Dopamine D_1 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 D_1 and D_2 receptors in the brain are associated with transformation of probabilities into decision weights in healthy volunteers. The binding of striatal D_1 receptors is negatively correlated with the degree of nonlinearity of weighting function. Individuals with lower striatal D_1 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

Effects of antipsychotic drug on dopamine synthesis in humans measured by PET with [C-11]DOPA

Objectives: Effects of antipsychotic drugs have been considered to be mediated by blockade of dopamine D2 receptors. In this study, changes in dopamine synthesis rate by administration of second-generation antipsychotics were measured by PET. Methods: PET studies were performed on 12 healthy men under resting condition (baseline study) and oral administration of single dose of antipsychotic drug, risperidone of 0.5-2.0 mg, (drug challenge study) on separate days. In each study, both PET scans with [C-11]raclopride and [C-11]DOPA were performed sequentially. The occupancy of dopamine D2 receptors by risperidone was calculated from binding potential values in the striatum for baseline and drug challenge studies with [C-11]raclopride determined by the SRTM method. The uptake rate constant, Ki, for [C-11]DOPA in the striatum indicating the dopamine synthesis rate was estimated by the graphical analysis. Results: The occupancies of dopamine D2 receptors were 39%-75%. The dopamine synthesis rate Ki were 0.0136+-0.0017 and 0.0142+-0.0010 (1/min) for the baseline and drug challenge studies, respectively, and no significant change in Ki by risperidone was observed. A significant negative correlation was observed between the baseline Ki and the change in Ki by risperidone (r=-0.87). Conclusions: The negative correlation between the baseline Ki and the change in Ki by risperidone, and smaller coefficient of variation of Ki in drug challenge studies than in baseline studies indicate that risperidone can be considered to stabilize the level of dopamine synthesis rate. Therapeutic effects of risperidone on schizophrenia might be related to stabilizing effects on dopaminergic neurotransmission responsivity in dopamine release.SNM 2009 Annual Meetin

The distribution of [11C]sulpiride in humans and the effect of an oral administration of clinical dose of sulpiride: A preliminary positron emission tomography study

Introduction: Positron emission tomography (PET) has enabled us to directly explore the pharmacokinetics of radiolabeled drugs in the living human body. Sulpiride, which is a benzamide derivative, is a dopamine D2 receptor antagonist and has been widely used as a psychotropic drug since the 1970\u27s. Although sulpiride is known to have low brain penetration possibly due to its low lipophilicity, 50% of dopamine D2 receptor in the brain was occupied by an oral administration of sulpiride (500mg) in previous PET studies with selective dopamine D2 receptor radioligands such as [11C]raclopride and [11C]FLB457. In the present study, we injected [11C]sulpiride to healthy men to directly examine the distribution of [11C]sulpiride. In addition, we tested whether an oral administration of clinical dose of sulpiride would affect the distribution of [11C]sulpiride since the drug is reported to be a substrate of membrane transporters. Methods: Two young healthy men participated in this study. Thirty minutes after intravenous injection of [11C]sulpiride, whole body static images were obtained from head to thighs (8 bed positions with 3 min for each bed position) in a three-dimensional mode with a PET/computed tomography (CT) system. Furthermore, we performed PET scans 3 hours after an oral administration of a clinical dose of non-radiolabeled sulpiride (500 mg) with the identical scan protocol on the same day. Volumes of interest were manually delineated with reference to their CT images. The ratio of radioactivity to the injected dose for each organ (percent injected dose) was calculated and used as an index of distribution. Results: At baseline, high accumulation of the tracer was observed in the liver, gallbladder, intestine, kidney, and urinary tract, while very low accumulation was observed in the brain with the exception of the pituitary. After the oral administration of sulpiride, the accumulation of the tracer in the brain did not show any significant change from the baseline (from 0.2% to 0.2 %), whereas that in the liver showed a marked reduction from 12.6% to 5.0% on average. Discussion: At baseline, the low accumulation in the brain and high accumulation in the pituitary indicate the low penetration of sulpiride in the brain. In the other organs, a high accumulation in the liver, gallbladder, kidney and urinary tract indicate the fact that sulpiride is eliminated through both bile and urine. After administrating a clinical dose of sulpiride, we found no difference in the accumulation in the brain compared to the baseline, which indicates that more concentration is required to alter the function of efflux transporters in the blood brain barrier such as P-glycoprotein. In contrast, we found a difference in the accumulation in the liver. One possible explanation is that the non-radiolabeled sulpiride might compete with [11C]sulpiride at the organic cation transporter (OCT1) in the liver and therefore hamper the uptake of [11C]sulpiride. Further studies with a larger sample size are required to investigate the time course of distribution of [11C]sulpiride. In addition, a focused study on the brain penetration of sulpiride is also needed.World Molecular Imaging Congress 201

Normal database of dopaminergic neurotransmission functions in living human brain measured by PET.

he central dopaminergic system is of interest in the pathophysiology of neuropsychiatric diseases. Both pre- and postsynaptic dopaminergic functions can be estimated by PET. However, the integrated database of both pre- and postsynaptic dopaminergic functions including receptors, transporter, and endogenous neurotransmitter synthesis has not been reported. In the present study, we have built the normal database of pre- and postsynaptic dopaminergic functions in the living human brain using PET.ＥＡＮＭ0

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

Changes in Dopamine Synthesis after Risperidone Administration in Patients with Schizophrenia: A Positron Emission Tomography Study with [11C]DOPA

The 8th NeuroReceptor Mapping Congress (NRM2010

Time Course of Dopamine Synthesis Capacity in the Striatum before and after Risperidone Treatment in Patients with Schizophrenia: A Positron Emission Tomography Study with [11C]DOPA

Brain\u2711 & BrainPET\u271

Inverse Correlation between Body Mass Index and Serotonin Transporter Binding in Human Brain: A [11C]DASB PET Study

Introduction: fThe regulation of eating behavior would be strongly related to body weight, and the serotonergic neural system has been suggested to be involved in the regulation of eating behavior [1]. The serotonin transporter (5-HTT), which can be measured by positron emission tomography (PET) in vivo, represents one of presynaptic functions in serotonergic neurotransmission. The aim of the present study was to investigate the relationship between 5-HTT in living human brain and body mass index (BMI).NeuroReceptor Mapping 200