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

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 D₂ receptor (D₂ R) that inhibits agonist-induced D₂ R internalisation. Moreover, animal studies have found large striatal increases in the proportion of D₂ R receptors in a high affinity state (D₂^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 D₂ R availability in the caudate and putamen. Therefore, despite a direct interaction between DISC1 and the D₂ R, none of its main functional polymorphisms impact striatal D_2/3 R binding potential, suggesting DISC1 variants act through other mechanisms.

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