Raclopride Positron Emission Tomography Study Research Articles

11 C]raclopride positron emission tomography study of dopamine-D2/3 receptor binding in patients with severe major depressive episodes before and after electroconvulsive therapy and compared to control subjects.

The aim of the study was to test: (i) if D2 /D3 binding in three functional subsections of striatum is different in patients with severe major depressive episodes than in controls; and (ii) if this difference is normalized after electroconvulsive therapy (ECT). Nine inpatients were examined with positron emission tomography (PET) and the radioligand [11 C]raclopride before and after an average of 8.4 ECT sessions. Treatment response was assessed using the Montgomery-Åsberg Depression Rating Scale. Nine age- and sex-matched controls were examined twice with PET and [11 C]raclopride. [11 C]raclopride binding was significantly lower in all three subsections of striatum in patients compared to controls (Cohen's dz , 1.14-1.68; P = 0.003-0.027). Montgomery-Åsberg Depression Ratings decreased significantly after ECT (P < 0.001; Cohen's dz , 2.9). ECT had no statistically significant effect on [11 C]raclopride binding, although post-ECT binding estimates were more similar to those obtained in controls in all subsections of striatum. Using PET and [11 C]raclopride, we found support for the notion that severe major depressive episodes are associated with significantly lower dopamine D2 /D3 binding in all three subsections of striatum compared to controls. We noted no significant effect on D2 /D3 binding in the patient group after response to ECT.

Dopamine, Opioids, and Positron Emission Tomography Imaging of the Human Brain: Contrasting Findings in Opioid Use Disorder and Healthy Volunteers

SEE CORRESPONDING ARTICLE ON PAGE 356 Striatal Dopamine Release in Response to Morphine: A [11C]Raclopride Positron Emission Tomography Study in Healthy MenBiological PsychiatryVol. 86Issue 5PreviewPreclinical and human positron emission tomography studies have produced inconsistent results regarding the effects of opioids on mesolimbic dopamine (DA). Here, we quantify striatal DA release (measured by [11C]raclopride displacement) in response to an intravenous infusion of morphine, and its relationship with morphine-induced subjective effects, in healthy, nondependent opioid–experienced participants. Full-Text PDF

Striatal Dopamine Release in Response to Morphine: A [11C]Raclopride Positron Emission Tomography Study in Healthy Men

BackgroundPreclinical and human positron emission tomography studies have produced inconsistent results regarding the effects of opioids on mesolimbic dopamine (DA). Here, we quantify striatal DA release (measured by [11C]raclopride displacement) in response to an intravenous infusion of morphine, and its relationship with morphine-induced subjective effects, in healthy, nondependent opioid–experienced participants. MethodsFifteen healthy male participants were initially included. Sessions were on separate days. On session 1, participants received intravenous morphine (10 mg/70 kg) in the clinic to ensure tolerability. Participants without adverse reactions (n = 10) then received intravenous morphine and placebo (saline) sessions, in counterbalanced order, while undergoing [11C]raclopride positron emission tomography scans. Subjective and physiological responses were assessed. Region-of-interest and voxelwise image analyses were used to assess changes in [11C]raclopride nondisplaceable binding potential. ResultsMorphine produced marked subjective and physiological effects and induced a significant decrease in [11C]raclopride nondisplaceable binding potential, particularly in the nucleus accumbens and globus pallidus, where the change in [11C]raclopride nondisplaceable binding potential was approximately 9%. However, the subjective effects of morphine did not show a simple pattern of correlation with DA release. ConclusionsThis is, to our knowledge, the first study providing in vivo human evidence that DA transmission in the ventral striatum is affected by morphine. Further studies are required to fully delineate the DA contribution to the reinforcing effects of opioids.

