Raclopride Positron Emission Tomography Research Articles

Importance of Low-Range CAG Expansion and CAA Interruption in SCA2 Parkinsonism

To examine the presence of an ATXN2 mutation in patients with parkinsonism in the Korean population and to find the difference in the ATXN2 mutation between ataxic and parkinsonian phenotypes. Survey. Seoul National University Hospital (a referral center). Patients Patients with Parkinson disease (PD) (n = 468) and the Parkinson variant of multiple system atrophy (MSA-P) (n = 135) who were seen at our Department of Neurology during the past 3 years. CAG expansion in spinocerebellar ataxia type 2 (SCA2) alleles was assessed by polymerase chain reaction amplification and fragment analysis, and its size and interruption were verified by cloning and sequencing. SCA2 was tested also in the family members of the probands. Striatal dopamine transporter (DAT) and D(2) receptor status were evaluated in the probands and their SCA2-positive family members using iodine I 123 [(123)I]-radiolabeled fluoropropyl (FP) 2-carbomethoxy-3-(4-iodophenyl) tropane (CIT) with single-photon emission computed tomography (SPECT) and carbon C 11 [(11)C]-radiolabeled raclopride positron emission tomography (PET). We found 3 patients with apparently sporadic disease with expanded CAG repeats in the ATXN2 locus. Two patients had a PD phenotype. The third patient showed an MSA-P phenotype. The CAG repeats in the ATXN2 locus of the patients were 35/22, 34/22, and 32/22, respectively (range in normal population, 19-27). The size of repeats was lower than the CAG repeats (38-51) in ataxic SCA2 in our population. The sequence of expanded CAG repeats was interrupted by CAA as (CAG)(n)(CAA)(CAG)(8) in all the patients. DNA analyses in 2 families showed 2 asymptomatic carriers in each family. In the patient with the PD phenotype, striatal DAT loss was more severe in the putamen than the caudate, and [(11)C]raclopride PET showed an increased relative putamen-caudate binding ratio. The patient with the MSA-P phenotype had severe DAT loss throughout the striatum. Two of 3 asymptomatic carriers had striatal DAT loss. This study demonstrates that SCA2 is one of the genetic causes of PD and MSA-P. All 3 patients had apparently sporadic disease, emphasizing the need to screen even in patients with nonfamilial disease. CAG repeats were in the low expansion range and interrupted by CAA in all patients in the low-range expansion. Therefore, accurate determination of CAG expansion and ATXN2 sequencing are warranted. [(123)I]FP-CIT SPECT and [(11)C]raclopride PET provide a useful way to evaluate the degree of nigrostriatal dopaminergic damage in SCA2-related parkinsonism and gene carriers.

D2 Receptor Occupancy of Olanzapine Pamoate Depot Using Positron Emission Tomography: An Open-label Study in Patients with Schizophrenia

A long-acting depot formulation of olanzapine that sustains plasma olanzapine concentrations for over a month after a single injection is currently under development. This multicenter, open-label study explored D(2) receptor occupancy of a fixed dose of olanzapine pamoate (OP) depot given every 4 weeks. Patients (nine male, five female) with schizophrenia or schizoaffective disorder previously stabilized on oral olanzapine were switched to OP depot 300 mg by intramuscular injection every 4 weeks for 6 months. No visitwise within-group significant changes were found in Brief Psychiatric Rating Scale Total or Clinical Global Impressions-Severity of Illness scores, although seven patients received oral olanzapine supplementation during the first four injection cycles. To minimize impact on D(2) occupancy, positron emission tomography (PET) scans were not completed during injection cycles that required supplemental oral olanzapine. Two patients reported transient injection site adverse events, which did not result in discontinuation. The most frequently reported treatment-emergent adverse events were insomnia, aggravated psychosis, and anxiety. Mean striatal D(2) receptor occupancy, as measured by [(11)C]-raclopride PET, was 69% on oral olanzapine (5-20 mg/day) and 50% (trough) on OP depot at steady state. Following an initial decline, occupancy returned to 84% of baseline oral olanzapine occupancy after six injections. Over the study period, D(2) receptor occupancy and plasma olanzapine concentrations were significantly correlated (r=0.76, P</=0.001). OP depot resulted in mean D(2) receptor occupancy of approximately 60% or higher at the end of the 6-month study period, a level consistent with antipsychotic efficacy and found during treatment with oral olanzapine. However, supplemental oral olanzapine or another dosing strategy may be necessary to maintain adequate therapeutic response during the first few injection cycles.

