Memory and frontal lobe functions; possible relations with dopamine D2 receptors in the hippocampus
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
References (73)
- et al.
Voxel-based morphometry—The methods
NeuroImage
(2000) - et al.
Physiological activation of a cortical network during performance of the Wisconsin Card Sorting Test: a positron emission tomography study
Neuropsychologia
(1995) Beware of frontal lobe deficits in hippocampal clothing
Trends Cogn. Sci.
(2001)- et al.
Molecular imaging of the dopaminergic system and its association with human cognitive function
Biol. Psychiatry
(2006) - et al.
Autoradiographic localization of D1 and D2 dopamine receptors in the human brain
Neurosci. Lett.
(1988) - et al.
Dopaminergic antagonists prevent long-term maintenance of posttetanic LTP in the CA1 region of rat hippocampal slices
Brain Res.
(1990) - et al.
Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the rhesus monkey
Neuroscience
(1984) - et al.
Parametric imaging of ligand–receptor binding in PET using a simplified reference region model
NeuroImage
(1997) - et al.
Wisconsin card sorting test in children with temporal lobe epilepsy
Brain Dev.
(2002) - et al.
Age-related reduction of extrastriatal dopamine D2 receptor measured by PET
Life Sci.
(2001)
Dopamine D2 receptor bands in normal human temporal cortex are absent in Alzheimer’s disease
Brain Res.
A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission
Neuron
Simplified reference tissue model for PET receptor studies
NeuroImage
Subpopulations of cortical GABAergic interneurons differ by their expression of D1 and D2 dopamine receptor subtypes
Brain Res. Mol. Brain Res.
Assessment of spatial normalization of PET ligand images using ligand-specific templates
NeuroImage
A modified card sorting test sensitive to frontal lobe defects
Cortex
The prefrontal cortex and working memory: physiology and brain imaging
Curr. Opin. Neurobiol.
Material-specific lateralization of memory encoding in the medial temporal lobe: blocked versus event-related design
NeuroImage
Neural substrates of fluid reasoning: an fMRI study of neocortical activation during performance of the Raven’s Progressive Matrices Test
Cogn. Psychol.
A positron emission tomography (PET) investigation of the role of striatal dopamine (D2) receptor availability in spatial cognition
NeuroImage
Effects of dopaminergic and serotonergic manipulation on emotional processing: a pharmacological fMRI study
NeuroImage
Cocaine-induced modulation of long-term potentiation in the CA1 region of rat hippocampus
Neuropharmacology
Involvement of dopamine D(2) receptors in complex maze learning and acetylcholine release in ventral hippocampus of rats
Neuroscience
Prefrontal dopamine D1 receptors and working memory in schizophrenia
J. Neurosci.
Parallel organization of functionally segregated circuits linking basal ganglia and cortex
Annu. Rev. Neurosci.
Age-related cognitive deficits mediated by changes in the striatal dopamine system
Am. J. Psychiatry
Poststroke aphasia: epidemiology, pathophysiology and treatment
Drugs Aging
Neuroprotective role of dopamine against hippocampal cell death
J. Neurosci.
Anticonvulsant action of hippocampal dopamine and serotonin is independently mediated by D and 5-HT receptors
J. Neurochem.
Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels
Synapse
A neural basis for general intelligence
Science
Dopamine D2 receptor plays a role in memory function: implications of dopamine–acetylcholine interaction in the ventral hippocampus
Psychopharmacology (Berlin)
Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits
J. Neurosci.
Dopamine D2 receptor expression in hippocampus and parahippocampal cortex of rat, cat, and human in relation to tyrosine hydroxylase-immunoreactive fibers
Hippocampus
Neural mechanisms of general fluid intelligence
Nat. Neurosci.
Essential role of D1 but not D2 receptors in the NMDA receptor-dependent long-term potentiation at hippocampal–prefrontal cortex synapses in vivo
J. Neurosci.
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