The relationship between dopamine receptor blockade and cognitive performance in schizophrenia: a [11C]-raclopride PET study with aripiprazole

Aripiprazole’s effects on cognitive function in patients with schizophrenia are unclear because of the difficulty in disentangling specific effects on cognitive function from secondary effects due to the improvement in other schizophrenic symptoms. One approach to address this is to use an intermediate biomarker to investigate the relationship between the drug’s effect on the brain and change in cognitive function. This study aims to investigate aripiprazole’s effect on working memory by determining the correlation between dopamine D2/3 (D2/3) receptor occupancy and working memory of patients with schizophrenia. Seven patients with schizophrenia participated in the study. Serial positron emission tomography (PET) scans with [11C]raclopride were conducted at 2, 26, and 74 h after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [11C]raclopride PET scan. The mean (±SD) D2/3 receptor occupancies were 66.9 ± 6.7% at 2 h, 65.0 ± 8.6% at 26, and 57.7 ± 11.2% at 74 h after administering aripiprazole. Compared with performance on the zero-back condition, performance in memory-loaded conditions (one-, two-, and three-back conditions) was significantly related to D2/3 receptor occupancy by aripiprazole (error rate: ß = −2.236, t = −6.631, df = 53.947, and p = 0.001; reaction time: ß = −9.567, t = −2.808, df = 29.967, and p = 0.009). Although the sample size was relatively small, these results suggest that aripiprazole as a dopamine-partial agonist could improve cognitive function in patients with schizophrenia.

The dopamine stabilizer (-)-OSU6162 occupies a subpopulation of striatal dopamine D2/D3 receptors: an [(11)C]raclopride PET study in healthy human subjects.

(-)-OSU6162 is a dopamine stabilizer that can counteract both hyperdopaminergic and hypodopaminergic states. In this study, D2/D3 receptor occupancy of (-)-OSU6162 in the human brain was investigated using positron emission tomography (PET). Twelve male healthy volunteers underwent [(11)C]raclopride PET scanning before and 1 h after a single oral dose of (-)-OSU6162 (15-90 mg). Blood samples for determination of (-)-OSU6162 and prolactin plasma levels were collected at Tmax. Parametric images of [(11)C]raclopride binding potential relative to nondisplaceable tissue (cerebellar grey matter) uptake (BPND) at baseline and after (-)-OSU6162 administration were generated using the simplified reference tissue model. MRI-based regions of interest were defined for the striatum, composed of caudate nucleus and putamen, and projected onto the co-registered parametric [(11)C]raclopride BPND image. Furthermore, three striatal subregions, ie, anterior dorsal caudate, anterior dorsal putamen, and ventral striatum, were defined manually and additionally analyzed. Plasma concentrations of (-)-OSU6162, ranging from 0.01 to 0.9 μM, showed a linear relationship with prolactin levels, reflecting blockade of pituitary D2 receptors. A concentration-dependent increase in striatal D2/D3 receptor occupancy was observed, reaching a value of about 20% at an (-)-OSU6162 plasma level of 0.2 μM, and which for higher concentrations leveled off to a maximal occupancy of about 40%. Findings were similar in the striatal subregions. The present data corroborate the notion that (-)-OSU6162 binds preferentially to a subpopulation of D2/D3 receptors, possibly predominantly extrasynaptic, and this may form the basis for the dopamine-stabilizing properties of (-)-OSU6162.

Evaluation of analytical reconstruction with a new gap-filling method in comparison to iterative reconstruction in [ $$_{ }^{11}\mathrm C$$ 11 C ]-raclopride PET studies

