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.

Abstract

Pain anticipation during conditions of uncertainty can unveil intrinsic biases, and understanding these biases can guide pain treatment interventions. This study used machine learning and functional magnetic resonance imaging to predict anticipatory responses in a pain anticipation experiment. One hundred forty-seven participants that included healthy controls (n = 57) and individuals with current and/or past mental health diagnosis (n = 90) received cues indicating upcoming pain stimuli: 2 cues predicted high and low temperatures, while a third cue introduced uncertainty. Accurate differentiation of neural patterns associated with specific anticipatory conditions was observed, involving activation in the anterior short gyrus of the insula and the nucleus accumbens. Three distinct response profiles emerged: subjects with a negative bias towards high pain anticipation, those with a positive bias towards low pain anticipation, and individuals whose predictions during uncertainty were unbiased. These profiles remained stable over one year, were consistent across diagnosed psychopathologies, and correlated with cognitive coping styles and underlying insula anatomy. The findings suggest that individualized and stable pain anticipation occurs in uncertain conditions.

Prescription opioids are a primary driver of opioid-related deaths. Although craving is a substantial component of OUD, the degree to which craving leads to misuse among chronic pain patients on long-term prescription opioids is unknown. A clear understanding of the factors that lead to misuse in this vulnerable population is needed for the development of safe and effective practices for opioid taper. This narrative review summarizes the relevant literature on the role of craving in addiction and chronic pain through epidemiological and behavioral studies. The first part of this review examines the role of craving in predicting opioid use/misuse in individuals with chronic pain with and without OUD. The second part covers methods on how craving is evaluated experimentally using both subjective and objective measures and provides related findings. The overall goal of this review is to facilitate the development of a population-specific description of craving in those who use opioids to control chronic pain and to describe how it may be mechanistically linked to patterns of opioid (mis)use.

The delta opioid receptor (DOR) agonist DPDPE decreases ethanol (EtOH) consumption when injected into the ventral tegmental area (VTA). We previously showed that DPDPE inhibition of GABAA receptor-mediated inhibitory postsynaptic currents (GABAAR IPSCs) is associated with reduced EtOH consumption. To determine whether self-administration of EtOH is required to change VTA DOR function, we compared the effects of passively administered (gavaged) and self-administered (two-bottle choice) EtOH. Because rats showed variability in DOR regulation of drinking and inhibition of GABAAR IPSCs, we examined whether these changes can be predicted before EtOH exposure by behavioral measures of anxiety or intoxication. Functional DORs were seen with both gavaged and self-administered EtOH, although the magnitude of DPDPE-induced inhibition correlated with behavioral measures only when EtOH was self-administered. Specifically, DPDPE-induced inhibition correlated with predrinking measures of open arm time in the plus maze (n = 19, R = .69, p = .001), with change in maximum fall latency on the rotarod (n = 17, R = .89, p = .000001), and with blood corticosterone (n = 17, R = .66, p = .004) in drinking animals. This DOR-mediated inhibition persisted for at least 14 days after EtOH access was terminated. Together, these findings indicate that anxious animals and those with the greatest EtOH-induced motor impairment have the most robust DPDPE-induced inhibition of GABAAR IPSCs in VTA neurons. These data also extend our understanding of the possible therapeutic value of the DOR for treatment of alcoholism by showing that its relevant synaptic action persists during abstinence.

Impulsivity, a risk factor for substance abuse disorders, is modulated by the Val158 variant of the catechol-O-methyltransferase (COMT) gene. Rodent studies have shown that opioids enhance impulsivity. Furthermore, alcohol consumption leads to endogenous opioid release in the cortex and nucleus accumbens (NAc), and this opioid release is correlated with greater positive hedonic effect. Using the selective mu opioid receptor radioligand [¹¹C] carfentanil, we find that, following alcohol consumption, individuals with the COMT Val158 allele have greater opioid release in the right NAc but less release in medial orbital frontal cortex (OFC). These data suggest that genetic regulation of dopamine levels can affect alcohol consumption in part by modulating endogenous opioid release in specific brain regions implicated in reward, which in turn promotes impulsive choice.