Levodopa increases memory encoding and dopamine release in the striatum in the elderly

Normal aging is associated with a decrease in dopaminergic function and a reduced ability to form new motor memories with training. This study examined the link between both phenomena. We hypothesized that levodopa would (a) ameliorate aging-dependent deficits in motor memory formation, and (b) increase dopamine availability at the dopamine type 2-like (D2) receptor during training in task-relevant brain structures. The effects of training plus levodopa (100 mg, plus 25 mg carbidopa) on motor memory formation and striatal dopamine availability were measured with [ 11C]raclopride (RAC) positron emission tomography (PET). We found that levodopa did not alter RAC-binding potential at rest but it enhanced training effects on motor memory formation as well as dopamine release in the dorsal caudate nucleus. Motor memory formation during training correlated with the increase of dopamine release in the caudate nucleus. These results demonstrate that levodopa may ameliorate dopamine deficiencies in the elderly by replenishing dopaminergic presynaptic stores, actively engaged in phasic dopamine release during motor training.

Striatal Vs Extrastriatal Dopamine D2 Receptors in Antipsychotic Response—A Double-Blind PET Study in Schizophrenia

Blockade of dopamine D2 receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D2 receptors may be more critical to antipsychotic response than the striatal dopamine D2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D2 occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D2 occupancy levels across subjects. Clinical response, side effects, striatal ([11C]-raclopride-positron emission tomography (PET)), and extrastriatal ([11C]-FLB 457-PET) D2 receptors were evaluated after treatment. The measured D2 occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D2 occupancy predicted response in positive psychotic symptoms (r=0.62, p=0.01), but not for negative symptoms (r=0.2, p=0.5). Extrastriatal D2 occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.

Spinocerebellar ataxia type 1, 2, and 3 and restless legs syndrome: Striatal dopamine D2 receptor status investigated by [11C]raclopride positron emission tomography

In spinocerebellar ataxias (SCAs), up to 30% of patients complain of restless legs syndrome (RLS). In primary RLS, a putative role of the dopaminergic system has been postulated. To assess dopaminergic function in SCA1, 2, and 3, dopamine D(2) receptor binding potential (BP) was assessed by [(11)C]raclopride positron emission tomography in 10 SCA patients, 4 of whom suffered from RLS as demonstrated by polysomnography. BP was compared to 9 age-matched control subjects. In 2 SCA patients, striatal BP was clearly reduced (<2 SD below the mean of controls). However, there were no significant group differences between SCA and controls, largely owing to a significantly higher variance of striatal BP in SCA. BP was negatively correlated with disease duration. The fit suggests an increased BP in early stages, followed by a moderate decline in all quantified regions (caudate, dorsal putamen, ventral striatum) presumably reflecting a progressive loss of D(2) receptors. RLS in SCA was not accompanied by a significant reduction of D(2) receptor availability in the striatum. This missing correlation may point to an extrastriatal origin of RLS.

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.

