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  • Animal studies investigating the role of D


    Animal studies investigating the role of D1 dopamine receptors in the PFC have focused on delayed response tasks, which require online maintenance of a previously presented stimulus. Striatal dopamine is thought to be important for flexibility and updating goal representations when new information is pertinent (Cools and D'Esposito, 2011). Research using non-human primates revealed that destruction of dopamine neurons in the PFC resulted in enhanced distractibility (poor cognitive stability), while dopamine depletion in the striatum resulted in reduced distractibility (poor cognitive flexibility) (Crofts et al., 2001). These opposing effects of PFC and striatal lesions on dopamine systems highlight the possible competition between the PFC and the striatum, and suggest that a dynamic balance between stabilization and flexible updating depends on balanced dopamine transmission within the PFC and striatum respectively. This functional opposition between flexibility and stability is consistent with the model of neurochemical reciprocity between dopamine in the PFC and the striatum in which variability in PFC dopaminergic activity leads to corresponding changes in striatal dopamine activity (Cools and D'Esposito, 2011; Tunbridge et al., 2006). Catechol-O-methyltransferase (COMT) enzyme activity is a significant regulator of synaptic DA in the prefrontal cortex (Chen et al., 2004). The rs4680 A>G polymorphism in COMT results in a valine to methionine amino Ramipril change which decreases the in vivo stability of the COMT enzyme, reducing DA catabolism, thus increasing synaptic DA. COMT activity in Val/Val homozygotes is approximately 38% higher than Met/Met homozygotes and 29% higher than Val/Met heterozygotes in the dorsolateral prefrontal cortex (DLPFC) (Chen et al., 2004). Thus, COMT genotype may be an important factor in mediating cognitive flexibility and stability supported by dopamine activity in the PFC and striatum respectively. Further, the Met allele is hypothesized to be associated with more tonic than phasic dopamine release in subcortical regions, and higher dopamine concentrations in the cortex that leads to greater cognitive stability and more limited cognitive flexibility (Bilder et al., 2004). In contrast, the Val allele is believed to be associated with more phasic dopamine activity in Ramipril subcortical regions and lower dopamine concentrations in the cortex, leading to greater cognitive flexibility and reduced behavioral stability, particularly in Val homozygotes (Bilder et al., 2004). In this study we examined the role of a well characterized genetic polymorphism in the COMT gene in mediating cognitive antipsychotic treatment effects in first episode psychosis (FEP). We considered catechol-O-methyltransferase (COMT) to be a potentially important baseline consideration in a pharmacogenomic context because Met carriers and Val homozygotes respond differently to antipsychotic therapy (Huang et al., 2016). In previous studies, Met carriers have demonstrated improved performance on the N-back task compared to Val homozygotes following antipsychotic pharmacotherapy (Bertolino et al., 2004; Weickert et al., 2004). Because COMT modulates dopaminergic systems differently in the PFC and striatum due to limited DA transporter (DAT) expression in PFC (Cools and D'Esposito, 2011; Tunbridge et al., 2006), evaluating the relation between COMT genotype and components of set-shifting that are differentially dependent on prefrontal and striatal function before and after treatment with antipsychotics may shed light on mechanisms underlying variable cognitive outcomes following antipsychotic therapy.
    Discussion Animal models have demonstrated that SGAs reduced phencyclidine- or methamphetamine-induced cognitive deficits (Abdul-Monim et al., 2003; Amitai et al., 2007; Hagiwara et al., 2008) yet beneficial effects on cognition have not been consistently observed in human studies. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study compared the cognitive effects of SGAs to FGAs. Findings from this project revealed that the magnitude of cognitive improvements following second generation antipsychotic treatment were relatively small and resemble practice effects in healthy controls (Keefe et al., 2007). Drugs targeting specific neurotransmitter systems are likely to give rise to specific as opposed to generalized effects on cognition (Hill et al., 2010). Many neuropsychological tests are multidimensional and require several cognitive brain systems to be integrated. Thus, many neuropsychological tests lack the specificity to detect specific cognitive changes resulting from alteration of specific neurotransmitter systems. This highlights the need for development of more sophisticated outcome measures that are sensitive and specific to cognitive processes supported by particular neurotransmitter systems. The current study utilized a translational approach to scoring a set shifting task and was able to identify specific cognitive changes following treatment. Set shifting tasks, which were once thought to be tests of frontal dysfunction but are now understood to reflect the integrity of the frontal-subcortical network, can now be examined in more detail to tease apart the specific cognitive processes mediated by frontal and subcortical brain regions.