Differential COMT expression and behavioral effects of COMT inhibition in male and female Wistar and alcohol preferring rats

McCane, Aqilah M.; DeLory, Michael J.; Timm, Maureen; Janetsian-Fritz, Sarine S.; Lapish, Christopher C.; Czachowski, Cristine L.

doi:10.1016/j.alcohol.2017.08.007

Cited by 17 publications

(14 citation statements)

References 59 publications

(84 reference statements)

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“…In P rats, tolcapone may diminish the influence that stimuli have over behavior by preventing the metabolism of cortical DA and increasing tone on DA auto receptors. The effect of increased DA would be blunted in Wistars who already exhibit greater levels of extracellular DA coupled with increased expression of COMT in mPFC and therefore a greater capacity to buffer changes in DA efflux (Engleman et al, 2006; McCane et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…To assess the influence of COMT inhibition on corticostriatal network dynamics, animals were treated with tolcapone (30 mg/kg) or vehicle (counterbalanced) as described previously (McCane et al, 2014, 2018).…”

Section: Methodsmentioning

confidence: 99%

“…The catechol-o-methyl-transferase (COMT) enzyme metabolizes catecholamine’s including DA in cortical regions (Mazei et al, 2002; Morón et al, 2002). Using the COMT inhibitor tolcapone, we have observed reductions in cued ethanol (EtOH) consumption in P rats (McCane et al, 2014) and reinforcer seeking (McCane et al, 2018). Tolcapone enhances cued medial (m)PFC DA efflux (Lapish et al, 2009) and therefore may remediate mPFC DA deficits in P rats (Engleman et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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COMT Inhibition Alters Cue-Evoked Oscillatory Dynamics during Alcohol Drinking in the Rat

McCane

Ahn

Rubchinsky

et al. 2018

eNeuro

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Alterations in the corticostriatal system have been implicated in numerous substance use disorders, including alcohol use disorder (AUD). Adaptations in this neural system are associated with enhanced drug-seeking behaviors following exposure to cues predicting drug availability. Therefore, understanding how potential treatments alter neural activity in this system could lead to more refined and effective approaches for AUD. Local field potentials (LFPs) were acquired simultaneously in the prefrontal cortex (PFC) and nucleus accumbens (NA) of both alcohol preferring (P) and Wistar rats engaged in a Pavlovian conditioning paradigm wherein a light cue signaled the availability of ethanol (EtOH). On test days, the catechol-o-methyl-transferase (COMT) inhibitor tolcapone was administered prior to conditioning. Stimulus-evoked voltage changes were observed following the presentation of the EtOH cue in both strains and were most pronounced in the PFC of P rats. Phase analyses of LFPs in the θ band (5–11 Hz) revealed that PFC-NA synchrony was reduced in P rats relative to Wistars but was robustly increased during drinking. Presentation of the cue resulted in a larger phase reset in the PFC of P rats but not Wistars, an effect that was attenuated by tolcapone. Additionally, tolcapone reduced cued EtOH intake in P rat but not Wistars. These results suggest a link between corticostriatal synchrony and genetic risk for excessive drinking. Moreover, inhibition of COMT within these systems may result in reduced attribution of salience to reward paired stimuli via modulation of stimulus-evoked changes to cortical oscillations in genetically susceptible populations.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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COMT Inhibition Alters Cue-Evoked Oscillatory Dynamics during Alcohol Drinking in the Rat

McCane

Ahn

Rubchinsky

et al. 2018

eNeuro

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“…However, a single dose of EGCG does not impair the COMT of red blood cells in healthy individuals [77]. A synthetic inhibitor of COMT (tolcapone) reduces the seeking or consumption of ethanol, specifically in male high drinkers [78]. Importantly, phenols can regulate the ratio between CYP enzyme/phase II enzymes, which can be a pivotal phenomenon for the life and death of cells after carcinogens [16].…”

