title: DRD2/CHRNA5 interaction on prefrontal biology and physiology during working memory.
abstract: BACKGROUND
  Prefrontal behavior and activity in humans are heritable. Studies in animals demonstrate an interaction between dopamine D2 receptors and nicotinic acetylcholine receptors on prefrontal behavior but evidence in humans is weak. Therefore, we hypothesize that genetic variation regulating dopamine D2 and nicotinic acetylcholine receptor signaling impact prefrontal cortex activity and related cognition. To test this hypothesis in humans, we explored the interaction between functional genetic variants in the D2 receptor gene (DRD2, rs1076560) and in the nicotinic receptor α5 gene (CHRNA5, rs16969968) on both dorsolateral prefrontal cortex mediated behavior and physiology during working memory and on prefrontal gray matter volume.
  
  
  METHODS
  A large sample of healthy subjects was compared for genotypic differences for DRD2 rs1076560 (G>T) and CHNRA5 rs16969968 (G>A) on prefrontal phenotypes, including cognitive performance at the N-Back task, prefrontal physiology with BOLD fMRI during performance of the 2-Back working memory task, and prefrontal morphometry with structural MRI.
  
  
  RESULTS
  We found that DRD2 rs1076560 and CHNRA5 rs16969968 interact to modulate cognitive function, prefrontal physiology during working memory, and prefrontal gray matter volume. More specifically, CHRNA5-AA/DRD2-GT subjects had greater behavioral performance, more efficient prefrontal cortex activity at 2Back working memory task, and greater prefrontal gray matter volume than the other genotype groups.
  
  
  CONCLUSIONS
  The present data extend previous studies in animals and enhance our understanding of dopamine and acetylcholine signaling in the human prefrontal cortex, demonstrating interactions elicited by working memory that are modulated by genetic variants in DRD2 and CHRNA5.
authors.affiliation: IRCCSS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
authors.forename: Annabella
authors.initials: A
authors.lastname: Di Giorgio
authors.affiliation: Department of Pharmacology, Center for Pharmacogenomics, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Smith
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Fazio
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: D'Ambrosio
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gelao
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Tomasicchio
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Selvaggi
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Taurisano
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy; Cognitive Brain Research Unit, Department of Behavioral Sciences, University of Helsinki, Helsinki, Finland.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Quarto
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Masellis
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rampino
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Caforio
authors.affiliation: IRCCSS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Popolizio
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Blasi
authors.affiliation: Department of Pharmacology, Center for Pharmacogenomics, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
authors.affiliation: IRCCSS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy; Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy; pRED, NORD DTA, F. Hoffman-La Roche Ltd., Basel, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
mesh_terms: D000328:Adult; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: C447158:CHRNA5 protein, human; C581293:DRD2 protein, human; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; D011978:Receptors, Nicotinic