D2 receptor genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans

• Published in: NeuroImage (Orlando, Fla.) Vol. 54; no. 4; pp. 2915 - 2921
• Main Authors: Fazio, Leonardo, Blasi, Giuseppe, Taurisano, Paolo, Papazacharias, Apostolos, Romano, Raffaella, Gelao, Barbara, Ursini, Gianluca, Quarto, Tiziana, Lo Bianco, Luciana, Di Giorgio, Annabella, Mancini, Marina, Popolizio, Teresa, Rubini, Giuseppe, Bertolino, Alessandro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.02.2011; Elsevier Limited
• Subjects: [123I] FP-CIT SPECT; Age; Alternative splicing; Behavior; Brain; Brain Mapping; Corpus Striatum - physiology; Dopamine; Dopamine - metabolism; Dopamine D2 Receptor Polymorphism; Female; fMRI; Genotype; Genotype & phenotype; Humans; Imaging genetics; Magnetic Resonance Imaging; Male; Motor Activity - genetics; Motor brain activity; Motor Cortex - physiology; Multimodal; Polymorphism, Single Nucleotide; Reaction Time; Receptors, Dopamine D2 - genetics; Signal transduction; Signal Transduction - genetics; Studies; Tomography, Emission-Computed, Single-Photon; Young Adult; Imaging genetics; fMRI; Dopamine D2 Receptor Polymorphism; Motor brain activity; Multimodal; [123I] FP-CIT SPECT
• DOI: 10.1016/j.neuroimage.2010.11.034
• ISSN: 1053-8119; 1095-9572

Pre-synaptic D2 receptors regulate striatal dopamine release and DAT activity, key factors for modulation of motor pathways. A functional SNP of DRD2 (rs1076560 G>T) is associated with alternative splicing such that the relative expression of D2S (mainly pre-synaptic) vs. D2L (mainly post-synaptic) receptor isoforms is decreased in subjects with the T allele with a putative increase of striatal dopamine levels. To evaluate how DRD2 genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans, we have investigated the association of rs1076560 with BOLD fMRI activity during a motor task. To further evaluate the relationship of this circuitry with dopamine signaling, we also explored the correlation between genotype based differences in motor brain activity and pre-synaptic striatal DAT binding measured with [123I] FP-CIT SPECT. Fifty healthy subjects, genotyped for DRD2 rs1076560 were studied with BOLD-fMRI at 3T while performing a visually paced motor task with their right hand; eleven of these subjects also underwent [123I]FP-CIT SPECT. SPM5 random-effects models were used for statistical analyses. Subjects carrying the T allele had greater BOLD responses in left basal ganglia, thalamus, supplementary motor area, and primary motor cortex, whose activity was also negatively correlated with reaction time at the task. Moreover, left striatal DAT binding and activity of left supplementary motor area were negatively correlated. The present results suggest that DRD2 genetic variation was associated with focusing of responses in the whole motor network, in which activity of predictable nodes was correlated with reaction time and with striatal pre-synaptic dopamine signaling. Our results in humans may help shed light on genetic risk for neurobiological mechanisms involved in the pathophysiology of disorders with dysregulation of striatal dopamine like Parkinson's disease. ► Intronic variant of D2 receptor gene modulated striatal and cortical motor activity. ► The T allele of DRD2 rs1076560 was associated with greater motor activity. ► DAT binding with [123]I FP-CIT SPECT was negatively correlated with SMA BOLD response.