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The Journal of Neuroscience, November 12, 2008, 28(46):12032-12038; doi:10.1523/JNEUROSCI.3446-08.2008

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Behavioral/Systems/Cognitive
Differential Contributions of Prefrontal and Hippocampal Dopamine D₁ and D₂ Receptors in Human Cognitive Functions

Hidehiko Takahashi,¹ Motoichiro Kato,² Harumasa Takano,¹ Ryosuke Arakawa,¹ Masaki Okumura,¹ Tatsui Otsuka,¹ Fumitoshi Kodaka,¹ Mika Hayashi,² Yoshiro Okubo,³ Hiroshi Ito,¹ and Tetsuya Suhara¹

¹Molecular Imaging Center, Department of Molecular Neuroimaging, National Institute of Radiological Sciences, Inage, Chiba 263-8555, Japan, ²Department of Neuropsychiatry, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan, and ³Department of Neuropsychiatry, Nippon Medical School, Bunkyo-ku, Tokyo 113-8603, Japan

Correspondence should be addressed to Dr. Hidehiko Takahashi, Department of Molecular Neuroimaging, National Institute of Radiological Sciences, 9-1, 4-chome, Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan. Email: hidehiko{at}nirs.go.jp

Dopamine D₁ receptors in the prefrontal cortex (PFC) are important for prefrontal functions, and it is suggested that stimulation of prefrontal D₁ receptors induces an inverted U-shaped response, such that too little or too much D₁ receptor stimulation impairs prefrontal functions. Less is known of the role of D₂ receptors in cognition, but previous studies showed that D₂ receptors in the hippocampus (HPC) might play some roles via HPC–PFC interactions. We measured both D₁ and D₂ receptors in PFC and HPC using positron emission tomography in healthy subjects, with the aim of elucidating how regional D₁ and D₂ receptors are differentially involved in frontal lobe functions and memory. We found an inverted U-shaped relation between prefrontal D₁ receptor binding and Wisconsin Card Sorting Test performance. However, prefrontal D₂ binding has no relation with any neuropsychological measures. Hippocampal D₂ receptor binding showed positive linear correlations not only with memory function but also with frontal lobe functions, but hippocampal D₁ receptor binding had no association with any memory and prefrontal functions. Hippocampal D₂ receptors seem to contribute to local hippocampal functions (long-term memory) and to modulation of brain functions outside HPC ("frontal lobe functions"), which are mainly subserved by PFC, via the HPC–PFC pathway. Our findings suggest that orchestration of prefrontal D₁ receptors and hippocampal D₂ receptors might be necessary for human executive function including working memory.

Key words: dopamine; D₁ receptors; D₂ receptors; prefrontal cortex; hippocampus; positron emission tomography

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Received July 23, 2008; revised Sept. 2, 2008; accepted Oct. 2, 2008.

Correspondence should be addressed to Dr. Hidehiko Takahashi, Department of Molecular Neuroimaging, National Institute of Radiological Sciences, 9-1, 4-chome, Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan. Email: hidehiko{at}nirs.go.jp

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