Brain catechol-O-methyltransferase (COMT) inhibition by tolcapone counteracts recognition memory deficits in normal and chronic phencyclidine-treated rats and in COMT-Val transgenic mice

Detrait, Eric; Carr, Gregory V.; Weinberger, Daniel R.; Lamberty, Yves

doi:10.1097/fbp.0000000000000208

Cited by 16 publications

(14 citation statements)

References 33 publications

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“…Moreover, we only used a single strain (C57BL/6J), so our results may also be strain-specific. We chose C57BL/6J mice because they are a commonly used strain for behavioral studies and many of the mutant models we use in our laboratory are on a C57BL/6J background (Carr et al, 2016Detrait et al, 2016.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Catechol-O-methyltransferase Does Not Alter Effort-Related Choice Behavior in a Fixed Ratio/Concurrent Chow Task in Male Mice

DeBrosse

Wheeler

Barrow

et al. 2020

Front. Behav. Neurosci.

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Effort-related choice (ERC) tasks allow animals to choose between high-value reinforcers that require high effort to obtain and low-value/low-effort reinforcers. Dopaminergic neuromodulation regulates ERC behavior. The enzyme catechol-O-methyltransferase (COMT) metabolizes synaptically-released dopamine. COMT is the predominant regulator of dopamine turnover in regions of the brain with low levels of dopamine transporters (DATs), including the prefrontal cortex (PFC). Here, we evaluated the effects of the COMT inhibitor tolcapone on ERC performance in a touchscreen-based fixedratio/concurrent chow task in male mice. In this task, mice were given the choice between engaging in a fixed number of instrumental responses to acquire a strawberry milk reward and consuming standard lab chow concurrently available on the chamber floor. We found no significant effects of tolcapone treatment on either strawberry milk earned or chow consumed compared to vehicle treatment. In contrast, we found that haloperidol decreased instrumental responding for strawberry milk and increased chow consumption as seen in previously published studies. These data suggest that COMT inhibition does not significantly affect effort-related decision making in a fixedratio/concurrent chow task in male mice.

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Section: Discussionmentioning

confidence: 99%

“…We dosed tolcapone at 3, 10, and 30 mg/kg. The 30 mg/kg dose has been shown to modulate behavior in both mice and rats in multiple assays (Tunbridge et al, 2004;Lapish et al, 2009;Detrait et al, 2016). Additionally, the exposure levels at 30 mg/kg dose produce over 90% inhibition of COMT activity in rats in vivo (Napolitano et al, 2003).…”

Section: Drugsmentioning

confidence: 99%

Inhibition of Catechol-O-methyltransferase Does Not Alter Effort-Related Choice Behavior in a Fixed Ratio/Concurrent Chow Task in Male Mice

DeBrosse

Wheeler

Barrow

et al. 2020

Front. Behav. Neurosci.

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“…The enzyme coding region contains a well-investigated single-nucleotide-polymorphism (SNP) in codon 158 (rs4680), in which valine (Val) is substituted to methionine (Met) through a substitution of guanine to adenine. This common functional A/G polymorphism in the COMT gene produces three genotype groups (homozygousVal158Val, heterozygous Val158Met, and homozygous Met158Met), which result in different enzyme activities based on changes in thermostability [ 11 , 12 ] as depicted in Table 1 . The three phenotypes of the COMT enzyme activities include COMT A/A with low enzyme activity, COMT A/G with medium enzyme activity and COMT G/G with high enzyme activity.…”

Section: Introductionmentioning

confidence: 99%

Potential Impact of COMT-rs4680 G > A Gene Polymorphism in Coronary Artery Disease