Effects of repetitive transcranial magnetic stimulation on [ 11C]raclopride binding and cognitive function in patients with depression

Background Several studies have demonstrated that repetitive transcranial magnetic stimulation (rTMS) elicits moderate antidepressant effects. Several previous studies suggested that the dopaminergic system might be related to this therapeutic action of rTMS. We attempted to determine the effects of chronic rTMS on central dopaminergic function in depression using positron emission tomography (PET) with [ 11C]raclopride. Methods Nine patients with depression were treated with 10 daily sessions of rTMS (10 Hz, 5 s train, 20 trains at 100% motor threshold per session) over the left dorsolateral prefrontal cortex (DLPFC). Each patient underwent two [ 11C]raclopride PET scans and neuropsychological tests — before rTMS and 1 day after rTMS. Results In five patients, the Hamilton Rating Scale for Depression (HRSD) significantly decreased. Patients showed significant improvement in verbal memory following rTMS. There were no changes in [ 11C]raclopride binding in the caudate nucleus and putamen after rTMS treatment. Limitations Our sample size was limited, and our study was an open trial lacking sham-treated controls. Conclusion This study suggests that rTMS may be effective for the treatment of depression and also may improve verbal memory function. We observed no changes in [ 11C]raclopride binding, suggesting that there was no measurable increase in the release of dopamine at the second PET scan. Several animal studies and healthy human studies have indicated that dopamine can be released soon after acute rTMS. Our results suggest that release of striatal dopamine induced by rTMS may be only transient, or that dopamine release may be attenuated following chronic rTMS.

Upregulation of dopamine D2 receptors in dopaminergic drug‐naive patients with parkin gene mutations

Medicated patients with Parkinsonism and parkin gene mutations have been reported to show a significant decrease in striatal dopamine D2 receptors (D2R) in comparison to medicated idiopathic Parkinson's disease (IPD) patients with similar age and disease severity. The aim of this study was to verify whether the genetic defect per se is responsible for this decrease. We have studied with [11C]raclopride (RAC) positron emission tomography (PET) in a group of 14 sporadic patients with parkin-linked Parkinsonism, 6 of whom had never received levodopa or dopamine agonists. The remaining 8 patients had been treated with levodopa for at least 5 years. Presynaptic striatal [18F]dopa storage was not significantly different between these two groups of patients. In untreated parkin-positive patients, significant putaminal increases in RAC-binding potential (BP) were found in comparison to an age-matched healthy control group by using a classical region of interest approach and statistical parametric mapping. In contrast, levodopa-treated parkin-positive patients showed significant decreases in RAC-BP in the caudate and putamen when compared to an age-matched healthy control group. The RAC PET findings revealed that striatal D2R upregulation occurs in dopaminergic drug-naive parkin-positive patients, in a similar fashion to the upregulation reported in drug-naive IPD. D2R downregulation observed in medicated parkin-positive patients, therefore, is not caused primarily by the genetic defect itself. Parkin-positive patients appear to have a greater susceptibility to the exposure to dopaminergic medication than IPD patients, which in turn might be an indirect effect of their genetic mutation.

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.

A PET Study Evaluating Dopamine D2 Receptor Occupancy for Long-Acting Injectable Risperidone

Long-acting injectable risperidone represents the first clinically available depot atypical antipsychotic. The present study used positron emission tomography (PET) to evaluate its dopamine D(2) binding profile at doses of 25, 50, or 75 mg administered every 2 weeks. After achieving stabilization with one of the doses, nine patients with a diagnosis of schizophrenia or schizoaffective disorder underwent [(11)C]raclopride PET to measure D(2) occupancy. Participants were scanned twice during the 2-week injection interval: within 3 days after injection (postinjection) and within 5 days before the next injection (preinjection). At the same time, plasma was collected for measurements of risperidone plus 9-hydroxyrisperidone. Mean post- and preinjection D(2) occupancy levels for the 25-, 50-, and 75-mg doses were 71.0% and 54.0%, 74.4% and 65.4%, and 81.5% and 75.0%, respectively. There was a significant correlation between dose and plasma concentrations of risperidone plus 9-hydroxyrisperidone, and the estimated plasma concentration associated with 50% D(2) occupancy (ED(50)) was 11.06 ng/ml. Prolactin levels were not correlated with drug levels or D(2) occupancy. All three doses of injectable risperidone showed peak D(2) occupancy levels above the 65% threshold associated with optimal clinical response; the 75-mg dose approximated the 80% threshold linked to increased risk of extrapyramidal symptoms. Doses of 25 or 50 mg should provide therapeutic efficacy while minimizing the risk of extrapyramidal symptoms.

