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NeuroImage Jan 2021To minimize motion-related distortion of reconstructed images, conventional positron emission tomography (PET) measurements of the brain inevitably require a firm and...
To minimize motion-related distortion of reconstructed images, conventional positron emission tomography (PET) measurements of the brain inevitably require a firm and tight head restraint. While such a restraint is now a routine procedure in brain imaging, the physiological and psychological consequences resulting from the restraint have not been elucidated. To address this problem, we developed a restraint-free brain PET system and conducted PET scans under both restrained and non-restrained conditions. We examined whether head restraint during PET scans could alter brain activities such as regional cerebral blood flow (rCBF) and dopamine release along with psychological stress related to head restraint. Under both conditions, 20 healthy male participants underwent [O]HO and [C]Raclopride PET scans during working memory tasks with the same PET system. Before, during, and after each PET scan, we measured physiological and psychological stress responses, including the State-Trait Anxiety Inventory (STAI) scores. Analysis of the [O]HO-PET data revealed higher rCBF in regions such as the parahippocampus in the restrained condition. We found the binding potential (BP) of [C]Raclopride in the putamen was significantly reduced in the restrained condition, which reflects an increase in dopamine release. Moreover, the restraint-induced change in BP was correlated with a shift in the state anxiety score of the STAI, indicating that less anxiety accompanied smaller dopamine release. These results suggest that the stress from head restraint could cause unsolicited responses in brain physiology and emotional states. The restraint-free imaging system may thus be a key enabling technology for the natural depiction of the mind.
Topics: Adult; Anxiety; Brain; Carbon Radioisotopes; Cerebrovascular Circulation; Dopamine; Functional Neuroimaging; Head; Healthy Volunteers; Humans; Male; Memory, Short-Term; Oxygen Radioisotopes; Positron-Emission Tomography; Putamen; Raclopride; Restraint, Physical; Stress, Physiological; Stress, Psychological; Young Adult
PubMed: 33039616
DOI: 10.1016/j.neuroimage.2020.117434 -
Human Brain Mapping Dec 2023Feeding induces dopamine release in the striatum, and a dysfunction of the dopaminergic reward system can lead to overeating, and obesity. Studies have reported... (Meta-Analysis)
Meta-Analysis
Feeding induces dopamine release in the striatum, and a dysfunction of the dopaminergic reward system can lead to overeating, and obesity. Studies have reported inconsistent findings of dopamine receptor (DR) positron emission tomography scans in obesity. Here we investigated the association between DR availability and overweight/obesity using Bayesian and frequentist meta-analysis. We performed a systematic search of Embase, Medline, Scopus and Web of Science for studies that compared striatal DR availability between lean subjects and overweight/obese subjects. The standardized mean difference (Hedge's g) of DR availability was calculated after extraction of data from each study. Studies were divided into two groups according to the definition of overweight/obese subjects (body mass index [BMI] cutoff of 25 and 30 kg/m ). Both Bayesian and frequentist meta-analysis was done in R Statistical Software version 4.2.2 (The R Foundation for Statistical Computing). Nine studies were eligible for inclusion in this study. Three studies with C11-raclopride, one with C11-PNHO, two with F18-fallypride, one with I123-IBZM, one with C11-NMB and one with both C11-raclopride and C11-PNHO were included. In Bayesian meta-analysis, the standardized mean difference of DR availability between lean and overweight/obese subjects markedly overlapped with zero regardless of BMI cutoff for obesity. In frequentist meta-analysis, the pooled standardized mean difference of DR availability did not show the significant difference between lean and overweight/obese subjects. There was an effect of the radiopharmaceutical on the standardized mean difference of DR availability in meta-analysis of BMI cutoff of 25 kg/m . In conclusion, brain DR availability is not different between lean and overweight/obese subjects. However, the effect is dependent on the radiopharmaceutical and the degree of obesity. Further studies with multi-radiopharmaceutical in the same individuals are needed to understand the association between DR and obesity.
Topics: Humans; Overweight; Raclopride; Bayes Theorem; Radiopharmaceuticals; Receptors, Dopamine D2; Obesity; Brain; Dopamine; Body Mass Index
PubMed: 37950852
DOI: 10.1002/hbm.26534 -
Psychiatry and Clinical Neurosciences Apr 2020The aim of the study was to test: (i) if D /D binding in three functional subsections of striatum is different in patients with severe major depressive episodes than in...
