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The Journal of Neuroscience, January 28, 2009, 29(4):1224-1234; doi:10.1523/JNEUROSCI.4858-08.2009

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Behavioral/Systems/Cognitive
Genetically Determined Interaction between the Dopamine Transporter and the D₂ Receptor on Prefronto-Striatal Activity and Volume in Humans

Alessandro Bertolino,¹ Leonardo Fazio,¹ Annabella Di Giorgio,¹ Giuseppe Blasi,¹ Raffaella Romano,¹ Paolo Taurisano,¹ Grazia Caforio,¹ Lorenzo Sinibaldi,^2,3 Gianluca Ursini,^1,2 Teresa Popolizio,⁴ Emanuele Tirotta,⁵ Audrey Papp,⁶ Bruno Dallapiccola,^2,3,4 Emiliana Borrelli,⁵ and Wolfgang Sadee⁶

¹Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University of Bari, 70124 Bari, Italy, ²Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Casa Sollievo della Sofferenza (CSS)–Mendel Institute, 00198 Rome, Italy, ³Department of Experimental Medicine, Sapienza University, 00100 Rome, Italy, ⁴Department of Neuroradiology, IRCCS CSS, 71013 San Giovanni Rotondo, Foggia, Italy, ⁵Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, California 92697, and ⁶Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, and Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, Ohio 43210

Correspondence should be addressed to Dr. Alessandro Bertolino, Dipartimento di Scienze Neurologiche e Psichiatriche, Università degli Studi di Bari, Piazza Giulio Cesare 9, 70124 Bari, Italy. Email: a.bertolino{at}psichiat.uniba.it

Dopamine modulation of neuronal activity during memory tasks identifies a nonlinear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D₂ receptors (encoded by DRD₂) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover, in vitro studies have demonstrated that DAT and D₂ proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between a DRD₂ polymorphism (rs1076560) causing reduced presynaptic D₂ receptor expression and the DAT 3'-VNTR variant (affecting DAT expression) in a large sample of healthy subjects undergoing blood oxygenation level-dependent (BOLD)-functional magnetic resonance imaging (MRI) during memory tasks and structural MRI. Results indicated a significant DRD₂/DAT interaction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of the DAT variant was mostly manifest in the context of the DRD₂ allele associated with lower presynaptic expression. Similar results were also evident for gray matter volume in caudate. These interactions describe a nonlinear relationship between compound genotypes and brain activity or gray matter volume. Complementary data from striatal protein extracts from wild-type and D₂ knock-out animals (D2R^–/–) indicate that DAT and D₂ proteins interact in vivo. Together, our results demonstrate that the interaction between genetic variants in DRD₂ and DAT critically modulates the nonlinear relationship between dopamine and neuronal activity during memory processing.

Key words: working memory; recognition memory; fMRI; dopamine; transport; D₂; receptor

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Received Oct. 8, 2008; revised Nov. 14, 2008; accepted Dec. 20, 2008.

Correspondence should be addressed to Dr. Alessandro Bertolino, Dipartimento di Scienze Neurologiche e Psichiatriche, Università degli Studi di Bari, Piazza Giulio Cesare 9, 70124 Bari, Italy. Email: a.bertolino{at}psichiat.uniba.it

This article has been cited by other articles:

				G. Blasi, L. Lo Bianco, P. Taurisano, B. Gelao, R. Romano, L. Fazio, A. Papazacharias, A. Di Giorgio, G. Caforio, A. Rampino, et al. Functional Variation of the Dopamine D2 Receptor Gene Is Associated with Emotional Control as well as Brain Activity and Connectivity during Emotion Processing in Humans J. Neurosci., November 25, 2009; 29(47): 14812 - 14819. [Abstract] [Full Text] [PDF]

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