Section: Pharmacokinetics Of Phenols: Influence Of Sex–gendermentioning

confidence: 99%

The Sex–Gender Effects in the Road to Tailored Botanicals

Campesi

Romani

Franconi³

2019

Nutrients

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Phenols are a wide family of phytochemicals that are characterized by large chemical diversity and are considered to bioactive molecules of foods, beverages, and botanicals. Although they have a multitude of biological actions, their beneficial effects are rarely evidenced in clinical practice. This may occur due to the presence of numerous confounders, such as the modulation of phenol bioavailability, which can be regulated by microbiota, age, sex-gender. Sex-gender is an important determinant of health and well-being, and has an impact on environmental and occupational risks, access to health care, disease prevalence, and treatment outcomes. In addition, xenobiotic responses may be strongly influenced by sex-gender. This review describes how sex–gender differentially influences the activities of phenols also in some critical periods of women life such as pregnancy and lactation, considering also the sex of fetuses and infants. Thus, sex–gender is a variable that must be carefully considered and should be used to propose directions for future research on the road to tailored medicine and nutrition.

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“…Our group has shown that the COMT val158met SNP plays a role in blood pressure (( Stewart et al, 2009)) and in aripiprazole response in individuals with AUD, in the same direction as DAT1 VNTR effects (( Schacht et al, 2017)). Interestingly, there have been some preliminary reports that COMT inhibitors might have efficacy in some reward-based disorders dependent on COMT val158met genotype both in animals (( McCane et al, 2018)) and in humans ( ( Grant et al, 2013)) suggesting, potentially, an important pharmacogenetic interaction.…”

mentioning

confidence: 99%

Opioid and Dopamine Genes Interact to Predict Naltrexone Response in a Randomized Alcohol Use Disorder Clinical Trial

Anton

Voronin

Book

et al. 2020

Alcoholism Clin & Exp Res

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Background: While the opiate antagonist, naltrexone, is approved for treating alcohol use disorder (AUD), not everyone who receives the medication benefits from it. This study evaluated whether the OPRM1 SNP rs1799971 interacts with the dopamine transporter gene DAT1/SLC6A3 VNTR rs28363170 or the catechol-O-methyltransferase (COMT) gene SNP rs4680 in predicting naltrexone response. Methods: Individuals who met DSM-IV alcohol dependence were randomly assigned to naltrexone (50 mg/d) or placebo based on their OPRM1 genotype (75 G-allele carriers and 77 A-allele homozygotes) and also genotyped for DAT1 VNTR (9 vs. 10 repeats) or COMT SNP (val/val vs. met carriers). Heavy drinking days (%HDD) were evaluated over 16 weeks and at the end of treatment. Effect sizes (d) for naltrexone response were calculated based on genotypes. Results: Naltrexone, relative to placebo, significantly reduced %HDD among OPRM1 G carriers who also had DAT1 10/10 (p = 0.021, d = 0.72) or COMT val/val genotypes (p = 0.05, d = 0.80), and to a lesser degree in those OPRM1 A homozygotes who were also DAT1 9-repeat carriers (p = 0.09, d = 0.70) or COMT met carriers (p = 0.03, d = 0.63). All other genotype combinations showed no differential response to naltrexone. Diarrhea/abdominal pain was more prominent in OPRM1 A homozygotes who were also DAT 9 or COMT met carriers. Conclusions: These results suggest that individuals with AUD with a more opioid-responsive genotype (OPRM1 G carriers) respond better to naltrexone if they have genotypes indicating normal/less dopamine tone (DAT1 10,10 or COMT val,val), while those with a less responsive opioid-responsive genotype (OPRM1 A homozygotes) respond better to naltrexone if they have genotypes indicating greater dopamine tone (DAT1 9-repeat or COMT met carriers). These results could lead to more personalized AUD treatments.

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Differential COMT expression and behavioral effects of COMT inhibition in male and female Wistar and alcohol preferring rats

Cited by 17 publications

References 59 publications

COMT Inhibition Alters Cue-Evoked Oscillatory Dynamics during Alcohol Drinking in the Rat

COMT Inhibition Alters Cue-Evoked Oscillatory Dynamics during Alcohol Drinking in the Rat

The Sex–Gender Effects in the Road to Tailored Botanicals

Opioid and Dopamine Genes Interact to Predict Naltrexone Response in a Randomized Alcohol Use Disorder Clinical Trial

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