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Disrupted‐in‐schizophrenia 1 functional polymorphisms and D₂/D₃ receptor availability: A [¹¹C]‐(+)‐PHNO imaging study

Dahoun, T; Nour, MM; Adams, RA; Trossbach, S; Lee, SH; Patel, H; Curtis, C; ... Howes, OD; + view all (2019) Disrupted‐in‐schizophrenia 1 functional polymorphisms and D₂/D₃ receptor availability: A [¹¹C]‐(+)‐PHNO imaging study. Genes, Brain and Behavior , Article e12596. 10.1111/gbb.12596. (In press). Green open access

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Abstract

The disrupted‐in‐schizophrenia 1 (DISC1) protein has been implicated in a range of biological mechanisms underlying chronic mental disorders such as schizophrenia. Schizophrenia is associated with abnormal striatal dopamine signalling, and all antipsychotic drugs block striatal dopamine 2/3 receptors (D_{2/3}Rs). Importantly, the DISC1 protein directly interacts and forms a protein complex with the dopamine D_{2} receptor (D_{2}R) that inhibits agonist‐induced D_{2}R internalisation. Moreover, animal studies have found large striatal increases in the proportion of D_{2}R receptors in a high affinity state (D_{2}^{high}R in DISC1 rodent models. Here, we investigated the relationship between the three most common polymorphisms altering the amino‐acid sequence of the DISC1 protein (Ser704Cys (rs821616), Leu607Phe (rs6675281) and Arg264Gln (rs3738401)) and striatal D_{2/3}R availability in 41 healthy human volunteers, using [{11}^C] ‐(+)‐PHNO positron emission tomography. We found no association between DISC1 polymorphisms and D_{2/3}R availability in the striatum and D_{2}R availability in the caudate and putamen. Therefore, despite a direct interaction between DISC1 and the D_{2}R, none of its main functional polymorphisms impact striatal D_{2/3}R binding potential, suggesting DISC1 variants act through other mechanisms.

Type: Article
Title: Disrupted‐in‐schizophrenia 1 functional polymorphisms and D₂/D₃ receptor availability: A [¹¹C]‐(+)‐PHNO imaging study
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/gbb.12596
Publisher version: https://doi.org/10.1111/gbb.12596
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Arg264Gln, DISC1, Leu607Phe, PET, PHNO, Ser704Cys, dopamine, polymorphism, psychosis, receptor
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Imaging Neuroscience
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Computer Science
URI: https://discovery.ucl.ac.uk/id/eprint/10078786
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