The aim of the study was (1) to evaluate the reconstruction strategies with dynamic [¹¹C]-raclopride human positron emission tomography (PET) studies acquired from ECAT high-resolution research tomograph (HRRT) scanner and (2) to justify for the selected gap-filling method for analytical reconstruction with simulated phantom data. A new transradial bicubic interpolation method has been implemented to enable faster analytical 3D-reprojection (3DRP) reconstructions for the ECAT HRRT PET scanner data. The transradial bicubic interpolation method was compared to the other gap-filling methods visually and quantitatively using the numerical Shepp-Logan phantom. The performance of the analytical 3DRP reconstruction method with this new gap-filling method was evaluated in comparison with the iterative statistical methods: ordinary Poisson ordered subsets expectation maximization (OPOSEM) and resolution modeled OPOSEM methods. The image reconstruction strategies were evaluated using human data at different count statistics and consequently at different noise levels. In the assessments, 14 [¹¹C]-raclopride dynamic PET studies (test-retest studies of 7 healthy subjects) acquired from the HRRT PET scanner were used. Besides the visual comparisons of the methods, we performed regional quantitative evaluations over the cerebellum, caudate and putamen structures. We compared the regional time-activity curves (TACs), areas under the TACs and binding potential (BPND) values. The results showed that the new gap-filling method preserves the linearity of the 3DRP method. Results with the 3DRP after gap-filling method exhibited hardly any dependency on the count statistics (noise levels) in the sinograms while we observed changes in the quantitative results with the EM-based methods for different noise contamination in the data. With this study, we showed that 3DRP with transradial bicubic gap-filling method is feasible for the reconstruction of high-resolution PET data with missing sinogram bins. The calculated intraclass correlation coefficient (ICC) values were similar for all tested methods and validated the test-retest study. The gap-filling and 3DRP method can be used for quantitative PET studies in which high temporal information is crucial and can serve as a reference method for comparison studies of the other reconstruction methods.

Population Pharmacokinetics of JNJ-37822681, a Selective Fast-Dissociating Dopamine D2-Receptor Antagonist, in Healthy Subjects and Subjects with Schizophrenia and Dose Selection Based on Simulated D2-Receptor Occupancy

JNJ-37822681 is a selective, fast-dissociating dopamine D2-receptor antagonist currently in development as a candidate antipsychotic. The aim of the analyses was to develop a population pharmacokinetic model to describe the pharmacokinetics of JNJ-37822681 in healthy subjects and patients with schizophrenia and to identify covariates of interest. The model was then used to simulate D2-receptor occupancy in support of dose selection for subsequent studies. Data were obtained from 378 subjects enrolled in three phase I and two phase II studies. Nonlinear mixed effects modeling of pooled data was conducted using NONMEM(®) to estimate population pharmacokinetic parameters and the effect of covariates on these parameters. The model was evaluated on a subset of data that was not used for model building and was subsequently used to simulate steady-state exposure for each subject in the phase IIb study. Striatal D2-receptor occupancy was predicted using simulated exposure combined with pharmacodynamic parameters from a sigmoid maximum effect model established from previous [(11)C]raclopride positron emission tomography studies. A two-compartment disposition model with zero-order input in a depot compartment followed by first-order absorption into and first-order elimination from the central compartment combined with a transit compartment provided the best fit to the data. Significant covariates were sex and bioavailability on apparent clearance and food intake on the absorption rate constant. Clearance was 11 % higher in females compared with males. The model passed external evaluation. The estimated pharmacokinetic parameters for the phase IIb study were similar to those observed in the phase IIa study. D2-receptor occupancy was predicted to be in the 65-80 % range at 10 mg twice daily and partially or fully reaching the 80 % threshold at doses of 20 and 30 mg twice daily. The population pharmacokinetic model of JNJ-37822681 successfully described the pharmacokinetics of JNJ-37822681 and allowed the reliable determination of individual exposure parameters in a phase IIb study. It was concluded that 5 or 7.5 mg twice daily would likely be minimal- or no-effect doses, whereas 10 mg twice daily was expected to provide an optimal balance of efficacy and tolerability.