[ C]raclopride positron emission tomography study of dopamine-D receptor binding in patients with severe major depressive episodes before and after electroconvulsive therapy and compared to control subjects.
AIM
The aim of the study was to test: (i) if D /D 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).
METHODS
Nine inpatients were examined with positron emission tomography (PET) and the radioligand [ 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 [ C]raclopride.
RESULTS
[ C]raclopride binding was significantly lower in all three subsections of striatum in patients compared to controls (Cohen's d , 1.14-1.68; P = 0.003-0.027). Montgomery-Åsberg Depression Ratings decreased significantly after ECT (P < 0.001; Cohen's d , 2.9). ECT had no statistically significant effect on [ C]raclopride binding, although post-ECT binding estimates were more similar to those obtained in controls in all subsections of striatum.
CONCLUSION
Using PET and [ C]raclopride, we found support for the notion that severe major depressive episodes are associated with significantly lower dopamine D /D binding in all three subsections of striatum compared to controls. We noted no significant effect on D /D binding in the patient group after response to ECT.
Topics: Adult; Aged; Brain Mapping; Carbon Radioisotopes; Corpus Striatum; Depressive Disorder, Major; Dopamine; Dopamine Antagonists; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Protein Binding; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 31943514
DOI: 10.1111/pcn.12980 -
Materials (Basel, Switzerland) Jan 2023In this work, we developed a novel approach to purify [C]Raclopride ([C]RAC), an important positron emission tomography radiotracer, based on tailored shape-recognition...
In this work, we developed a novel approach to purify [C]Raclopride ([C]RAC), an important positron emission tomography radiotracer, based on tailored shape-recognition polymers, with the aim to substitute single-pass HPLC purification with an in-flow trap & release process. Molecular imprinting technology (MIT) applied to solid phase extraction (MISPE) was investigated to develop a setting able to selectively extract [C]RAC in a mixture containing a high amount of its precursor, (S)-O-Des-Methyl-Raclopride (DM-RAC). Two imprinted polymers selective for unlabeled RAC and DM-RAC were synthesized through a radical polymerization at 65 °C using methacrylic acid and trimethylolpropane trimethacrylate in the presence of template molecule (RAC or DM-RAC). The prepared polymer was characterized by scanning electron microscopy and Fourier transform infrared spectroscopy and tested in MISPE experiments. The polymers were used in testing conditions, revealing a high retention capacity of RAC-MISPE to retain RAC either in the presence of similar concentrations of RAC and DM-RAC precursor (96.9%, RSD 6.6%) and in the presence of a large excess of precursor (90%, RSD 4.6%) in the loading solution. Starting from these promising results, preliminary studies for selective purification of [C]Raclopride using this RAC-MISPE were performed and, while generally confirming the selectivity capacity of the polymer, revealed challenging applicability to the current synthetic process, mainly due to high backpressures and long elution times.
PubMed: 36770098
DOI: 10.3390/ma16031091 -
Molecular Psychiatry Jun 2018Recent genetic, molecular and post-mortem studies suggest impaired dopamine (DA)-D2 receptor (D2R) trafficking in patients with schizophrenia (SZ). Imaging and...
Recent genetic, molecular and post-mortem studies suggest impaired dopamine (DA)-D2 receptor (D2R) trafficking in patients with schizophrenia (SZ). Imaging and preclinical studies have shown agonist-induced D2R internalization can be imaged with positron emission tomography (PET) using D2R radiotracers combined with psychostimulant challenge. This is feasible if radiotracer binding is measured when postchallenge DA levels have returned to baseline, following the initial competition phase between DA and radiotracer for binding to D2R. Here we used 'late-phase' imaging after challenge to test the hypothesis that impaired D2R internalization in SZ leads to blunted late-phase displacement, or a faster return to baseline, in patients compared with healthy controls (HCs). We imaged 10 patients with SZ and 9 HCs with PET and [C]raclopride at baseline and two times (3-5 and 6-10 h) following 0.5 mg kg dextroamphetamine. We measured binding potential relative to non-displaceable compartment (BP) and derived percent reduction from baseline (ΔBP) for each postamphetamine scan. To test the hypothesis that time course of return of striatal BP to baseline differed between SZ and HCs, we implemented a linear model with ΔBP as dependent variable, time after amphetamine as repeated measure and time after amphetamine and diagnostic group as fixed effects. Neither diagnostic group nor interaction of diagnostic group-by-time after amphetamine significantly affected striatal ΔBP (F=1.38, P=0.26; F=0.51, P=0.61). These results show similar pattern of return of BP to baseline as a function of time in patients with SZ and HC, suggesting that striatal D2R internalization as measured by our imaging paradigm is normal in patients with SZ.
