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    • br Introduction The dopaminergic system and its projections

    2019-12-11


    Introduction The dopaminergic system and its projections including both the prefrontal ionomycin receptor (PFC) and striatum are known as being crucial to synaptic plasticity, skill acquisition and higher order functions (e.g., working memory and cognitive control; Matsumoto et al., 2003). Variations in dopaminergic transmission can contribute to individual differences observed in behavior and cognition. A range of genetic polymorphisms has been shown to affect the dopaminergic metabolism which may result in interindividual performance variations (Erickson et al., 2008). Among these polymorphisms are the ones associated with the Cathecol-O-Methyltransferase (COMT), the dopamine receptor D2 (DRD2) and the brain-derived neurotrophic factor (BDNF) (Savitz et al., 2006). COMT and DRD2 along with BDNF polymorphisms are, respectively, direct and indirectly related to dopamine (DA) signaling. In the human brain, the dopaminergic levels are affected by the COMT enzyme (Matsumoto et al., 2003), which is highly expressed in the entire brain, and seems to play an important role in the DA flux inside the PFC (Chen et al., 2004). This enzyme is crucial for the DA metabolism (Nolan et al., 2004) being responsible for more than 60% of its metabolic degradation in the frontal cortex (Malloy-Diniz et al., 2013). It is more abundantly expressed in cortical than in the striatal neurons (Dreher et al., 2009) differing itself from the dopamine transporter (DAT), a protein predominantly found in areas related to the functions of the striatum and that is responsible for retaking the extracellular DA from the presynaptic terminal (Witte and Floel, 2012). The COMT gene, located at the chromosome 22 band q11.2 (Diamond et al., 2004; Tunbridge et al., 2006; Wahlstrom et al., 2007; Witte and Floel, 2012), is associated with genotypes related to DA availability inside the PFC and corticostriatal circuits, which highlights the role of a single nucleotide polymorphism of the COMT gene (Frank et al., 2009). The polymorphism aforementioned, named COMT Val158Met, provides a trimodal distribution of the enzyme activity in human populations (Tunbridge et al., 2006). Its coding sequence consists on a transition of guanine to adenine at codon 158 of the MB-COMT (108 of S-COMT), which results in a valine (Val) being replaced by a methionine (Met) (Egan et al., 2001; Diamond et al., 2004; Tunbridge et al., 2006; Wahlstrom et al., 2007). The Met allele presents lower thermostability resulting in lower COMT activity at physiological temperature (Chen et al., 2004). Due to its degradation rate that is ⅓ to ¼ slower, DA availability at the synaptic clefts is increased. On the other hand, homozygous subjects for the Val allele show a higher enzyme activity and lower DA concentrations at the synaptic clefts. Because the alleles are codominant, heterozygous present intermediate concentrations (Egan et al., 2001; Tunbridge et al., 2006; Wahlstrom et al., 2007). Thus, the COMT activity variation can have neurobiological effects such as the regulation of DA levels, more specifically in the PFC (Witte and Floel, 2012). The notion that an increased flux of DA in the PFC is directly associated with an increase in cognitive performance is an oversimplification (Tunbridge et al., 2006). Interactions between the PFC states (increased tonic or phasic dopamine) with the nature of the task performed produce different levels of cognitive processing. Met allele seems to be associated with increased tonic dopamine transmission, which favors the stabilization and maintenance of relevant information in working memory and executive tasks that demand this type of cognitive processing. Conversely, Val allele is associated with increased phasic dopamine transmission, which favors cognitive flexibility required in task demanding updating and manipulation of information (Bilder et al., 2004; Rosa et al., 2010). Cognitive stability suggests a necessary and beneficial state for some functions in specific contexts. For example, working memory maintenance tasks in which the subject needs to keep some online representation or sustained attention during a task. On the other hand, excessive stability yields inflexibility and difficulty in responding appropriately to external perturbations by modifying ongoing planning or shifting attention to new foci (Bilder et al., 2004).