Volunteerism and self-selection bias in human positron emission tomography neuroimaging research

Scientists have known for decades that persons who volunteer for behavioral research may be different from those who decline participation and that characteristics differentiating volunteers from non-volunteers may vary depending on the nature of the research. There is evidence that volunteer self-selection can impact representativeness of samples in studies involving physically or psychologically stressful procedures, such as electric shocks, sensory isolation, or drug effects. However, the degree to which self-selection influences sample characteristics in "stressful" studies involving positron emission tomography (PET) has not been evaluated. Since estimation of population parameters, robustness of findings, and validity of inferred relationships can all be impacted by volunteer bias, it is important to determine if self-selection may act as an unrecognized confound in such studies. In the present investigation, we obtained baseline data on 114 (56M, 58F) subjects who participated in a study involving completion of several self-report questionnaires and behavioral performance tasks. Participants were later given the opportunity to enroll in an [11C]raclopride PET study involving intravenous amphetamine (AMPH) administration. Demographic characteristics, personality traits, and task performance of subjects who consented to the latter study were compared with those who declined participation. Findings showed that the principal personality trait that distinguished the two groups was sensation-seeking; volunteers scored significantly higher on this dimension than non-volunteers. Males were more likely to volunteer than females. However, results of mediation analysis suggested that the relationship between gender and volunteer status was mediated by greater sensation-seeking traits in the males. Implications of these findings are discussed.

In vivo quantification of striatal dopamine D2receptor occupancy by JNJ-37822681 using [11C]raclopride and positron emission tomography

JNJ-37822681 is a novel, fast-dissociating dopamine D(2) receptor antagonist, currently in development as an antipsychotic drug candidate. A previous first-in-human study demonstrated mild central nervous system effects of JNJ-37822681 in healthy male volunteers. Significant but transient serum prolactin elevations were demonstrated, whereas other neurophysiological effects were relatively small. To investigate striatal dopamine D(2) receptor occupancy by variable single doses of JNJ-37822681, an open-label [(11)C]raclopride positron emission tomography study was performed in 12 healthy male volunteers, using the simplified reference tissue model with cerebellum as reference tissue. Oral administration of JNJ-37822681 resulted in dose-dependent dopamine D(2) receptor occupancy. Receptor occupancy increased from 9-19% at 2 mg doses to 60-74% at 20 mg doses of JNJ-37822681. Therefore, single oral doses of JNJ-37822681 can produce occupancy levels that are generally associated with clinical efficacy for registered antipsychotic drugs.

Imaging human reward processing with positron emission tomography and functional magnetic resonance imaging

Functional neuroimaging (fMRI) studies show activation in mesolimbic circuitry in tasks involving reward processing, like the Monetary Incentive Delay Task (MIDT). In voltammetry studies in animals, mesolimbic dopamine release is associated with reward salience. This study examined the relationship between fMRI activation and magnitude of dopamine release measured with Positron emission tomography study (PET) in the same subjects using MIDT in both modalities to test if fMRI activation is related to dopamine release. Eighteen healthy subjects were scanned with [¹¹C]raclopride PET at baseline and after MIDT. Binding potential (BP(ND)) was derived by equilibrium analysis in striatal subregions and percent change across conditions (∆BP(ND)) was measured. Blood oxygen level dependence (BOLD) signal changes with MIDT were measured during fMRI using voxelwise analysis and ROI analysis and correlated with ∆BP(ND). ∆BP(ND) was not significant in the ventral striatum (VST) but reached significance in the posterior caudate. The fMRI BOLD activation was highest in VST. No significant associations between ∆BP(ND) and change in fMRI BOLD were observed with VST using ROI analysis. Voxelwise analysis showed positive correlation between BOLD activation in anticipation of the highest reward and ∆BP(ND) in VST and precommissural putamen. Our study indicates that endogenous dopamine release in VST is of small magnitude and is related to BOLD signal change during performance of the MIDT in only a few voxels when rewarding and nonrewarding conditions are interspersed. The lack of correlation at the ROI level may be due to the small magnitude of release or to the particular dependence of BOLD on glutamatergic signaling.