A positron emission tomography (PET) investigation of the role of striatal dopamine (D2) receptor availability in spatial cognition

The functional significance of age-related changes in regional brain dopamine (DA) function is poorly understood in health. Two recent studies have reported positive linear associations between measures of striatal DA (D2) receptor availability (binding potential) and specific aspects of motor and cognitive performance, after controlling for the effects of age [(Volkow, N.D., Gur, R.C., Wang, G.-J., Fowler, J.S., Moberg, P.J., Ding, Y.-S., Hitzemann, R., Smith, G., Logan, J., 1998. Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals. Am. J. Psychiatry 155 (3), 344–349; Backman, L., Ginovart, N., Dixon, R.A., Wahlin, T.-B.R., Wahlin, A., Halldin, C., Farde, L., 2000. Age-related cognitive deficits mediated by changes in the striatal dopamine system. Am. J. Psychiatry 157 (4), 635–637)]. We investigated the relationship between measures of striatal DA (D2) receptor availability and visuo-spatial cognitive performance in thirty healthy post-menopausal women aged 58–90 years. [11C] Raclopride (RAC) positron emission tomography (PET) was used to assess dopamine (D2) receptor availability. The CANTAB neuropsychological test battery was used to assess spatial span, spatial working memory (SWM) and planning ability. Age showed significant linear correlations with several of the CANTAB performance measures. After controlling for age effects, DA (D2) receptor measures in left-sided striatal regions (caudate and putamen) were significantly and positively correlated with ‘perfect solution’ scores—the measure of performance accuracy—on the Tower of London (TOL) test of spatial planning. When this relationship was examined in relation to task difficulty, only perfect scores for the most ‘difficult’ (4-move) problems were significantly correlated with BP measures in all striatal regions, most notably the right and left caudate nuclei. Paradoxically, individuals with higher DA (D2) receptor measures in the right caudate performed less accurately on the SWM task, exhibiting a higher number of errors within each search sequence. The relative contribution of striatal DA (D2) receptor availability to specific aspects of cognitive performance needs to be evaluated in larger mixed-sex samples to facilitate the meaningful investigation of the potential therapeutic benefits of DA (D2) agonists in later life.

The effects of acute tyrosine and phenylalanine depletion on spatial working memory and planning in healthy volunteers are predicted by changes in striatal dopamine levels

Dopamine (DA) is considered important in the modulation of tasks of spatial working memory. However, the findings from studies in humans to date are mixed. While this may be due to the characteristics of the tasks used, it is also possible that these findings are explained by variable central effects of the manipulations used. To test the effects of acute tyrosine and phenylalanine depletion (TPD, which reduces synthesis and release of brain DA) on cognitive function and relate changes in performance accuracy to the central effects of TPD measured with [11C]raclopride positron emission tomography (PET). Fourteen participants were given tests of spatial working memory, planning, verbal memory span and trial-and-error learning after acute TPD, seven of whom also received PET scans to measure changes in striatal DA levels. Although TPD produced a clear reduction in tyrosine and phenylalanine availability to the brain, no impairments on any of the cognitive tests were observed. However, changes in spatial working memory and planning accuracy after TPD showed a highly significant relationship with the changes in striatal DA levels. Our findings suggest that the effects of TPD on spatial working memory and planning may be unreliable due to the variability of the changes in brain DA levels achieved with this manipulation.

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.

