Functional significance of central D1 receptors in cognition: beyond working memory

The role of dopamine D1 receptors in prefrontal cortex function, including working memory, is well acknowledged. However, relatively little is known about their role in other cognitive or emotional functions. We measured both D1 and D2 receptors in the brain using positron emission tomography in healthy subjects, with the aim of elucidating how regional D1 and D2 receptors are differentially involved in cognitive and emotional functions beyond working memory. We found an inverted U-shaped relation between prefrontal D1 receptor availability and Wisconsin Card Sorting Test performance, indicating that too little or too much D1 receptor stimulation impairs working memory or set shifting. In addition, variability of D1 receptor availability in the amygdala and striatum was related to individual differences in emotional responses and decision-making processes, respectively. These observations suggest that the variability of available D1 receptors might be associated with individual differences in brain functions that require phasic dopamine release. An interdisciplinary approach combining molecular imaging of dopamine neurotransmission with cognitive neuroscience and clinical psychiatry will provide new perspectives for understanding the neurobiology of neuropsychiatric disorders such as schizophrenia, addiction and Parkinson's disease, as well as novel therapeutics for cognitive impairments observed in them

Normal Database of Dopaminergic Neurotransmission System in Human Brain Measured by Positron Emission Tomography

The central dopaminergic system is of interest in the pathophysiology ofschizophrenia and other neuropsychiatric disorders. Both pre- andpostsynaptic dopaminergic functions can be estimated by positronemission tomography (PET) with different radiotracers. However, anintegrated database of both pre- and postsynaptic dopaminergicneurotransmission components including receptors, transporter, andendogenous neurotransmitter synthesis has not yet been reported. In thepresent study, we constructed a normal database for the pre- andpostsynaptic dopaminergic functions in the living human brain usingPET. To measure striatal and extrastriatal dopamine D1 and D2 receptorbindings, dopamine transporter binding, and endogenous dopaminesynthesis rate, PET scans were performed on healthy men after intravenousinjection of [11C]SCH23390, [11C]raclopride, [11C]FLB457,[11C]PE2I, or L-[β-11C]DOPA. All PET images were anatomicallystandardized using SPM2, and a database was built for each radiotracer.Gray matter images were segmented and extracted from all anatomicallystandardized magnetic resonance images using SPM2, and theywere used for partial volume correction. These databases allow thecomparison of regional distributions of striatal and extrastriataldopamine D1 and D2 receptors, dopamine transporter, and endogenousdopamine synthesis capability. These distributions were in goodagreement with those from human postmortem studies. This databasecan be used in various researches to understand the physiology ofdopaminergic functions in the living human brain. This database couldalso be used to investigate regional abnormalities of dopaminergicneurotransmission in neuropsychiatric disorders.© 2007 Elsevier Inc. All rights reserved