Analysis of Variance in Neuroreceptor Ligand Imaging Studies

Radioligand positron emission tomography (PET) with dual scan paradigms can provide valuable insight into changes in synaptic neurotransmitter concentration due to experimental manipulation. The residual t-test has been utilized to improve the sensitivity of the t-test in PET studies. However, no further development of statistical tests using residuals has been proposed so far to be applied in cases when there are more than two conditions. Here, we propose the residual f-test, a one-way analysis of variance (ANOVA), and examine its feasibility using simulated [11C]raclopride PET data. We also re-visit data from our previously published [11C]raclopride PET study, in which 10 individuals underwent three PET scans under different conditions. We found that the residual f-test is superior in terms of sensitivity than the conventional f-test while still controlling for type 1 error. The test will therefore allow us to reliably test hypotheses in the smaller sample sizes often used in explorative PET studies.

Combined FDG and raclopride PET study in a case of ALS with the R521C FUS gene mutation

Mutations in the fused in sarcoma (FUS) gene have been associated with familial and apparently sporadic cases of amyotrophic lateral sclerosis (ALS) [8]. This study evaluated the cerebral glucose metabolism and postsynaptic dopaminergic function in the striatum using positron emission tomography (PET) in an ALS patient with a FUS gene mutation. The patient was a 25 year-old Japanese female who presented with difficulty in flexing her neck in the supine position. She developed difficulty in raising her arms 2 months later followed by swallowing difficulties. Her mother had been diagnosed with ALS at age 29 years and died 10 years later. An examination 10 months after the onset of the disease revealed symmetric weakness and atrophy of the proximal muscles including the upper limbs and neck flex muscles. There was neither atrophy nor fasciculation in her tongue. The lower limb reflexes were brisk, but she had absence of upper limbs reflexes and flexor planter responses. There was no sensory disturbance, extrapyramidal signs or cerebellar signs. Neuropsychological assessments revealed that her Mini-Mental State Examination score was 30 and her Frontal Assessment Battery score was 17, which was normal in comparison to age-matched normal subjects. Her verbal, performance, and full-scale scores of Wechsler Adult Intelligence Scale were, 86, 114, and 94, respectively. She achieved six sorting categories in the Nelson modification of the Wisconsin card sorting test. Magnetic resonance imaging (MRI) of the brain was normal (Fig. 1a). A genetic analysis revealed that she had a heterozygous R521C mutation in the FUS gene. Functional brain imaging was performed using [F]-fluorodeoxyglucose (FDG)-PET to measure the cerebral metabolic rate of glucose (CMRGlc) and [C] raclopride-PET for investigation of post synaptic dopaminergic neuronal activity. In addition the semi-quantitative regions of interest (ROIs)/cerebellum ratio was analyzed as described previously [6]. Analyses of the PET images showed that CMRGlc did not apparently decrease in either the cerebral cortices or basal ganglia (Table 1), while [C] raclopride binding decreased in the putamen (Table 1; Fig. 1b). Pathological studies of ALS patients with an R521C mutation showed cytoplasmic basophilic inclusions containing FUS to be distributed in the neurons in widespread brain areas including the frontotemporal cortex, the striatum, the substantia nigra, thalamus and cerebellum in addition to the upper and lower motor neurons [8, 9, 11]. Four ALS patients with an R521C mutation and one with a G156E mutation have been reported to present with parkinsonism or frontotemporal dementia (FTD) [1, 12, 13]. There have so far been few reports on functional brain imaging in ALS patients with FUS mutations. A SPECT study shows a decrease in cerebral blood flow in the frontotemporal cortex and striatum in an ALS patient with an R521C mutation who presented neither dementia nor parkinsonism [11]. The findings of a raclopride PET study in this patient showed postsynaptic dopaminergic dysfunction in the putamen, which may thus suggest that the S. Kono (&) T. Terada M. Suzuki H. Miyajima First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1, Handayama, Hamamatsu 431-3192, Japan e-mail: satokono@hama-med.ac.jp

