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  • Collectively these data suggest the

    2020-02-26

    Collectively, these data suggest the potential clinical utility of COMT inhibitors for the treatment of addiction disorders. Similar to current pharmacotherapies such as naltrexone, tolcapone\'s effects were not ethanol specific, therefore tolcapone may be effective in reducing other drug reinforced behaviors and should be investigated accordingly. Importantly, the degree to which tolcapone may suppress natural reinforcers in clinical populations is unknown, and as such, future clinical studies should exercise caution when working with this compound. It should be noted that the differential effects in P rats and Wistars suggest that this BQ-123 may be more efficacious for “at risk” populations susceptible to drug abuse. Preclinical findings support this hypothesis where allelic variation of the COMT gene was associated with differences in tolcapone\'s efficacy in ameliorating cognitive deficits (Farrell et al., 2012, Grant et al., 2013). Tolcapone\'s sex specific effects are consist with observations made in COMT deficient mice (Tammimäki et al., 2008) and suggest that sex differences in COMT activity may be associated with differences in the neurophysiological mechanisms underlying drinking behaviors (Harrison & Tunbridge, 2008). Lastly, it should be noted that sex and strain differences in pharmacokinetics may underlie the results attained here, and should be considered as a caveat to be investigated in future studies. Overall however, the behavior-specific effects observed suggest this compound may hold promise as a means to remediate reward seeking behaviors, indicating that COMT inhibitors should be investigated as a tool to mitigate reward craving and reduce propensity to relapse.
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    Preeclampsia (PE) is one of the leading causes of maternal and fetal morbidity and mortality, affecting 5%–8% of pregnant women worldwide . The pathogenesis of this disease is still not completely understood. Recent evidences suggest that a deficiency in catechol--methyltransferase (COMT) is associated with PE , , because COMT is a key enzyme in the metabolization of estrogens . 2-Methoxyestradiol (2-ME) is generated by hydroxylation at the 2-position of 17β-E by cytochrome P450 enzymes, and the subsequent O-methylation of the catechol ring by COMT . Normal 2-ME plasma levels in women are in the picomolar range and increase more than 1,000-fold during pregnancy in women, reaching a plateau during the third trimester . Increased 2-ME levels during pregnancy are thought to be necessary for cytotrophoblast invasion of the maternal decidua, and its deficiency might be involved in the altered placentation present in PE . Recently, we have reported lower plasmatic 2-ME in PE than in normal pregnancies, and also found a significant association between lower plasma levels of 2-ME and clinical indexes of severity of the disease . Kanasaki et al. described that both circulating concentrations of 2-ME and placental COMT activity were significantly reduced in women diagnosed with PE, raising the possibility that altered production of 2-ME may contribute to the pathophysiology of PE by altering placental vascularization and its response to hypoxia . In mammals, COMT is present in two molecular forms: a soluble cytoplasmic form (S-COMT) and a membrane protein (MB-COMT) with similar kinetic mechanism. The main difference is the lower Michaelis constant (K) value for MB-COMT for catecholamines and higher maximum reaction rate (V) for S-COMT from human brain and from cells containing recombinant S- or MB-COMT . This makes S-COMT the predominant isoform of the enzyme, especially at high concentrations of substrate (i.e., during pregnancy). However, the mechanisms linking human COMT to PE remain unclear. It is not entirely known, for example, why both lower concentrations and lower activity of COMT have been noted in human preeclamptic placentas. A possible explanation involves a common polymorphism in the gene encoding for COMT in exon 5 (substitution of valine [Val] for methionine [Met] at codon 108 for the S-COMT and at 158 for the MB-COMT; rs4680) , resulting in reduced thermostability and activity of the enzyme . An association between the functional Val158Met polymorphism and PE has been reported, but most of the studies derived only from maternal genotyping. However, it is clear that the placenta plays a key role in the pathogenesis of this disease, because its expulsion terminates the syndrome. Therefore, the fetal genes may be of critical importance influencing the mother\'s susceptibility to PE, but at the present little is known about placental COMT genotypes and PE. Additionally, previous data further suggest that COMT activity is more precisely determined by three haplotypes of four SNPs inherited together, rs6269, rs4633, rs4818, and rs4680, which may result in a 25-fold difference in enzyme activity . In this regard, Hill et al. reported the association of the low-activity COMT haplotype with an increased risk for preeclampsia in Chilean maternal-fetal dyads population.