Fumitoshi Kodaka

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

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.

Dopamine D1 Receptors and Nonlinear Probability Weighting in Risky Choice

Misestimating risk could lead to disadvantaged choices such as initiation of drug use (or gambling) and transition to regular drug use (or gambling). Although the normative theory in decision-making under risks assumes that people typically take the probability-weighted expectation over possible utilities, experimental studies of choices among risks suggest that outcome probabilities are transformed nonlinearly into subjective decision weights by a nonlinear weighting function that overweights low probabilities and underweights high probabilities. Recent studies have revealed the neurocognitive mechanism of decision-making under risk. However, the role of modulatory neurotransmission in this process remains unclear. Using positron emission tomography, we directly investigated whether dopamine D1 and D2 receptors in the brain are associated with transformation of probabilities into decision weights in healthy volunteers. The binding of striatal D1 receptors is negatively correlated with the degree of nonlinearity of weighting function. Individuals with lower striatal D1 receptor density showed more pronounced overestimation of low probabilities and underestimation of high probabilities. This finding should contribute to a better understanding of the molecular mechanism of risky choice, and extreme or impaired decision-making observed in drug and gambling addiction.

Honesty mediates the relationship between serotonin and reaction to unfairness

How does one deal with unfair behaviors? This subject has long been investigated by various disciplines including philosophy, psychology, economics, and biology. However, our reactions to unfairness differ from one individual to another. Experimental economics studies using the ultimatum game (UG), in which players must decide whether to accept or reject fair or unfair offers, have also shown that there are substantial individual differences in reaction to unfairness. However, little is known about psychological as well as neurobiological mechanisms of this observation. We combined a molecular imaging technique, an economics game, and a personality inventory to elucidate the neurobiological mechanism of heterogeneous reactions to unfairness. Contrary to the common belief that aggressive personalities (impulsivity or hostility) are related to the high rejection rate of unfair offers in UG, we found that individuals with apparently peaceful personalities (straightforwardness and trust) rejected more often and were engaged in personally costly forms of retaliation. Furthermore, individuals with a low level of serotonin transporters in the dorsal raphe nucleus (DRN) are honest and trustful, and thus cannot tolerate unfairness, being candid in expressing their frustrations. In other words, higher central serotonin transmission might allow us to behave adroitly and opportunistically, being good at playing games while pursuing self-interest. We provide unique neurobiological evidence to account for individual differences of reaction to unfairness.

Quantification of Dopamine Transporter in Human Brain Using PET with 18F-FE-PE2I

18F-(E)-N-(3-iodoprop-2E-enyl)-2β-carbofluoroethoxy-3β-(4-methylphenyl)nortropane (18F-FE-PE2I) is a new PET radioligand with a high affinity and selectivity for the dopamine transporter (DAT). In nonhuman primates, 18F-FE-PE2I showed faster kinetics and less production of radiometabolites that could potentially permeate the blood–brain barrier than did 11C-PE2I. The aims of this study were to examine the quantification of DAT using 18F-FE-PE2I and to assess the effect of radiometabolites of 18F-FE-PE2I on the quantification in healthy humans. Methods: A 90-min dynamic PET scan was obtained for 10 healthy men after intravenous injection of 18F-FE-PE2I. Kinetic compartment model analysis with a metabolite-corrected arterial input function was performed. The effect of radiometabolites on the quantification was evaluated by time-stability analyses. The simplified reference tissue model (SRTM) method with the cerebellum as a reference region was evaluated as a noninvasive method of quantification. Results: After the injection of 18F-FE-PE2I, the whole-brain radioactivity showed a high peak (∼3–5 standardized uptake value) and fast washout. The radioactive uptake of 18F-FE-PE2I in the brain was according to the relative density of the DAT (striatum > midbrain > thalamus). The cerebellum showed the lowest uptake. Tissue time–activity curves were well described by the 2-tissue-compartment model (TCM), as compared with the 1-TCM, for all subjects in all regions. Time stability analysis showed stable estimation of total distribution volume with 60-min or longer scan durations, indicating the small effect of radiometabolites. Binding potentials in the striatum and midbrain were well estimated by the SRTM method, with modest intersubject variability. Although the SRTM method yielded a slight underestimation and overestimation in regions with high and low DAT densities, respectively, binding potentials by the SRTM method were well correlated to the estimates by the indirect kinetic method with 2-TCM. Conclusion: 18F-FE-PE2I is a promising PET radioligand for quantifying DAT. The binding potentials could be reliably estimated in both the striatum and midbrain using both the indirect kinetic and SRTM methods with a scan duration of 60 min. Although radiometabolites of 18F-FE-PE2I in plasma possibly introduced some effects on the radioactivity in the brain, the effects on estimated binding potential were likely to be small.

Relation between Presynaptic and Postsynaptic Dopaminergic Functions Measured by Positron Emission Tomography: Implication of Dopaminergic Tone

Both presynaptic and postsynaptic dopaminergic functions can be estimated by positron emission tomography (PET). While both presynaptic and postsynaptic dopaminergic functions would be regulated by corresponding genes and related to personality traits, the relation between presynaptic and postsynaptic functions in terms of interindividual variation has hardly been investigated. In the present study, both striatal dopamine D2 receptor binding and endogenous dopamine synthesis rate were measured in the same healthy subjects using PET with [11C]raclopride and l-[β-11C]DOPA, respectively, and these two parameters were compared. Two PET studies with [11C]raclopride and l-[β-11C]DOPA were performed sequentially at rest condition on 14 healthy men. For [11C]raclopride PET, the binding potential was calculated by the reference tissue model method. For l-[β-11C]DOPA PET, the endogenous dopamine synthesis rate was estimated by graphical analysis. A significant negative correlation was observed between the binding potential of dopamine D2 receptors and endogenous dopamine synthesis rate (r = −0.66, p < 0.05). Although the interindividual variation of binding potential of [11C]raclopride would be due to both the interindividual difference in the receptor density and that in the concentration of endogenous dopamine in the synaptic cleft, the negative correlation between parameters for both presynaptic and postsynaptic functions might indicate a compensative relation between the two functions.

