title: Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance.
abstract: BACKGROUND
  Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known.
  
  
  METHODS
  Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory.
  
  
  RESULTS
  Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT.
  
  
  CONCLUSIONS
  Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.
authors.affiliation: Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy. a.bertolino@psichiat.uniba.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
authors.forename: Paolo
authors.initials: P
authors.lastname: Taurisano
authors.forename: Nicola Marco
authors.initials: NM
authors.lastname: Pisciotta
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Blasi
authors.forename: Leonardo
authors.initials: L
authors.lastname: Fazio
authors.forename: Raffaella
authors.initials: R
authors.lastname: Romano
authors.forename: Barbara
authors.initials: B
authors.lastname: Gelao
authors.forename: Luciana
authors.initials: L
authors.lastname: Lo Bianco
authors.forename: Madia
authors.initials: M
authors.lastname: Lozupone
authors.forename: Annabella
authors.initials: A
authors.lastname: Di Giorgio
authors.forename: Grazia
authors.initials: G
authors.lastname: Caforio
authors.forename: Fabio
authors.initials: F
authors.lastname: Sambataro
authors.forename: Artor
authors.initials: A
authors.lastname: Niccoli-Asabella
authors.forename: Audrey
authors.initials: A
authors.lastname: Papp
authors.forename: Gianluca
authors.initials: G
authors.lastname: Ursini
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Sinibaldi
authors.forename: Teresa
authors.initials: T
authors.lastname: Popolizio
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rubini
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001549:Benzamides / Q000378:metabolism; D001667:Binding, Competitive; D003342:Corpus Striatum / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000033:anatomy & histology / Q000502:physiology*; D011597:Psychomotor Performance / Q000502:physiology; D011759:Pyrrolidines / Q000378:metabolism; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D001549:Benzamides; D018492:Dopamine Antagonists; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; C055743:3-iodo-2-hydroxy-6-methoxy-N-((1-ethyl-2-pyrrolidinyl)methyl)benzamide