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  • crenolanib WM refers to the storage of information in the


    WM refers to the storage of information in the context of processing, and coordination of elements into new structures (Oberauer, Süß, Wilhelm, & Wittman, 2003). Concerning the impact of WM on ISV facets, a strong negative association between WM and ex-Gaussian tau, suggesting that improved WM performance was related to smaller tau, has previously been reported (Schmiedek, Oberauer, Wilhelm, Süss, & Wittmann, 2007). If this association is stronger than that of other ISV facets, altering WM loads would have a greater impact on tau than the others; but a systematic examination of the impact of these task effects on ISV facets is required to clarify whether this is the case. Additionally, it is intriguing whether the modulation of ISV facets by WM differs for the COMT genotypes as WM relies on, both, cognitive stability and cognitive flexibility (Bilder et al., 2004), and as the possibility that WM modulating increased ISV in ADHD (Klein et al., 2006) may be related to the involvement of the COMT gene in the disorder (Bellgrove et al., 2005). In this context, Val allele carriers may have a lower load-related increase in tau given that they better suppressed DMN-related neural activity than in Met allele carriers while performing an n-Back task (NBT) of WM (Stokes et al., 2011). Response-switching involves the ability to shift between responding to frequent and rare stimuli; thus, requiring cognitive flexibility. Based on the tonic-phasic theory, Val allele carriers with high phasic dopaminergic state can be considered to be at an advantage here (Bilder et al., 2004). Indeed, previous work has shown that these carriers were more accurate (Nolan, Ph, Bilder, Lachman, & Volavka, 2004) and had lower switch costs (Colzato, Waszak, Nieuwenhuis, Posthuma, & Hommel, 2010) in tasks demanding high cognitive flexibility. Although little is known about the impact of response-switching or its interaction with COMT on ISV facets, it is possible that Val homozygotes have lower tau when responding to less-frequent trials as they better suppressed DMN-related activity during performance of tasks with high demands of cognitive flexibility (Ettinger et al., 2008, Stokes et al., 2011).
    Introduction Differences in catechol-O-methyl transferase (COMT) crenolanib have been linked to illicit drug use (Chen, Lin, Chiang, Su, & Wang, 2014) and polysubstance abuse (Vandenbergh, Rodriguez, Miller, Uhl, & Lachman, 1997). However, with regard to alcohol use, the role of COMT is unclear. Associations between allelic variations in COMT and drinking behaviors are mixed, with some finding associations (Hendershot et al., 2012, Kauhanen et al., 2000, Tammimäki et al., 2008, Tiihonen et al., 1999, Wang et al., 2001), while others do not (Hallikainen et al., 2000, Kweon et al., 2005, Samochowiec et al., 2006, Shibuya et al., 1999). Similarly, the relationship between COMT and the propensity to relapse is complex, and while an association has been observed (Wojnar et al., 2009) other studies have failed to find one (Foroud et al., 2007, Köhnke et al., 2003). COMT is hypothesized to play a role in executive function (Egan et al., 2001, Goldberg et al., 2003, Tammimäki and Mannisto, 2010) and deficits in executive function are associated with risk for alcohol use disorder (AUD; Finn et al., 2009). As such, manipulations of COMT may ameliorate maladaptive drug seeking and taking behaviors. Alcohol preferring (P) rats are selectively bred for free-choice alcohol preference, exhibit excessive reward consumption (Lankford et al., 1991, McCane et al., 2014), and deficits in executive function (Beckwith and Czachowski, 2016, Linsenbardt et al., 2016). Additionally, reduced dopamine (DA) levels in the medial prefrontal cortex (PFC) have been observed in P rats, when compared with their progenitor strain, the Wistar rat (Engleman, Ingraham, McBride, Lumeng, & Murphy, 2006). Given the well documented role of COMT in degrading cortical DA (Käenmäki et al., 2010, Yavich et al., 2007), we hypothesized that differences in COMT may be associated with the excessive alcohol seeking and consuming phenotype of the P rats. Using the COMT inhibitor tolcapone, we have previously observed a tolcapone-mediated suppression of cued ethanol seeking in male P rats but not Wistars, with no effect on free choice ethanol consumption in either strain (McCane et al., 2014). However, it is unclear how differences in COMT might account for differences in tolcapone's efficacy. Strain differences in tolcapone's efficacy may be attributable to differences in COMT, and would suggest a link between COMT and an excessive alcohol seeking/drinking phenotype.