Serotonergic neurotransmission in the living human brain: A positron emission tomography study using [11C]DASB and [11C]WAY100635 in young healthy men

The central serotonergic (5‐HT) system is closely involved in regulating various mental functions such as mood and emotion. In this system, the serotonin transporter (5‐HTT) and the 5‐HT1A receptor play important roles in the pathophysiology and treatment of mood and anxiety disorders. However, only a few integrated databases have considered the intraindividual relationship between pre‐ and postsynaptic serotonergic transmission. In the present study, we constructed a database of 5‐HTT and 5‐HT1A receptors using positron emission tomography (PET) with [11C]DASB and [11C]WAY100635, respectively. Seventeen healthy young men participated in this study. After anatomic standardization of original images, BPND was calculated on a voxel‐by‐voxel basis using reference tissue methods. The highest binding to 5‐HTT was observed in the dorsal raphe nucleus, striatum, and thalamus; moderate binding, in the insula and cingulate cortex; and very low binding, in the cerebral neocortex. In contrast, the highest binding to 5‐HT1A receptors was seen in the hippocampal regions, insula, neocortical regions, and dorsal raphe nucleus, and very low binding was found in the thalamus and basal ganglia. These distribution patterns were in agreement with those reported in human postmortem studies and previous PET investigations. In addition, exploratory analysis indicated significant negative correlations between the BPND values with both radiotracers in certain regions of the brain, such as the cingulate, insula, and frontal, temporal and parietal cortices (Pearsons correlation, P < 0.05). These databases facilitate the understanding of the regional distribution of serotonergic neurotransmission function in the living human brain and the pathophysiology of various neuropsychiatric disorders. Synapse, 2011.

Contribution of dopamine D1 and D2 receptors to amygdala activity in human.

Several animal studies have demonstrated functional roles of dopamine (DA) D1 and D2 receptors in amygdala activity. However, the contribution of DA D1 and D2 receptors to amygdala response induced by affective stimuli in human is unknown. To investigate the contribution of DA receptor subtypes to amygdala reactivity in human, we conducted a multimodal in vivo neuroimaging study in which DA D1 and D2 receptor bindings in the amygdala were measured with positron emission tomography (PET), and amygdala response induced by fearful faces was assessed by functional magnetic resonance imaging (fMRI) in healthy volunteers. We used multimodality voxelwise correlation analysis between fMRI signal and DA receptor binding measured by PET. DA D1 binding in the amygdala was positively correlated with amygdala signal change in response to fearful faces, but DA D2 binding in the amygdala was not related to amygdala signal change. DA D1 receptors might play a major role in enhancing amygdala response when sensory inputs are affective.

Effects of the Antipsychotic Risperidone on Dopamine Synthesis in Human Brain Measured by Positron Emission Tomography with l-[β-11C]DOPA: A Stabilizing Effect for Dopaminergic Neurotransmission?

Effects of antipsychotic drugs have widely been considered to be mediated by blockade of postsynaptic dopamine D2 receptors. Effects of antipsychotics on presynaptic functions of dopaminergic neurotransmission might also be related to therapeutic effects of antipsychotics. To investigate the effects of antipsychotics on presynaptic functions of dopaminergic neurotransmission in relation with occupancy of dopamine D2 receptors, changes in dopamine synthesis capacity by antipsychotics and occupancy of dopamine D2 receptors were measured by positron emission tomography (PET) in healthy men. PET studies using [11C]raclopride and l-[β-11C]DOPA were performed under resting condition and oral administration of single dose of the antipsychotic drug risperidone on separate days. Although occupancy of dopamine D2 receptors corresponding dose of risperidone was observed, the changes in dopamine synthesis capacity by the administration of risperidone were not significant, nor was the relation between the occupancy of dopamine D2 receptors and these changes. A significant negative correlation was observed between the baseline dopamine synthesis capacity and the changes in dopamine synthesis capacity by risperidone, indicating that this antipsychotic can be assumed to stabilize the dopamine synthesis capacity. The therapeutic effects of risperidone in schizophrenia might be related to such stabilizing effects on dopaminergic neurotransmission responsivity.

Norepinephrine in the brain is associated with aversion to financial loss

Understanding the molecular mechanism of extreme or impaired decision-making observed in neuropsychiatric disorders, such as pathological gambling and attention-deficit hyperactivity disorder (ADHD), could contribute to better assessment and the development of novel pharmacological therapies for those disorders. Typically, most people show a disproportionate distaste for possible losses compared with equal-sized gains. This human in vivo molecular imaging study has demonstrated that individuals with lower thalamic norepinephrine transporters (NET) showed more exaggerated aversion to financial loss.

Occupancy of serotonin and norepinephrine transporter by milnacipran in patients with major depressive disorder: a positron emission tomography study with [11C]DASB and (S,S)-[18F]FMeNER-D2

Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported >80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2), in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED(50) was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupancies were observed in a dose-dependent manner. Both 5-HTT and NET occupancies were about 40% by milnacipran at 100 mg, the dose most commonly administered to MDD patients.