The use of healthy volunteers instead of patients to inform drug dosing studies: a [11C]raclopride PET study

Receptor occupancy study has been performed to evaluate pharmacokinetic profiles in new antipsychotic drug development. While these findings highlight the value of positron emission tomography (PET) for dose-finding study, what is unclear is if it is necessary to conduct these studies in patients with schizophrenia or whether studies in healthy volunteers are adequate. To determine if it is necessary to conduct dopamine receptor occupancy studies in patients with schizophrenia or whether studies in healthy volunteers are adequate for dose-finding study, we compared the concentration-occupancy relationship in terms of EC(50) between patients and healthy volunteers. Ten healthy volunteers and eight patients with schizophrenia participated in the study. We measured dopamine receptor occupancy using [(11)C]raclopride PET and plasma concentration of YKP1358, a novel antipsychotic drug under clinical development, at a number of time points after the administration of YKP1358. Pharmacokinetic data including area under the plasma concentration versus time curve, elimination half-life, maximum observed plasma concentration, and the time to reach the maximum observed plasma concentration were obtained. We explored the relationship between plasma concentration and dopamine D(2) receptor occupancy using E (max) model and calculated EC(50). The elimination half-life was longer in healthy volunteers than in patients. Other pharmacokinetic parameters were not significantly different between two groups. The EC(50) was 7.6 ng/ml (95% confidence interval (CI) 6.2-9.0) in healthy volunteers and 8.6 (95% CI 7.4-9.9) in patients. The antipsychotic concentration-occupancy relationship in patients can be estimated from the EC(50) data of healthy volunteers.

Acute effect of the anti-addiction drug bupropion on extracellular dopamine concentrations in the human striatum: An [11C]raclopride PET study

Bupropion is an effective medication in treating addiction and is widely used as an aid to smoking cessation. Bupropion inhibits striatal dopamine reuptake via dopamine transporter blockade, but it is unknown whether this leads to increased extracellular dopamine levels at clinical doses in man. The effects of bupropion on extracellular dopamine levels in the striatum were investigated using [11C]raclopride positron emission tomography (PET) imaging in rats administered saline, 11 or 25 mg/kg bupropion i.p. and in healthy human volunteers administered either placebo or 150 mg bupropion (Zyban® Sustained-Release). A cognitive task was used to stimulate dopamine release in the human study. In rats, bupropion significantly decreased [11C]raclopride specific binding in the striatum, consistent with increases in extracellular dopamine concentrations. In man, no significant decreases in striatal [11C]raclopride specific binding were observed. Levels of dopamine transporter occupancy in the rat at 11 and 25 mg/kg bupropion i.p. were higher than predicted to occur in man at the dose used. Thus, these data indicate that, at the low levels of dopamine transporter occupancy achieved in man at clinical doses, bupropion does not increase extracellular dopamine levels. These findings have important implications for understanding the mechanism of action underlying bupropions' therapeutic efficacy and for the development of novel treatments for addiction and depression.

Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study

Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson's disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson's disease patients with impulse control disorders. We describe results of a [(11)C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson's disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson's disease patients may provide a model into the pathophysiology of this disorder.

Modulation of striatal dopamine release by 5-HT2A and 5-HT2C receptor antagonists: [11C]raclopride PET studies in the rat

