E M Tunbridge

Catechol-o-methyltransferase, cognition, and psychosis : Val158met and beyond

This review summarizes our current understanding of catechol-o-methyltransferase (COMT) and how it relates to brain function and schizophrenia. We begin by considering the COMT gene, its transcripts and proteins, and its relevance for central catecholamine function. We then describe how variation in COMT activity affects the function of the prefrontal cortex (PFC) and associated areas, reviewing evidence that COMT modulates executive function and working memory and highlighting recent data that also implicate it in emotional processing. Finally, we discuss briefly the genetic association between COMT and schizophrenia, focusing in particular on the complex interaction of functional loci within the gene that may underlie the mixed results of studies to date. We conclude by outlining preliminary data indicating that COMT is a promising therapeutic target for ameliorating the cognitive deficits associated with schizophrenia.

Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex.

The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene affects activity of the enzyme and influences performance and efficiency of the prefrontal cortex (PFC); however, although catecholaminergic neurotransmission is implicated, the underlying mechanisms remain elusive because studies of the role of COMT in PFC function are sparse. This study investigated the effect of tolcapone, a brain-penetrant COMT inhibitor, on a rat model of attentional set shifting, which is dependent on catecholamines and the medial PFC (mPFC). Additionally, we investigated the effect of tolcapone on extracellular catecholamines in the mPFC using microdialysis in awake rats. Tolcapone significantly and specifically improved extradimensional (ED) set shifting. Tolcapone did not affect basal extracellular catecholamines, but significantly potentiated the increase in extracellular dopamine (DA) elicited by either local administration of the depolarizing agent potassium chloride or systemic administration of the antipsychotic agent clozapine. Although extracellular norepinephrine (NE) was also elevated by local depolarization and clozapine, the increase was not enhanced by tolcapone. We conclude that COMT activity specifically affects ED set shifting and is a significant modulator of mPFC DA but not NE under conditions of increased catecholaminergic transmission. These data suggest that the links between COMT activity and PFC function can be modeled in rats and may be specifically mediated by DA. The interaction between clozapine and tolcapone may have implications for the treatment of schizophrenia.

Tryptophan depletion alters the decision-making of healthy volunteers through altered processing of reward cues.

While accumulating evidence suggests that effective real-life decision-making depends upon the functioning of the orbitofrontal cortex, much less is known about the involvement of the monoamine neurotransmitter systems and, in particular, serotonin. In the present study, we explored the impact of depleting the serotonin precursor, tryptophan, on human decision-making. Eighteen healthy volunteers consumed an amino-acid drink containing tryptophan and 18 healthy volunteers consumed an amino-acid drink without tryptophan, before choosing between simultaneously presented gambles, differing in the magnitude of expected gains (ie reward), the magnitude of expected losses (ie punishment), and the probabilities with which these outcomes were delivered. Volunteers also chose between gambles probing identified non-nomative biases in human decision-making, namely, risk-aversion when choosing between gains and risk-seeking when choosing between losses. Tryptophan-depleted volunteers showed reduced discrimination between magnitudes of expected gains associated with different choices. There was little evidence that tryptophan depletion was associated with altered discrimination between the magnitudes of expected losses, or altered discrimination between the relative probabilities with which these positive or negative outcomes were delivered. Risk-averse and risk-seeking biases were also unchanged. These results suggest that serotonin mediates decision-making in healthy volunteers by modulating the processing of reward cues, perhaps represented within the orbitofrontal cortex. It is possible that such a change in the cognition mediating human choice is one mechanism associated with the onset and maintenance of anhedonia and lowered mood in psychiatric illness.

Catechol- O -Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

Sex differences in the genetic epidemiology and clinical features of psychiatric disorders are well recognized, but the individual genes contributing to these effects have rarely been identified. Catechol-O-methyltransferase (COMT), which metabolizes catechol compounds, notably dopamine, is a leading candidate. COMT enzyme activity, and the neurochemistry and behavior of COMT null mice, are both markedly sexually dimorphic. Genetic associations between COMT and various psychiatric phenotypes frequently show differences between men and women. Many of these differences are unconfirmed or minor, but some appear to be of reasonable robustness and magnitude; eg the functional Val158Met polymorphism in COMT is associated with obsessive-compulsive disorder in men, with anxiety phenotypes in women, and has a greater impact on cognitive function in boys than girls. Sex-specific effects of COMT are usually attributed to transcriptional regulation by estrogens; however, additional mechanisms are likely to be at least as important. Here we review the evidence for a sexually dimorphic influence of COMT upon psychiatric phenotypes, and discuss its potential basis. We conclude that despite the evidence being incomplete, and lacking a unifying explanation, there are accumulating and in places compelling data showing that COMT differentially impacts on brain function and dysfunction in men and women. Since sex differences in the genetic architecture of quantitative traits are the rule not the exception, we anticipate that additional evidence will emerge for sexual dimorphisms, not only in COMT but also in many other autosomal genes.

Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation.

Amyloid β (Aβ) and tau protein are both implicated in memory impairment, mild cognitive impairment (MCI), and early Alzheimers disease (AD), but whether and how they interact is unknown. Consequently, we asked whether tau protein is required for the robust phenomenon of Aβ-induced impairment of hippocampal long-term potentiation (LTP), a widely accepted cellular model of memory. We used wild-type mice and mice with a genetic knock-out of tau protein and recorded field potentials in an acute slice preparation. We demonstrate that the absence of tau protein prevents Aβ-induced impairment of LTP. Moreover, we show that Aβ increases tau phosphorylation and that a specific inhibitor of the tau kinase glycogen synthase kinase 3 blocks the increased tau phosphorylation induced by Aβ and prevents Aβ-induced impairment of LTP in wild-type mice. Together, these findings show that tau protein is required for Aβ to impair synaptic plasticity in the hippocampus and suggest that the Aβ-induced impairment of LTP is mediated by tau phosphorylation. We conclude that preventing the interaction between Aβ and tau could be a promising strategy for treating cognitive impairment in MCI and early AD.

COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition

Background Catechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val158Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype. Methods Thirty-four COMT Met158Met (Met-COMT) and 33 COMT Val158Val (Val-COMT) men were given a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. They completed the N-back task of working memory and a gambling task. Results In the placebo group, Met-COMT subjects outperformed Val-COMT subjects on the 2- back, and they were more risk averse. Tolcapone had opposite effects in the two genotype groups: it worsened N-back performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Tolcapone made Met-COMT subjects less risk averse but Val-COMT subjects more so. In both tasks, tolcapone reversed the baseline genotype differences. Conclusions Depending on genotype, COMT inhibition can enhance or impair working memory and increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinsons disease and are under evaluation in schizophrenia and other disorders.

Neuregulin1-induced cell migration is impaired in schizophrenia: association with neuregulin1 and catechol-o-methyltransferase gene polymorphisms

Neuregulin1 (NRG1), a candidate susceptibility gene for schizophrenia, plays a critical role in neuronal migration and central nervous system development. However, its relation to schizophrenia pathogenesis is unknown. Here we show that B lymphoblasts migrate to NRG1 through the ErbB-signaling system as observed in neuronal cells. We assessed NRG1-induced cell migration in B lymphoblasts from patients with schizophrenia and found that NRG1-induced migration is significantly decreased compared with control individuals in two independent cohorts. This impaired migration is related at least in part to reduced AKT phosphorylation in the patients. Moreover, the magnitude of NRG1-induced migration is associated with polymorphisms of the NRG1 and catechol-o-methyltransferase genes and with an epistatic interaction of these genes. This study demonstrates that the migratory response of schizophrenia-derived cells to NRG1 is impaired and is associated with genetic variations in more than one schizophrenia susceptibility gene, providing a novel insight into potential neurodevelopmental mechanisms of schizophrenia.

Computer Game Play Reduces Intrusive Memories of Experimental Trauma via Reconsolidation-Update Mechanisms

Memory of a traumatic event becomes consolidated within hours. Intrusive memories can then flash back repeatedly into the mind’s eye and cause distress. We investigated whether reconsolidation—the process during which memories become malleable when recalled—can be blocked using a cognitive task and whether such an approach can reduce these unbidden intrusions. We predicted that reconsolidation of a reactivated visual memory of experimental trauma could be disrupted by engaging in a visuospatial task that would compete for visual working memory resources. We showed that intrusive memories were virtually abolished by playing the computer game Tetris following a memory-reactivation task 24 hr after initial exposure to experimental trauma. Furthermore, both memory reactivation and playing Tetris were required to reduce subsequent intrusions (Experiment 2), consistent with reconsolidation-update mechanisms. A simple, noninvasive cognitive-task procedure administered after emotional memory has already consolidated (i.e., > 24 hours after exposure to experimental trauma) may prevent the recurrence of intrusive memories of those emotional events.

How Cannabis Causes Paranoia: Using the Intravenous Administration of ∆9-Tetrahydrocannabinol (THC) to Identify Key Cognitive Mechanisms Leading to Paranoia

Paranoia is receiving increasing attention in its own right, since it is a central experience of psychotic disorders and a marker of the health of a society. Paranoia is associated with use of the most commonly taken illicit drug, cannabis. The objective was to determine whether the principal psychoactive ingredient of cannabis—∆9-tetrahydrocannabinol (THC)—causes paranoia and to use the drug as a probe to identify key cognitive mechanisms underlying paranoia. A randomized, placebo-controlled, between-groups test of the effects of intravenous THC was conducted. A total of 121 individuals with paranoid ideation were randomized to receive placebo, THC, or THC preceded by a cognitive awareness condition. Paranoia was assessed extensively via a real social situation, an immersive virtual reality experiment, and standard self-report and interviewer measures. Putative causal factors were assessed. Principal components analysis was used to create a composite paranoia score and composite causal variables to be tested in a mediation analysis. THC significantly increased paranoia, negative affect (anxiety, worry, depression, negative thoughts about the self), and a range of anomalous experiences, and reduced working memory capacity. The increase in negative affect and in anomalous experiences fully accounted for the increase in paranoia. Working memory changes did not lead to paranoia. Making participants aware of the effects of THC had little impact. In this largest study of intravenous THC, it was definitively demonstrated that the drug triggers paranoid thoughts in vulnerable individuals. The most likely mechanism of action causing paranoia was the generation of negative affect and anomalous experiences.

The Catechol-O-Methyltransferase Gene: Its Regulation and Polymorphisms

The catechol-O-methyltransferase (COMT) gene is of significant interest to neuroscience, due to its role in modulating dopamine function. COMT is dynamically regulated; its expression is altered during normal brain development and in response to environmental stimuli. In many cases the underlying molecular basis for these effects is unknown; however, in some cases (e.g., estrogenic regulation in the case of sex differences) regulatory mechanisms have been identified. COMT contains several functional polymorphisms and haplotypes, including the well-studied Val158Met polymorphism. Here I review the regulation of COMT and the functional polymorphisms within its sequence with respect to brain function.