Amphetamine pretreatment induces a change in both D2-Receptor density and apparent affinity: a [11C]raclopride positron emission tomography study in cats

BackgroundMeasuring changes in dopamine (DA) levels in humans using radioligand-displacement studies and positron emission tomography (PET) has provided important empirical findings in disease and normal neurophysiology. These studies are based on the assumption that DA exerts a competitive inhibition on radioligand binding. To test this, we used PET and a Scatchard approach to investigate whether the decrease in [11C]raclopride binding following amphetamine results from competitive or noncompetitive interactions with DA. MethodsScatchard analyses of [11C]raclopride/PET data were used to quantify changes in apparent D2-receptor density (Bmax) and radioligand apparent affinity (K′D) at baseline and after amphetamine pretreatment (2 mg/kg; intravenous) in cats. ResultsAmphetamine induced a 46% decrease in [11C]raclopride binding in the striatum of five cats. Scatchard analyses revealed that this decrease in binding was due to a 28% decrease in Bmax and a concomitant 35% increase in K′D. ConclusionsCompetition with DA is an insufficient explanation for the decrease in [11C]raclopride binding observed after amphetamine. Noncompetitive interactions, likely representing D2-receptor internalization, also play an important role in this phenomenon. This finding may have important implications for the interpretation of amphetamine–raclopride PET studies in schizophrenia because dysregulation of the agonist-induced internalization of D2 receptors was recently suggested in this disorder.

Dopaminergic effects of caffeine in the human striatum and thalamus.

Epidemiological studies have provided evidence that caffeine, an adenosine receptor antagonist, reduces the risk for Parkinson's disease. There are indications of specific interactions between striatal adenosine A(2A) and dopamine D(2) receptors, but the in vivo effects of caffeine on human dopamine system have not been investigated. In the present study, the dopaminergic effects of caffeine were examined with [(11)C]raclopride positron emission tomography (PET) in eight healthy habitual coffee drinkers after 24 h caffeine abstinence. Compared to oral placebo, 200 mg oral caffeine induced a 12% decrease in midline thalamic binding potential (p < 0.001). A trend-level increase in ventral striatal [(11)C]raclopride binding potential was seen with a correlation between caffeine-related arousal and putaminal dopamine D(2) receptor binding (r = -0.81, p = 0.03). The findings indicate that caffeine has effects on dopaminergic neurotransmission in the human brain, which may be differential in the striatum and the thalamus.

Endogenous dopamine release induced by repetitive transcranial magnetic stimulation over the primary motor cortex: an [11C]raclopride positron emission tomography study in anesthetized macaque monkeys

BackgroundRepetitive transcranial magnetic stimulation (rTMS) has been used as a treatment for neuropsychiatric disorders such as depression and Parkinson's disease (PD). Despite the growing interest in therapeutic application of rTMS, precise mechanisms of its action remain unknown. With respect to PD, activation of the mesostriatal dopaminergic pathway is likely to be a candidate mechanism underlying the therapeutic effects; however, modulating effects of rTMS over the primary motor cortex (M1) on the dopaminergic system have not been studied. MethodsWe used [11C]raclopride positron emission tomography to measure changes of extracellular dopamine concentration after 5Hz rTMS over the M1 in eight anesthetized monkeys. ResultsrTMS over the right M1 induced a reduction of [11C]raclopride binding potential (BP) in the bilateral ventral striatum, including the nucleus accumbens, and a significant increase of BP in the right putamen; no significant BP reduction was found in the dorsal striatum. These data indicate that rTMS over the motor cortex induces a release of endogenous dopamine in the ventral striatum. ConclusionsOur results suggest that therapeutic mechanisms of rTMS may be explained in part by an activation of the mesolimbic dopaminergic pathway, which plays critical roles in rewards, reinforcement, and incentive motivation.