Antagonism at serotonin 5-HT2A and 5-HT2C receptors modulates cortical and striatal dopamine (DA) release and may underlie some aspects of the clinical efficacy of 'atypical' antipsychotic compounds. However, it is not known whether 5-HT2A/2C receptor-mediated modulation of DA release can be quantified with non-invasive neurochemical imaging, as would be required for investigation of these processes in man. The objective of the study was to perform a feasibility study in the rat in order to determine whether 5-HT2A/2C modulation of DA release can be observed using positron emission tomography (PET) imaging. Rats were administered with either vehicle, a combined 5-HT2A/2C antagonist (ketanserin, 3 mg/kg i.p.), or the more selective 5-HT2C antagonist SB 206,553 (10 mg/kg i.p.) 30 min before administration of the PET DA D2 receptor radiotracer [11C]raclopride ( approximately 11 MBq) and were then scanned for 60 min using a quad-high-density avalanche chamber small animal tomograph. Using the same technique, modulation of amphetamine (4 mg/kg)-induced decreases in [11C]raclopride binding by 5-HT2A antagonism (SR 46349B, 0.2 mg/kg i.v.) was also determined. Consistent with the increase in DA release measured by others using microdialysis, 5-HT2C antagonism markedly reduced striatal [11C]raclopride binding (p < 0.003), while amphetamine-induced reductions in striatal [11C]raclopride binding (p < 0.001) were attenuated by 5-HT2A antagonist administration (p = 0.04). These results inform the feasibility of monitoring 5-HT2A/2C receptor-mediated modulation of DA systems in man using PET and, more generally, demonstrate that D2 radiotracer PET imaging may be used to monitor the efficacy of new DA modulators in attenuating stimulated DA release.

An extended simplified reference tissue model for the quantification of dynamic PET with amphetamine challenge

Background: Equilibrium analysis to quantify dynamic positron emission tomography (PET) with bolus followed by continuous tracer infusion and acute amphetamine challenge assumes that all tissue kinetics attain steady states during pre- and post-challenge phases. Violations of this assumption may result in unreliable estimation of the amphetamine-induced percent change in the binding potential (ΔBP%). Method: We derived an extended simplified reference tissue model (ESRTM) for modeling tracer kinetics in the pre- and post-challenge phases. Ninety-minute [ 11C]raclopride PET studies with bolus injection followed by continuous tracer infusion were performed on 18 monkeys and 2 baboons. Forty minutes after the bolus injection, a single acute intravenous amphetamine administration was given of 2.0 mg/kg to monkeys and of 0.05, 0.1, 0.5, and 1.5 mg/kg to baboons. Computer simulations further evaluated and characterized the ESRTM. Results: In monkey studies, the ΔBP% estimated by the ESRTM was 32 ± 11, whereas, the ΔBP% obtained using the equilibrium methods was 32% to 81% lower. In baboon studies, the ΔBP% values estimated with the ESRTM showed a linear relationship between the ΔBP% and the natural logarithm of amphetamine dose ( R 2 = 0.96), where the ΔBP% = 10.67Ln(dose) + 33.79 (0.05 ≤ dose in mg/kg ≤ 1.5). At 1.5 mg/kg amphetamine, the ΔBP% estimates from equilibrium methods were 18% to 40% lower than those estimated by the ESRTM. Results showed that the nonsteady state of tracer kinetics produced an underestimation of the ΔBP% from the equilibrium analysis. The accuracy of the ΔBP% estimates from the equilibrium analysis was significantly improved by the ESRTM. The ΔBP% estimated by the ESRTM in the study was consistent with that from previous [ 11C]raclopride PET with amphetamine challenge. Conclusion: In conclusion, the ESRTM is a robust kinetic modeling approach and is proposed for the quantification of dynamic PET with acute amphetamine stimulation.

Is psychological stress in man associated with increased striatal dopamine levels?: A [11C]raclopride PET study

In rodents, stress causes rapid increases in extracellular dopamine (DA) concentration in cortical and subcortical brain regions, and positron emission tomography (PET) studies in healthy humans have suggested psychological and pharmacological stressors are associated with increased DA concentration in the striatum. In this experiment, we measured the effect of stress, induced by difficult mental arithmetic, on [11C]raclopride binding in order to index striatal DA release. To refine measurements and facilitate interpretation of results a combination of head movement correction, a carefully designed control condition and bolus infusion administration of [11C]raclopride were employed. Fourteen healthy volunteers were scanned using [11C]raclopride PET. Physiological and psychological responses to the task were consistent with a stress response with changes in cardiovascular, hormonal, and subjective state indices. No change of ventral or dorsal striatal [11C]raclopride binding was found in the stress condition compared to nonstress. This negative result suggests that significant DA release does not occur in the striatum in healthy humans after mild, psychological stress.

