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Drug and Alcohol Dependence Oct 2021Dopaminergic mechanisms that may underlie cannabis' reinforcing effects are not well elucidated in humans. This positron emission tomography (PET) imaging study used the...
BACKGROUND
Dopaminergic mechanisms that may underlie cannabis' reinforcing effects are not well elucidated in humans. This positron emission tomography (PET) imaging study used the dopamine D receptor antagonist [C]raclopride and kinetic modelling testing for transient changes in radiotracer uptake to assess the striatal dopamine response to smoked cannabis in a preliminary sample.
METHODS
PET emission data were acquired from regular cannabis users (n = 14; 7 M/7 F; 19-32 years old) over 90 min immediately after [C]raclopride administration (584 ± 95 MBq) as bolus followed by constant infusion (K = 105 min). Participants smoked a cannabis cigarette, using a paced puff protocol, 35 min after scan start. Plasma concentrations of Δ-THC and metabolites and ratings of subjective "high" were collected during imaging. Striatal dopamine responses were assessed voxelwise with a kinetic model testing for transient reductions in [C]raclopride binding, linear-parametric neurotransmitter PET (lp-ntPET) (cerebellum as a reference region).
RESULTS
Cannabis smoking increased plasma Δ-THC levels (peak: 0-10 min) and subjective high (peak: 0-30 min). Significant clusters (>16 voxels) modeled by transient reductions in [C]raclopride binding were identified for all 12 analyzed scans. In total, 26 clusters of significant responses to cannabis were detected, of which 16 were located in the ventral striatum, including at least one ventral striatum cluster in 11 of the 12 analyzed scans.
CONCLUSIONS
These preliminary data support the sensitivity of [C]raclopride PET with analysis of transient changes in radiotracer uptake to detect cannabis smoking-induced dopamine responses. This approach shows future promise to further elucidate roles of mesolimbic dopaminergic signaling in chronic cannabis use. ClinicalTrials.gov Identifier: NCT02817698.
Topics: Adult; Cannabis; Corpus Striatum; Dopamine; Humans; Marijuana Smoking; Positron-Emission Tomography; Raclopride; Ventral Striatum; Young Adult
PubMed: 34399137
DOI: 10.1016/j.drugalcdep.2021.108920 -
Synapse (New York, N.Y.) May 2021The radiotracers [ C]-raclopride and [ C]-(+)-PHNO are commonly used to measure differences in amphetamine-induced dopamine release between healthy persons and persons... (Meta-Analysis)
Meta-Analysis Review
The radiotracers [ C]-raclopride and [ C]-(+)-PHNO are commonly used to measure differences in amphetamine-induced dopamine release between healthy persons and persons with neuropsychiatric diseases. As an agonist radiotracer, [ C]-(+)-PHNO should theoretically be roughly 2.7 times more sensitive to displacement by endogenous dopamine than [ C]raclopride. To date, only one study has been published comparing the sensitivity of these two radiotracers to amphetamine-induced dopamine release in healthy persons. Unfortunately, conflicting findings in the literature suggests that the dose of amphetamine they employed (0.3 mg/kg, p.o.) may not reliably reduce [ C]-raclopride binding in the caudate. