based decision-making tasks.MethodsWe used daily self-report and a novel group laboratory bar task to assess the effects of randomized double-blind crossover administration of tolcapone (100 mg TID for 5 days) on alcohol consumption and laboratory tasks assessing impulsivity in 55 non-treatment-seeking subjects with AUD.ResultsTolcapone significantly reduced self-reported alcohol consumption (t (54) = 2.05, p = 0.045). The effects of tolcapone on drinking significantly correlated with changes in impulsive decision-making, such that subjects with the greatest decrease in impulsive choice on tolcapone also reported the greatest decrease in alcohol consumption (r (45) = 0.40, p = 0.0053). We did not see effects of tolcapone on laboratory bar consumption. Adverse event (AE) reporting was low, with no significant difference in frequency or severity of AEs on tolcapone versus placebo.ConclusionsThese data demonstrate that COMT inhibitors such as tolcapone may be useful therapeutics for AUD.Trial registrationClinicalTrials.gov Identifier: NCT 02740582

Motivations shape our behaviour: the promise of reward invigorates, while in the face of punishment, we hold back. Abnormalities of motivational processing are implicated in clinical disorders characterised by excessive habits and loss of top-down control, notably substance and behavioural addictions. Striatal and frontal dopamine have been hypothesised to play complementary roles in the respective generation and control of these motivational biases. However, while dopaminergic interventions have indeed been found to modulate motivational biases, these previous pharmacological studies used regionally non-selective pharmacological agents. Here, we tested the hypothesis that frontal dopamine controls the balance between Pavlovian, bias-driven automated responding and instrumentally learned action values. Specifically, we examined whether selective enhancement of cortical dopamine either (i) enables adaptive suppression of Pavlovian control when biases are maladaptive; or (ii) non-specifically modulates the degree of bias-driven automated responding. Healthy individuals (n = 35) received the catechol-o-methyltransferase (COMT) inhibitor tolcapone in a randomised, double-blind, placebo-controlled cross-over design, and completed a motivational Go NoGo task known to elicit motivational biases. In support of hypothesis (ii), tolcapone globally decreased motivational bias. Specifically, tolcapone improved performance on trials where the bias was unhelpful, but impaired performance in bias-congruent conditions. These results indicate a non-selective role for cortical dopamine in the regulation of motivational processes underpinning top-down control over automated behaviour. The findings have direct relevance to understanding neurobiological mechanisms underpinning addiction and obsessive-compulsive disorders, as well as highlighting a potential trans-diagnostic novel mechanism to address such symptoms.

PurposeTolcapone is an efficacious catechol-O-methyltransferase inhibitor for Parkinson’s disease (PD). However, safety issues hampered its use in clinical practice. We aimed to provide evidence of safety and efficacy of tolcapone by a systematic literature review to support clinicians’ choices in the use of an enlarging PD therapeutic armamentarium.MethodsWe searched PubMed for studies on PD patients treated with tolcapone, documenting the following outcomes: liver enzyme, adverse events (AEs), daily Off-time, levodopa daily dose, unified Parkinson’s disease rating scale (UPDRS) part-III, quality of life (QoL), and non-motor symptoms. FAERS and EudraVigilance databases for suspected AEs were interrogated for potential additional cases of hepatotoxicity.ResultsThirty-two studies were included, for a total of 4780 patients treated with tolcapone. Pertaining safety, 0.9% of patients showed liver enzyme elevation > 2. Over 23 years, we found 7 cases of severe liver injury related to tolcapone, 3 of which were fatal. All fatal cases did not follow the guidelines for liver function monitoring. FAERS and EudraVigilance database search yielded 61 reports of suspected liver AEs possibly related to tolcapone.Pertaining efficacy, the median reduction of hours/day spent in Off was 2.1 (range 1–3.2), of levodopa was 108.9 mg (1–251.5), of “On” UPDRS-III was 3.6 points (1.1–6.5). Most studies reported a significant improvement of QoL and non-motor symptoms.ConclusionLiterature data showed the absence of relevant safety concerns of tolcapone when strict adherence to hepatic function monitoring is respected. Given its high efficacy on motor fluctuations, tolcapone is probably an underutilized tool in the therapeutic PD armamentarium.

Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone’s effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone.ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934

•We examined whether groups that differ in the activity of catechol-O-methyltransferase (COMT), either genetically or as the result of a pharmacological challenge, show differences in regional cerebral blood flow (CBF).•COMT genotype influenced frontal CBF, whilst COMT inhibition altered CBF in parietal and temporal regions.•Our findings demonstrate that both acute and trait differences in dopamine signalling influence regional CBF.•We recommend the inclusion of CBF measures in fMRI studies of the impact of dopaminergic manipulations on BOLD signal. Dopamine has direct and complex vasoactive effects on cerebral circulation. Catechol-O-methyltransferase (COMT) regulates cortical dopamine, and its activity can be influenced both genetically and pharmacologically. COMT activity influences the functional connectivity of the PFC at rest, as well as its activity during task performance, determined using blood oxygen level-dependent (BOLD) fMRI. However, its effects on cerebral perfusion have been relatively unexplored. Here, 76 healthy males, homozygous for the functional COMT Val158Met polymorphism, were administered either the COMT inhibitor tolcapone or placebo in a double-blind, randomised design. We then assessed regional cerebral blood flow at rest using pulsed arterial spin labelling. Perfusion was affected by both genotype and drug. COMT genotype affected frontal regions (Val158 > Met158), whilst tolcapone influenced parietal and temporal regions (placebo > tolcapone). There was no genotype by drug interaction. Our data demonstrate that lower COMT activity is associated with lower cerebral blood flow, although the regions affected differ between those affected by genotype compared with those altered by acute pharmacological inhibition. The results extend the evidence for dopaminergic modulation of cerebral blood flow. Our findings also highlight the importance of considering vascular effects in functional neuroimaging studies, and of exercising caution in ascribing group differences in BOLD signal solely to altered neuronal activity if information about regional perfusion is not available.

Rationale The prefrontal cortex (PFC) and basal ganglia (BG) have been associated with cognitive stability and cognitive flexibility, respectively. We hypothesized that increasing PFC dopamine tone by administering tolcapone (a catechol-O-methyltransferase (COMT) inhibitor) to human subjects should promote stability; conversely, increasing BG dopamine tone by administering bromocriptine (a D2 receptor agonist) should promote flexibility. Objective We assessed these hypotheses by administering tolcapone, bromocriptine, and a placebo to healthy subjects who performed a saccadic eye movement task requiring stability and flexibility. Methods We used a randomized, double-blind, within-subject design that was counterbalanced across drug administration sessions. In each session, subjects were cued to prepare for a pro-saccade (look towards a visual stimulus) or anti-saccade (look away) on every trial. On 60% of the trials, subjects were instructed to switch the response already in preparation. We hypothesized that flexibility would be required on switch trials, whereas stability would be required on non-switch trials. The primary measure of performance was efficiency (the percentage correct divided by reaction time for each trial type). Results Subjects were significantly less efficient across all trial types under tolcapone, and there were no significant effects of bromocriptine. After grouping subjects based on Val158Met COMT polymorphism, we found that Met/Met and Val/Met subjects (greater PFC dopamine) were less efficient compared to Val/Val subjects. Conclusions Optimal behavior was based on obeying the environmental stimuli, and we found reduced efficiency with greater PFC dopamine tone. We suggest that greater PFC dopamine interfered with the ability to flexibly follow the environment.

Evidence supports an important link between mitochondrial DNA (mtDNA) variation and adverse drug reactions such as idiosyncratic drug-induced liver injury (iDILI). Here, we describe the generation of HepG2-derived transmitochondrial cybrids, to investigate the impact of mtDNA variation on mitochondrial (dys)function and susceptibility to iDILI. This study created 10 cybrid cell lines, each containing distinct mitochondrial genotypes of haplogroup H or haplogroup J backgrounds. HepG2 cells were depleted of mtDNA to make rho zero cells, before the introduction of known mitochondrial genotypes using platelets from healthy volunteers (n=10), thus generating 10 transmitochondrial cybrid cell lines. The mitochondrial function of each was assessed at basal state and following treatment with compounds associated with iDILI; flutamide, 2-hydroxyflutamide, and tolcapone, and their less toxic counterparts bicalutamide and entacapone utilizing ATP assays and extracellular flux analysis. Whilst only slight variations in basal mitochondrial function were observed between haplogroups H and J, haplogroup-specific responses were observed to the mitotoxic drugs. Haplogroup J showed increased susceptibility to inhibition by flutamide, 2-hydroxyflutamide, and tolcapone, via effects on selected mitochondrial complexes (I and II), and an uncoupling of the respiratory chain. This study demonstrates that HepG2 transmitochondrial cybrids can be created to contain the mitochondrial genotype of any individual of interest. This provides a practical and reproducible system to investigate the cellular consequences of variation in the mitochondrial genome, against a constant nuclear background. Additionally, the results show that inter-individual variation in mitochondrial haplogroup may be a factor in determining sensitivity to mitochondrial toxicants. This work was supported by the Centre for Drug Safety Science supported by the Medical Research Council, United Kingdom (Grant Number G0700654); and GlaxoSmithKline as part of an MRC-CASE studentship (grant number MR/L006758/1).

Extensive studies have been carried out on the impact of human activities on air pollution, but systematic investigation on the relationship between air pollutant and meteorological conditions is still insufficient, especially in the context of China’s site scale and recent comprehensive environmental pollution control. Here, we used a spatial interpolation technology to establish a set of data sets of pollutants and meteorological elements that are spatially matched at 896 stations in China to reveal the air pollutant-meteorological interactions between 2014 and 2019. We found that air pollution and meteorological elements have obvious seasonal and regional characteristics. Over the last few years, the concentration of most air pollutants in China has dropped significantly except for O 3 . The increase in O 3 concentration was closely related to the decrease of particulate matter and NO 2 concentration. The concentration of most air pollutants was affected by meteorological conditions, but the level of impact depended on the type of pollutants and varied across regions. The concentration of air pollutants at most stations was significantly negatively correlated with wind speed, precipitation and relative humidity, but positively correlated with atmospheric pressure. As the latitude increases, the impact of temperature on the concentration of air pollutants becomes more obvious. To effectively control air pollution, it is further urgent to reveal the relationship between air pollution and meteorological conditions based on long-term daily or real-time data.

Rationale Impairment in time perception, a critical component of decision-making, represents a risk factor for psychiatric conditions including substance abuse. A therapeutic that ameliorates this impairment could be advantageous in the treatment of impulsivity and decision-making disorders. Objectives Here we hypothesize that the catechol- O -methyltransferase (COMT) inhibitor tolcapone, which increases dopamine tone in frontal cortex (Ceravolo et al Synapse 43:201–207, 2002 ), improves time perception, with predictive behavioral, genetic, and neurobiological components. Methods Subjects ( n  = 66) completed a duration estimation task and other behavioral testing in each of two sessions after receiving a single oral dose of tolcapone (200 mg) or placebo in randomized, double-blind, counterbalanced, crossover fashion. Resting state fMRI data were obtained in a subset of subjects ( n  = 40). Subjects were also genotyped for the COMT (rs4680) polymorphism. Results Time perception was significantly improved across four proximal time points ranging from 5 to 60 s ( T (524) = 2.04, p  = 0.042). The degree of this improvement positively correlated with subjective measures of stress, depression, and alcohol consumption and was most robust in carriers of the COMT Val158 allele. Using seed regions defined by a previous meta-analysis (Wiener et al Neuroimage 49:1728–1740, 2010 ), we found not only that a connection from right inferior frontal gyrus (RIFG) to right putamen decreases in strength on tolcapone versus placebo ( p  < 0.05, corrected), but also that the strength of this decrease correlates inversely with the increase in duration estimation on tolcapone versus placebo ( r  = − 0.37, p  = 0.02). Conclusions Compressed time perception can be ameliorated by administration of tolcapone. Additional studies should be conducted to determine whether COMT inhibitors may be effective in treating decision-making disorders and addictive behaviors.

We present a selection design that couples S-adenosylmethionine-dependent methylation to growth. We demonstrate its use in improving the enzyme activities of not only N-type and O-type methyltransferases by 2-fold but also an acetyltransferase of another enzyme category when linked to a methylation pathway in Escherichia coli using adaptive laboratory evolution. We also demonstrate its application for drug discovery using a catechol O-methyltransferase and its inhibitors entacapone and tolcapone. Implementation of this design in Saccharomyces cerevisiae is also demonstrated.