First visualization of adenosine A2A receptors in the human brain by positron emission tomography with [11C]TMSX

[11C]TMSX is a new positron emission tomography (PET) radioligand that provides visualization of adenosine A(2A) receptors (A(2A)Rs) in the brain, heart and skeletal muscle. Here we report on the first visualization of the A(2A)Rs in the human brain by PET and [11C]TMSX in a male healthy volunteer, compared with the adenosine A1 receptors (A1Rs) and dopamine D2 receptors (D2Rs) which were measured by PET with [11C]MPDX and [11C]raclopride, respectively. The distribution volume (DV) of [11C]TMSX in the baseline was relatively high in the head of caudate nucleus, putamen, and thalamus and relatively low in the cortical regions. Infusion of theophylline, a nonselective A(2A)R antagonist (Ki for A(2A)Rs = 16000 nM for theophylline vs 5.9 nM for TMSX), slightly reduced the DVs in the head of caudate nucleus (8.0% reduction) and putamen (4.5% reduction), but not in the other regions having much lower levels of A(2A)Rs, demonstrating the A(2A)R-specific binding of [11C]TMSX. On the other hand, the A1Rs were widely distributed in the whole brain except for the cerebellum, while the binding potential of [11C]raclopride was predominantly high in the striatum. We concluded that [11C]TMSX is an applicable PET ligand for mapping the A(2A)Rs in the caudate nucleus and putamen in clinical studies because of no availability of other radioligands until now. The [11C]TMSX PET is of great interest for studying the pathophysiology of neurological and psychiatric disorders together with the [11C]raclopride PET for D2Rs evaluation and/or the [11C]MPDX PET for A1Rs evaluation.

Feeding-induced dopamine release in dorsal striatum correlates with meal pleasantness ratings in healthy human volunteers

Seven healthy subjects underwent two [ 11C]raclopride positron emission tomography (PET) scans, one following a 16-h fast and the other after consumption of a favorite meal (following a 16-h fast) in counterbalanced fashion. Before and after each scan subjects gave ratings of hunger/fullness and desire to eat. In addition, meal pleasantness ratings were collected immediately after consumption of the favorite meal. PET data were analyzed using brain parametric maps to generate regions of statistically significant change, as well as regions of interest manually drawn on each individual's coregistered anatomical image. [ 11C]Raclopride binding potential was compared across the two states (hungry and full). A significant reduction in binding potential was observed in the full compared to the hungry state in the dorsal putamen and caudate nucleus, indicative of dopamine release. There were no changes elsewhere in the striatum. A correlation was observed between the reduction in [ 11C]raclopride binding and meal pleasantness ratings, but not with desire to eat (hunger) or satiety after eating. These results suggest that feeding is associated with dopamine release in the dorsal, but not the ventral striatum, and that the amount of dopamine released correlates with the degree of experienced pleasure.

Effects of catecholamine depletion on D 2 receptor binding, mood, and attentiveness in humans: a replication study

The effect of catecholamine depletion, achieved by per-oral administration of 5250 mg α-methyl- para-tyrosine (AMPT) given in the 29 h prior to [ 11C]raclopride positron emission tomography (PET) was studied on measures of dopamine (DA) release, mood, and attention. Neostriatal DA levels in vivo were estimated by comparing the neostriatal DA D 2 receptor binding potential (D 2RBP) before and after catecholamine depletion using PET and the radiotracer [ 11C]raclopride. Six healthy subjects completed the protocol. The AMPT treatment increased D 2RBP significantly by 13.3±5.9% (average±standard deviation) and decreased plasma levels of the DA metabolite homovanillic acid (HVA) by 62±17%, and levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) by 66±5%. Catecholamine depletion resulted in decreased happiness, euphoria, energy, talkativeness, vigor, and attentiveness, and in increased sleepiness, fatigue, sedation, and eye blink rate (EBR). These changes were not correlated with the D 2RBP increments. The results of this study are overall consistent with previous findings by our group using the same methodology in a different cohort of six healthy subjects.