Mir

Bhat

Javid

et al. 2018

JCDD

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Purpose: Catechol-O-methyltransferase (COMT) plays a central role in DNA repair and estrogen-induced carcinogenesis. The nonsynonymous single nucleotide polymorphism (SNP) in exon 4 G > A or Val108 > 158Met or rs4680 G > A influences COMT enzyme activity. The three phenotypes of the COMT enzyme activities include COMT A/A with low enzyme activity, COMT A/G with medium enzyme activity and COMT G/G with high enzyme activity. The Met allele is associated with low enzymatic activity resulting in higher levels of prefrontal dopamine. Conversely, the Val allele is associated with high enzymatic activity and lower levels of prefrontal dopamine. The Met allele has been associated with several psychiatric disorders such as panic disorder. Many recent epidemiologic studies have investigated the association between the COMT Val158Met polymorphism and coronary artery diseases risk, but the results are inconclusive. Therefore our study was aimed to explore the association between COMT Val158Met polymorphism and the risk of coronary artery disease in India. Methology: This study was conducted on 100 clinically confirmed cases of coronary artery diseases and 100 healthy controls. COMT Val158Met genotyping was performed by allele-specific polymerase chain reaction (AS-PCR). Results: A significant correlation was observed in the COMT Val158Met genotype distribution between the coronary artery disease cases and healthy controls (p = 0.008). The frequencies of all three genotypes, GG, GA, AA, reported in the CAD patients were 10%, 70%, and 20%, and 30%, 60%, and 10% in the healthy controls respectively. An increased risk of coronary artery disease was observed in the codominant inheritance model for COMT-GA vs. GG genotype with an OR of 3.5, 95% CI (1.58–7.74) p = 0.002) and COMT-AA vs. GG genotype with an OR of 6.0 95% CI (2.11–17.3) p = 0.003). The higher risk of coronary artery disease was observed in the dominant inheritance model for COMT (GA + AA) vs. GG genotype (OR 3.85, 95% CI 1.76–8.4, p < 0.007), whereas a non-significant association was found in recessive model for COMT (GG + GA vs. AA) (OR = 2.01, 95% CI (0.86–4.7) p = 0.72). The results indicated that A allele significantly increased the risk of coronary artery disease compared to the G allele (OR = 1.8, 95% CI (1.20–2.67) p = 0.004). COMT Val158Met polymorphism leads to a 6.0, 3.5 and 1.8-fold increased risk of developing coronary artery disease in the Indian population and providing novel insights into the genetic etiology and underlying biology of coronary artery disease. Conclusions: It is concluded that COMT-AA genotype and A allele are significantly associated with an increased susceptibility to coronary artery disease in Indian population. A larger sample size can be the key to progress in establishing the genetic co-relationship of COMT polymorphism and cardiovascular disease.

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“…7), and its selectivity towards the membrane-bound form of catechol-o-methyl transferase (MB-COMT) compared with its water-soluble form (S-COMT) [146]. The COMT inhibitors are used together with L-dopa in the treatment of Parkinson's disease to prevent dopamine deficit [147,148]. L-Dopa is converted into dopamine inside the neurons, and the role of COMT inhibitors in the drug formulation is to prevent L-dopa degradation.…”

Section: The Effect Of Membrane Sorting For Drugs and Beyondmentioning

confidence: 99%

A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

Postila

Róg

2019

Mol Neurobiol

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Synaptic neurotransmission is generally considered as a function of membrane-embedded receptors and ion channels in response to the neurotransmitter (NT) release and binding. This perspective aims to widen the protein-centric view by including another vital component-the synaptic membrane-in the discussion. A vast set of atomistic molecular dynamics simulations and biophysical experiments indicate that NTs are divided into membrane-binding and membrane-nonbinding categories. The binary choice takes place at the water-membrane interface and follows closely the positioning of the receptors' binding sites in relation to the membrane. Accordingly, when a lipophilic NT is on route to a membrane-buried binding site, it adheres on the membrane and, then, travels along its plane towards the receptor. In contrast, lipophobic NTs, which are destined to bind into receptors with extracellular binding sites, prefer the water phase. This membrane-based sorting splits the neurotransmission into membraneindependent and membrane-dependent mechanisms and should make the NT binding into the receptors more efficient than random diffusion would allow. The potential implications and notable exceptions to the mechanisms are discussed here. Importantly, maintaining specific membrane lipid compositions (MLCs) at the synapses, especially regarding anionic lipids, affect the level of NT-membrane association. These effects provide a plausible link between the MLC imbalances and neurological diseases such as depression or Parkinson's disease. Moreover, the membrane plays a vital role in other phases of the NT life cycle, including storage and release from the synaptic vesicles, transport from the synaptic cleft, as well as their synthesis and degradation.

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Brain catechol-O-methyltransferase (COMT) inhibition by tolcapone counteracts recognition memory deficits in normal and chronic phencyclidine-treated rats and in COMT-Val transgenic mice

Cited by 16 publications

References 33 publications

Inhibition of Catechol-O-methyltransferase Does Not Alter Effort-Related Choice Behavior in a Fixed Ratio/Concurrent Chow Task in Male Mice

Inhibition of Catechol-O-methyltransferase Does Not Alter Effort-Related Choice Behavior in a Fixed Ratio/Concurrent Chow Task in Male Mice

Potential Impact of COMT-rs4680 G > A Gene Polymorphism in Coronary Artery Disease

A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

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