Value-based decisions optimize behavioral outcomes. Because delayed rewards are discounted, an increased tendency to choose smaller, immediate rewards can lead to suboptimal choice. Steep discounting of delayed rewards (impulsivity) characterizes subjects with frontal lobe damage and behavioral disorders including substance abuse. Correspondingly, animal studies and indirect evidence in humans suggest that lower dopamine in the frontal cortex contributes to steeper discounting by impairing corticostriatal function. To test this hypothesis directly, we performed a randomized, double-blind, counterbalanced, placebo-controlled study in which we administered the brain penetrant catechol-O-methyltransferase inhibitor tolcapone or placebo to healthy subjects performing a delay discounting task. Tolcapone significantly increased choice of delayed monetary rewards, and this tolcapone-induced increase covaried with increased BOLD activity in the left ventral putamen and anterior insula. Tolcapone also changed corticostriatal connectivity: specifically, by inducing a decrease in the coherence between ventral putamen and pregenual cingulate cortex. These results indicate that raising cortical dopamine levels attenuates impulsive choice by changing corticostriatal function.

Whether to continue to exploit a source of reward, or to search for a new one of potentially greater value, is a fundamental and underconstrained decision. Recent computational studies of this exploration-exploitation tradeoff have found that variability in exploration across individuals is influenced by a functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene, whose protein product degrades synaptically released dopamine. However, these and other genotype-phenotype associations have rarely been causally tested. To directly test this association and to evaluate additional behavioral characteristics, including perceived locus of control (LOC), here we used the COMT inhibitor tolcapone in a randomized, double-blind, counterbalanced, within-subject study of 66 subjects genotyped for the Val158Met allele to assess the hypothesis that reducing COMT enzymatic activity interacts with genotype to increase uncertainty-driven exploration. In keeping with our initial hypothesis, tolcapone led to an increase in exploratory, but not exploitative, behavior in Met/Met rather than Val/Val subjects. Independent of genotype, those subjects with a more external LOC also showed increases in uncertainty-driven exploration on tolcapone relative to placebo. However, we did not replicate our previous finding that Met/Met subjects show greater exploration at baseline. Together these findings support a model in which exploration is hypothesized to have a dopaminergic basis. Moreover, in keeping with findings in other behavioral and cognitive domains, the response to an increase in presumptively frontal dopamine is dependent upon baseline dopamine tone.

Value-based decisions optimize behavioral outcomes. Because delayed rewards are discounted, an increased tendency to choose smaller, immediate rewards can lead to suboptimal choice. Steep discounting of delayed rewards (impulsivity) characterizes subjects with frontal lobe damage and behavioral disorders including substance abuse. Correspondingly, animal studies and indirect evidence in humans suggest that lower dopamine in the frontal cortex contributes to steeper discounting by impairing corticostriatal function. To test this hypothesis directly, we performed a randomized, double-blind, counterbalanced, placebo-controlled study in which we administered the brain penetrant catechol-O-methyltransferase inhibitor tolcapone or placebo to healthy subjects performing a delay discounting task. Tolcapone significantly increased choice of delayed monetary rewards, and this tolcapone-induced increase covaried with increased BOLD activity in the left ventral putamen and anterior insula. Tolcapone also changed corticostriatal connectivity: specifically, by inducing a decrease in the coherence between ventral putamen and pregenual cingulate cortex. These results indicate that raising cortical dopamine levels attenuates impulsive choice by changing corticostriatal function.

Rationale

Individuals 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.

Objectives

To 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.

Methods

We 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.

Results

Tolcapone 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.

Conclusions

These data demonstrate that COMT inhibitors such as tolcapone may be useful therapeutics for AUD.

Trial registration

ClinicalTrials.gov Identifier: NCT02740582.