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Genetic polymorphisms regulating dopamine signaling in the frontal cortex interact to affect target detection under high working memory load.

Smith CT, Swift-Scanlan T, Boettiger CA
J Cogn Neurosci. 2014 26 (2): 395-407

PMID: 24144248 · PMCID: PMC3877727 · DOI:10.1162/jocn_a_00501

Frontal-dependent task performance is typically modulated by dopamine (DA) according to an inverted-U pattern, whereby intermediate levels of DA signaling optimizes performance. Numerous studies implicate trait differences in DA signaling based on differences in the catechol-O-methyltransferase (COMT) gene in executive function task performance. However, little work has investigated genetic variations in DA signaling downstream from COMT. One candidate is the DA- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), which mediates signaling through the D1-type DA receptor, the dominant DA receptor in the frontal cortex. Using an n-back task, we used signal detection theory to measure performance in a healthy adult population (n = 97) genotyped for single nucleotide polymorphisms in the COMT (rs4680) and DARPP-32 (rs907094) genes. Correct target detection (hits) and false alarms were used to calculate d' measures for each working memory load (0-, 2-, and 3-back). At the highest load (3-back) only, we observed a significant COMT × DARPP-32 interaction, such that the DARPP-32 T/T genotype enhanced target detection in COMT(ValVal) individuals, but impaired target detection in COMT(Met) carriers. These findings suggest that enhanced dopaminergic signaling via the DARPP-32 T allele aids target detection in individuals with presumed low frontal DA (COMT(ValVal)) but impairs target detection in those with putatively higher frontal DA levels (COMT(Met) carriers). Moreover, these data support an inverted-U model with intermediate levels of DA signaling optimizing performance on tasks requiring maintenance of mental representations in working memory.

MeSH Terms (25)

Adult African Continental Ancestry Group Catechol O-Methyltransferase Data Interpretation, Statistical Discrimination, Psychological DNA Dopamine Dopamine and cAMP-Regulated Phosphoprotein 32 Educational Status European Continental Ancestry Group Executive Function Female Genotype Humans Male Memory, Short-Term Minisatellite Repeats Polymerase Chain Reaction Polymorphism, Genetic Polymorphism, Single Nucleotide Prefrontal Cortex Psychomotor Performance Receptors, Dopamine D1 Signal Transduction Young Adult

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