Topics: Adult; Amphetamine; Carbon Radioisotopes; Case-Control Studies; Central Nervous System Stimulants; Dextroamphetamine; Dopamine; Dopamine Agonists; Female; Humans; Male; Positron-Emission Tomography; Raclopride; Radionuclide Imaging; Receptors, Dopamine D2; Schizophrenia
PubMed: 28507321
DOI: 10.1038/mp.2017.107 -
Neuropsychopharmacology : Official... May 2024The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced... (Randomized Controlled Trial)
Randomized Controlled Trial
The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = -0.54, p < 0.001). GBC showed "fast>slow" associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and "slow>fast" associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex (p < 0.05). "Fast>slow" GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [C]SCH23390 binding; rho = 0.22, p < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported 'high' ratings to intravenous MP across individuals (r = -0.68, p = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.
Topics: Humans; Male; Adult; Female; Brain; Positron-Emission Tomography; Magnetic Resonance Imaging; Dopamine; Methylphenidate; Double-Blind Method; Young Adult; Raclopride; Central Nervous System Stimulants; Receptors, Dopamine D1; Neural Pathways; Dopamine Antagonists; Brain Mapping
PubMed: 38326458
DOI: 10.1038/s41386-024-01803-8 -
Communications Biology Feb 2023Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat...
Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate's brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [C]raclopride's binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of "high". We show for the first time that the "high" is associated with the fast dopamine increases induced by methylphenidate.
Topics: Humans; Methylphenidate; Dopamine; Raclopride; Brain; Attention Deficit Disorder with Hyperactivity; Dopamine Antagonists
PubMed: 36765261
DOI: 10.1038/s42003-023-04545-3 -
Brain, Behavior, and Immunity Nov 2022Immune-brain interactions influence the pathophysiology of addiction. Lipopolysaccharide (LPS)-induced systemic inflammation produces effects on reward-related brain... (Randomized Controlled Trial)
Randomized Controlled Trial
Immune-brain interactions influence the pathophysiology of addiction. Lipopolysaccharide (LPS)-induced systemic inflammation produces effects on reward-related brain regions and the dopamine system. We previously showed that LPS amplifies dopamine elevation induced by methylphenidate (MP), compared to placebo (PBO), in eight healthy controls. However, the effects of LPS on the dopamine system of tobacco smokers have not been explored. The goal of Study 1 was to replicate previous findings in an independent cohort of tobacco smokers. The goal of Study 2 was to combine tobacco smokers with the aforementioned eight healthy controls to examine the effect of LPS on dopamine elevation in a heterogenous sample for power and effect size determination. Eight smokers were each scanned with [C]raclopride positron emission tomography three times-at baseline, after administration of LPS (0.8 ng/kg, intravenously) and MP (40 mg, orally), and after administration of PBO and MP, in a double-blind, randomized order. Dopamine elevation was quantified as change in [C]raclopride binding potential (ΔBP) from baseline. A repeated-measures ANOVA was conducted to compare LPS and PBO conditions. Smokers and healthy controls were well-matched for demographics, drug dosing, and scanning parameters. In Study 1, MP-induced striatal dopamine elevation was significantly higher following LPS than PBO (p = 0.025, 18 ± 2.9 % vs 13 ± 2.7 %) for smokers. In Study 2, MP-induced striatal dopamine elevation was also significantly higher under LPS than under PBO (p < 0.001, 18 ± 1.6 % vs 11 ± 1.5 %) in the combined sample. Smoking status did not interact with the effect of condition. This is the first study to translate the phenomenon of amplified dopamine elevation after experimental activation of the immune system to an addicted sample which may have implications for drug reinforcement, seeking, and treatment.
