PET neuroimaging of extrastriatal dopamine receptors and prefrontal cortex functions

https://doi.org/10.1016/j.jphysparis.2013.07.001Get rights and content

Highlights

  • Dopamine D1 receptors in prefrontal cortex (PFC) are widely investigated.

  • Less attention has been paid to the role of D2 receptors in PFC functions.

  • Hippocampal dopamine transmission might also be important for PFC functions.

  • A single PET index about dopamine is not sufficient to understand PFC functions.

Abstract

The role of prefrontal dopamine D1 receptors in prefrontal cortex (PFC) functions, including working memory, is widely investigated. However, human (healthy volunteers and schizophrenia patients) positron emission tomography (PET) studies about the relationship between prefrontal D1 receptors and PFC functions are somewhat inconsistent. We argued that several factors including an inverted U-shaped relationship between prefrontal D1 receptors and PFC functions might be responsible for these inconsistencies. In contrast to D1 receptors, relatively less attention has been paid to the role of D2 receptors in PFC functions. Several animal and human pharmacological studies have reported that the systemic administration of D2 receptor agonist/antagonist modulates PFC functions, although those studies do not tell us which region(s) is responsible for the effect. Furthermore, while prefrontal D1 receptors are primarily involved in working memory, other PFC functions such as set-shifting seem to be differentially modulated by dopamine. PET studies of extrastriatal D2 receptors including ours suggested that orchestration of prefrontal dopamine transmission and hippocampal dopamine transmission might be necessary for a broad range of normal PFC functions. In order to understand the complex effects of dopamine signaling on PFC functions, measuring a single index related to basic dopamine tone is not sufficient. For a better understanding of the meanings of PET indices related to neurotransmitters, comprehensive information (presynaptic, postsynaptic, and beyond receptor signaling) will be required. Still, an interdisciplinary approach combining molecular imaging techniques with cognitive neuroscience and clinical psychiatry will provide new perspectives for understanding the neurobiology of neuropsychiatric disorders and their innovative drug developments.

Introduction

The prefrontal cortex (PFC) receives dense dopaminergic input originating in the ventral tegmental area. Due to the fact that dopamine D1 receptors in PFC are several times more abundant than D2 receptors (Hall et al., 1994), the roles of D1 receptors in PFC functions have been widely investigated. It has been demonstrated that local administration of D1 receptor antagonists into PFC induced impairment in working memory task in non-human primate (Sawaguchi and Goldman-Rakic, 1991). In human, positron emission tomography (PET) has been utilized to quantify prefrontal D1 receptors in vivo, and their role in human PFC functions has been studied. In contrast to D1 receptors, initial PET studies of D2 receptors were limited to the striatal region because of a lack of appropriate PET ligands for measuring D2 receptors outside the striatum where their expression is very low (Hall et al., 1994). With the introduction of high-affinity PET radioligands such as [11C]FLB457 (Halldin et al., 1995) and [18F]-fallypride (Mukherjee et al., 1996), it has become possible to quantify extrastriatal D2 receptors by PET. In this short review, we summarize PET studies investigating the role of extrastriatal dopamine D1 and D2 receptors in PFC functions.

Section snippets

PET imaging of prefrontal D1 receptors in schizophrenia

Because schizophrenia patients are known to have impairments of PFC functions including working memory and set-shifting (Kalkstein et al., 2010), prefrontal D1 receptors in schizophrenia have been investigated using PET. An initial PET study with [11C]SCH23390 revealed that D1 receptors in PFC were decreased in schizophrenia, which was associated with poor performance on the Wisconsin Card Sorting Test (WCST), a test requiring working memory and set-shifting abilities (Okubo et al., 1997).

Central D2 receptors stimulation and PFC functions

In contrast to D1 receptors, relatively less attention has been paid to the role of prefrontal D2 receptors in cognitive functions partly because their density in extrastriatal regions is very low (Suhara et al., 1999). It was reported that blockade of D2 receptors in PFC did not impair working memory in non-human primate (Sawaguchi and Goldman-Rakic, 1991). Müller et al. (1998) reported that the systemic administration of the mixed D1/D2 receptor agonist pergolide facilitated working memory

Measurements of tonic and phasic dopamine transmission

First, for a better understanding of the role of dopamine in PFC functions, we should consider the fact that dopamine neurons are known to show tonic (basic) firing and phasic (burst) firing and that, in turn, tonic and phasic dopamine release is induced, respectively (Grace, 1991, Grace et al., 2007). Although the release of both tonic and phasic dopamine is necessary for PFC functions, phasic dopamine release plays a crucial role in working memory and set-shifting (Braver et al., 1999,

Conclusion

In conclusion, in order to understand the complex effects of dopamine signaling on PFC functions, not only multi-faceted assessment of PFC functions containing various components with substantial overlaps, but also clever extraction and delineation of each component are needed. Equally, it certainly does not seem enough just to measure a single index related to basic dopamine tone. For a better understanding of the meanings of the PET indices related to neurotransmitters, comprehensive

Acknowledgements

A part of this study is the result of “Integrated Research on Neuropsychiatric Disorders” carried out under the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), a Grant-in-Aid for Scientific Research on Innovative Areas: Prediction and Decision Making (23120009), a Grant-in-Aid for Young Scientist A (23680045), a grant from the Smoking Research Foundation, a research grant from the Takeda Science Foundation, a

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