Genetic Variation of a DRD2 Co-expression Network is Associated with Changes in Prefrontal Function After D2 Receptors Stimulation

Pierluigi Selvaggi, Giulio Pergola, Barbara Gelao, Pasquale Di Carlo, Maria Antonietta Nettis, Graziella Amico, Leonardo Fazio, Antonio Rampino, Fabio Sambataro, Giuseppe Blasi, Alessandro Bertolino

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Abstract

Dopamine D2 receptors (D2Rs) contribute to the inverted U-shaped relationship between dopamine signaling and prefrontal function. Genetic networks from post-mortem human brain revealed 84 partner genes co-expressed with DRD2. Moreover, eight functional single nucleotide polymorphisms combined into a polygenic co-expression index (PCI) predicted co-expression of this DRD2 network and were associated with prefrontal function in humans. Here, we investigated the non-linear association of the PCI with behavioral and Working Memory (WM) related brain response to pharmacological D2Rs stimulation. Fifty healthy volunteers took part in a double-blind, placebo-controlled, functional MRI (fMRI) study with bromocriptine and performed the N-Back task. The PCI by drug interaction was significant on both WM behavioral scores (P = 0.046) and related prefrontal activity (all corrected P < 0.05) using a polynomial PCI model. Non-linear responses under placebo were reversed by bromocriptine administration. fMRI results on placebo were replicated in an independent sample of 50 participants who did not receive drug administration (P = 0.034). These results match earlier evidence in non-human primates and confirm the physiological relevance of this DRD2 co-expression network. Results show that in healthy subjects, different alleles evaluated as an ensemble are associated with non-linear prefrontal responses. Therefore, brain response to a dopaminergic drug may depend on a complex system of allelic patterns associated with DRD2 co-expression.

Original languageEnglish
Pages (from-to)1162–1173
JournalCerebral cortex (New York, N.Y. : 1991)
Early online date3 Feb 2018
DOIs
Publication statusE-pub ahead of print - 3 Feb 2018

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