Topics: Central Nervous System Stimulants; Corpus Striatum; Dopamine; Humans; Inflammation; Lipopolysaccharides; Methylphenidate; Positron-Emission Tomography; Raclopride; Smokers
PubMed: 36058419
DOI: 10.1016/j.bbi.2022.08.016 -
NeuroImage Feb 2021Dopamine D2 receptors (D2-R) in extrastriatal brain regions are of high interest for research in a wide range of psychiatric and neurologic disorders. Pharmacological... (Randomized Controlled Trial)
Randomized Controlled Trial
Dopamine D2 receptors (D2-R) in extrastriatal brain regions are of high interest for research in a wide range of psychiatric and neurologic disorders. Pharmacological competition studies and test-retest experiments have shown high validity and reliability of the positron emission tomography (PET) radioligand [C]FLB 457 for D2-R quantification in extrastriatal brain regions. However, this radioligand is not available at most research centers. Instead, the medium affinity radioligand [C]raclopride, which has been extensively validated for quantification of D2-R in the high-density region striatum, has been applied also in studies on extrastriatal D2-R. Recently, the validity of this approach has been questioned by observations of low occupancy of [C]raclopride in extrastriatal regions in a pharmacological competition study with quetiapine. Here, we utilise a data set of 16 healthy control subjects examined with both [C]raclopride and [C]FLB 457 to assess the correlation in binding potential (BP) in extrastriatal brain regions. BP was quantified using the simplified reference tissue model with cerebellum as reference region. The rank order of mean regional BP values were similar for both radioligands, and corresponded to previously reported data, both post-mortem and using PET. Nevertheless, weak to moderate within-subject correlations were observed between [C]raclopride and [C]FLB 457 BP extrastriatally (Pearson's R: 0.30-0.56), in contrast to very strong correlations between repeated [C]FLB 457 measurements (Pearson's R: 0.82-0.98). In comparison, correlations between repeated [C]raclopride measurements were low to moderate (Pearson's R: 0.28-0.75). These results are likely related to low signal to noise ratio of [C]raclopride in extrastriatal brain regions, and further strengthen the recommendation that extrastriatal D2-R measures obtained with [C]raclopride should be interpreted with caution.
Topics: Brain; Brain Mapping; Carbon Radioisotopes; Dopamine Antagonists; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Pyrrolidines; Raclopride; Radioligand Assay; Radiopharmaceuticals; Receptors, Dopamine D2; Salicylamides
PubMed: 33144221
DOI: 10.1016/j.neuroimage.2020.117523 -
The International Journal of... Aug 2014Dopamine D3 receptor (D3R) antagonists may be effective medications for multiple substance use disorders (SUDs). However, no selective D3R antagonists are currently...
Dopamine D3 receptor (D3R) antagonists may be effective medications for multiple substance use disorders (SUDs). However, no selective D3R antagonists are currently available for clinical testing. Buspirone, originally characterized as a 5-HT1A partial agonist and used as an anxiolytic, also binds to D3R and D4R with high affinity, with lower affinity to D2R, and interferes with cocaine reward. Here we used PET with [11C]PHNO (D3R-preferring radioligand), [11C]raclopride (D2R/D3R radioligand) and [11C]NNC-112 (D1R radioligand) to measure occupancy of oral and parenteral buspirone in the primate brain. Intramuscular buspirone (0.19 and 0.5 mg/kg) blocked both [11C]PHNO and [11C]raclopride binding to striatum, exhibiting high occupancy (50-85%) at 15 min and rapid wash-out over 2-6 h. In contrast, oral buspirone (3 mg/kg) significantly blocked [11C]PHNO binding in D3-rich regions (globus pallidum and midbrain) at 3 h, but had minimal effects on [11C]raclopride binding (28-37% at 1 h and 10% at 3 h). Buspirone did not block [11C]NNC-112. Our findings provide evidence that i.m. buspirone blocks D3R and D2R, whereas oral buspirone is more selective towards D3R blockade in vivo, consistent with extensive first pass metabolism and supporting the hypothesis that its metabolites (5- and 6'-hydroxybuspirone) merit evaluation for treating SUDs. They also indicate that for oral buspirone to achieve greater than 80% sustained D3R occupancy, as might be needed to treat addiction, higher doses (at least three-fold) than those used to treat anxiety (maximal 60 mg) will be required. Nonetheless, based on previous clinical studies, these doses would be safe and well tolerated.
Topics: Administration, Oral; Animals; Anti-Anxiety Agents; Benzazepines; Benzofurans; Buspirone; Corpus Striatum; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Female; Functional Neuroimaging; Globus Pallidus; Injections, Intramuscular; Mesencephalon; Oxazines; Papio anubis; Positron-Emission Tomography; Raclopride; Radioligand Assay; Receptors, Dopamine D3
PubMed: 24679922
DOI: 10.1017/S1461145714000194