fludarabine Neuropsychological studies of adults with proble
Neuropsychological studies of adults with problem gambling indicate impairments in many cognitive areas including inhibition, working memory, decision-making, cognitive flexibility, and executive planning (Ledgerwood et al., 2012, Goudriaan et al., 2006). Dopamine is a neurotransmitter that regulates cognitive functions dependent on the fronto-striatal circuitry, and dopamine dysregulation has been suggested as playing a key role in a range of impulsive behaviors, particularly those related to inhibitory control and decision-making (Malloy-Diniz et al., 2013). The catechol-O-methyltransferase (COMT) enzyme plays a unique role in the regulation of dopamine in the prefrontal cortex (Tunbridge et al., 2004) and has been posited as a potential pharmacological target for the treatment of cognitive dysfunction in a number of psychiatric illnesses, especially those characterized by high rates of impulsivity (Scheggia et al., 2012). A recent treatment study for problem gambling found that the COMT inhibitor, tolcapone, improved gambling behavior and that this improvement was associated with enhanced fronto-parietal fludarabine activation during planning (Grant et al., 2013). In the frontal lobes, COMT is the enzyme largely responsible for the inactivation of synaptic dopamine (Tunbridge et al., 2004). A common functional polymorphism in the COMT gene, the Val substitution at codon 158[rs4680 (val158met)], results in a ∼40% increase in enzymatic activity and thereby reduced cortical dopamine levels (Lotta et al., 1995). Carriers of the Val allele exhibit less efficient prefrontal neural signaling and relative deficits in executive cognitive functioning (Diaz-Asper et al., 2008, Dumontheil et al., 2011). Therefore, individuals homozygous for the Val allele are expected to have decreased levels of dopamine in comparison to individuals with two met alleles and should exhibit greater problems with executive functioning and impulsivity. Studies of healthy control subjects, however, have demonstrated mixed results with respect to COMT genotype, cognitive performance, trait impulsivity, and impulsive behaviors. In an early study, the Met allele was predictive of enhanced performance on the Wisconsin Card Sorting test, and more efficient physiological responses in the prefrontal cortices (Egan et al., 2001). Another study found that Met subjects outperformed Val subjects on an N-Back working memory task (Farrell et al., 2012), while the same research group also found that the COMT polymorphism affected functional connectivity of the brain in the resting state (Tunbridge et al., 2013). One study found no differences between COMT groups on a battery of 19 cognitive tasks including cognitive flexibility, memory, and visual processing (Dennis et al., 2010). A later study, however, found that healthy controls homozygous for the met allele demonstrated better performance on a cognitive task of executive functioning (Trail-Making Test) (Wishart et al., 2011). Other studies have shown that healthy control subjects homozygous for the Met allelic variant exhibited better performance on tasks of working memory and the Wisconsin Card Sorting Task compared to subjects homozygous for Val (Malhotra et al., 2002, Rosa et al., 2004). Conversely, van Den Bos et al., (2009) found that healthy control female subjects who were Met/Met homozygous chose more disadvantageously on the Iowa Gambling Task than subjects homozygous for valine (Val/Val). Similarly, a study of 82 healthy volunteers found that those with a Met/Met genotype had higher impulsivity scores on the Barratt Impulsiveness Scale compared to either Val/Met or Val/Val subjects (Soeiro-De-Souza et al., 2013). Clinically, a study of 139 healthy controls found that COMT met/met homozygotes were more likely to be at-risk gamblers and mild problem drinkers compared to Val/Val homozygotes (Guillot et al., 2014). To further complicate the picture, a small genome-wide association study from the national community-based Australian Twin Registry did not find a significant association between COMT rs4680 and disordered gambling in 1312 twins (Lind et al., 2013). One potential explanation for discordant results in relation to cognition and the COMT polymorphism is that different optimal levels of dopamine are required for different cognitive functions; there may be a ‘trade off’ with higher dopamine (as seen with the Met variant) being associated with relatively superior improvement in some domains, with relative impairments in others. This suggestion would fit with an inverted ‘U’ model of executive functioning (e.g. Robbins and Arnsten, 2009, Kehagia et al., 2013).