Elsevier

NeuroImage

Volume 34, Issue 4, 15 February 2007, Pages 1643-1649
NeuroImage

Memory and frontal lobe functions; possible relations with dopamine D2 receptors in the hippocampus

https://doi.org/10.1016/j.neuroimage.2006.11.008Get rights and content

Abstract

Cerebral cortical regions are thought to be important for cognitive functions such as memory and executive function. Although the functional associations between dopamine D2 receptors and motor and cognitive functions have been extensively examined in the striatum using positron emission tomography (PET), the role of dopamine D2 receptors in extrastriatal regions has been unexplored. We aimed to investigate the relationship between dopamine D2 receptors in extrastriatal regions and the performance of a broad spectrum of cognitive functions including memory, language, attention, and executive function in healthy subjects. Extrastriatal dopamine D2 receptors were measured in 25 male subjects using PET with [11C]FLB457. After the PET scans, a battery of neuropsychological tests was administered to all subjects. We found that the binding potential (BP) of [11C]FLB457 in the hippocampus was positively correlated with memory function. Furthermore, BP of [11C]FLB457 in the hippocampus, but not in the prefrontal cortex, was associated with frontal lobe functions such as executive function and verbal fluency. Our findings suggest that dopamine D2 receptors in the hippocampus might affect the local hippocampal function, but also brain functions outside the hippocampus such as the prefrontal cortex.

Introduction

Cognitive functions such as long-term memory, working memory, and executive function are associated with cerebral cortical regions like the hippocampus and prefrontal cortex (Miller, 2000, Passingham and Sakai, 2004, Squire et al., 2004). The relationship between prefrontal dopamine D1 receptors and cognitive function has been investigated both in animal studies (Sawaguchi and Goldman-Rakic, 1991) and human studies (Abi-Dargham et al., 2002, Okubo et al., 1997). In contrast, studies investigating the role of extrastriatal dopamine D2 receptors in cognitive function have been limited (Cropley et al., 2006) by the fact that the density of dopamine D2 receptors in the cortical regions is several times lower than that of D1 receptors (De Keyser et al., 1988, Hall et al., 1994, Suhara et al., 1999). Using positron emission tomography (PET), the functional associations between dopamine D2 receptors and cognitive functions have been investigated in the striatum where dopamine D2 receptors are abundant (Backman et al., 2000, Cropley et al., 2006, Reeves et al., 2005, Volkow et al., 1998). Systemic administration of drugs that stimulate dopamine D2 receptors has been reported to improve cognitive functions such as working memory, executive function, and verbal fluency (Berthier, 2005, Kimberg et al., 1997, McDowell et al., 1998), and blockade of dopamine D2 receptors impaired those functions (Mehta et al., 1999). Although striatal dopamine D2 receptors could contribute to these drug effects on cognitive functions via the fronto-striato-thalamic circuit (Alexander et al., 1986), recent studies have demonstrated that dopamine D2 agonist and antagonist directly modulate cortical activity (Kimberg et al., 2001, Takahashi et al., 2005, Wang et al., 2004). With the introduction of high-affinity radioligands, such as [11C]FLB 457, [123I]epidepride, and [18F]fallypride, it has become possible to visualize and quantify extrastriatal D2 receptors in vivo (Halldin et al., 1995). Using the high-affinity radioligand [11C]FLB457, Kemppainen et al. (2003) reported a correlation between memory impairment and the reduction of dopamine D2 receptor binding in the hippocampus of patients with Alzheimer’s disease (AD). In the present study, we aimed to examine the individual variations of dopamine D2 receptor binding in extrastriatal regions in relation to the cognitive level of brain functions including memory, language, attention, high-level spatial cognition, and executive function in healthy subjects.

Section snippets

Subjects

Twenty-five healthy male volunteers (mean age 26.7 ± 4.5 years) were studied. Since extrastriatal D2 receptors were reported to decrease with age (Inoue et al., 2001), and sex differences in extrastriatal D2 receptors were also reported (Kaasinen et al., 2001), the subjects were restricted to young males in their 20s and 30s in this study. They were judged to be free of any psychiatric disorders on the basis of unstructured psychiatric screening interviews. None of the subjects was a user of

Results

Mean score (SD) of immediate recall, delayed recall, and recognition of RAVLT (verbal learning test) were 54.5 (12.5), 12.9 (1.8), and 14.7 (0.5), respectively. Mean score (SD) of copy, immediate recall, and delayed recall of ROCFT (non-verbal learning test) were 35.6 (0.8), 27.3 (4.6), and 27.2 (5.2), respectively. Mean (SD) of WCST categories was achieved and perseverative errors were 5.1 (1.4) and 1.2 (1.8), respectively. Mean score (SD) of phonemic and semantic verbal fluency was 27.8 (9.2)

Discussion

In this study, we found that dopamine D2 receptor binding in the hippocampus was associated not only with memory function but also with “frontal lobe” functions such as executive function and verbal fluency in young volunteers. Those associations might be regulated by different mechanisms, as there were minimal, if any, interrelations across different neuropsychological tests. All subjects had achieved higher education, and scores of RCPM, a test of reasoning and general fluid intelligence,

Acknowledgments

This study was supported by a consignment expense for Molecular Imaging Program on “Research Base for PET Diagnosis” from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japanese Government, a Grant-in-Aid for Scientific Research from MEXT (18790858). We thank Mr. Katsuyuki Tanimoto, Mr. Takahiro Shiraishi, Mr. Akira Ando, and Mr. Toshio Miyamoto for their assistance in performing the PET experiments at the National Institute of Radiological Sciences. We also thank

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