Effect of sensory stimulus on striatal dopamine release in humans and cats: a [ 11C]raclopride PET study

Background : Sensory stimulation of the forelimb extremities constitutes a well-established experimental model that has consistently shown to activate dopamine (DA) neurotransmission in the mammals’ forebrain. Objectives: To visualize in vivo this modification of striatal DA release in healthy human volunteers using Positron Emission Tomography (PET) and [ 11C]raclopride. Experiments in humans were paralled by experiments in anesthetized cats. Changes in endogenous DA release were assessed through its competition with [ 11C]raclopride binding (BP raclo), a radioligand probing DA D2-receptors. Results: In humans no significant difference of BP raclo in caudate (with sensory stimulation: 2.0 ± 0.3 versus without sensory stimulation: 2.2 ± 0.3; P = 0.3) or putamen (2.6 ± 0.3 versus 2.6 ± 0.2; P = 0.9) ipsilateral to the stimulus was disclosed as a result of sensory stimulation. Similarly, no change of BP raclo was observed contralaterally to the stimulation in the caudate nucleus (with sensory stimulation: 2.0 ± 0.4 versus without sensory stimulation: 2.1 ± 0.2; P = 0.5) and the putamen (2.5 ± 0.4 versus 2.6 ± 0.2; P = 0.4). In cats the same results were obtained in the ipsilateral to stimulation striatum (with sensory stimulation: 2.5 ± 0.03 versus without sensory stimulation: 2.4 ± 0.05; P = 0.7). No change was also observed contralaterally to the stimulation (2.4 ± 0.04 versus 2.5 ± 0.06; P = 0.6). The [ 11C]raclopride binding remained unchanged by sensory stimuli in both humans and cats. Conclusion: This suggests that the DA release induced by sensory stimulus is mostly extrasynaptic whereas the synaptic DA release is probably small, which fits well with the absence of [ 11C]raclopride displacement. The mechanism of this extrasynaptic DA release could be related to a local action of glutamate on dopaminergic terminals via a thalamo-cortico-striatal loop. Present results also underline homology between cat and human responses to sensory stimuli and validate the use of cat brain to find physiological concepts in humans.

Dopamine transmission in the human striatum during monetary reward tasks.

Previous studies have demonstrated the ability of the [11C]raclopride positron emission tomography (PET) technique to measure behaviorally induced changes in endogenous dopamine transmission in humans. However, these studies have lacked well matched sensorimotor control conditions, making it difficult to know what sensory, cognitive, or motor features contributed to changes in dopaminergic activity. Here we report on [11C]raclopride PET studies in which healthy humans performed card selection tasks for monetary rewards. During separate scans, subjects completed a variable ratio (VR) reward schedule with a 25% reward rate in which they did not know the outcome of their responses in advance, a fixed ratio (FR) 25% reward schedule in which outcomes were fully predictable, and a sensorimotor control (SC) condition involving similar sensory and motor demands but no rewards. Relative to the SC condition, the FR schedule produced only modest increases in dopamine transmission and no decreases relative to the SC condition. In contrast, the VR schedule produced significant increases in dopamine transmission in the left medial caudate nucleus while simultaneously producing significant decreases in other areas of the caudate and putamen. These data indicate: (1) the feasibility of measuring alterations in dopamine transmission even after controlling for sensorimotor features and (2) the complex and regionally specific influence of VR schedules on dopamine transmission. The implications of these results are discussed in relation to conflicting models of dopaminergic functioning arising from studies using electrophysiological and microdialysis techniques in animals.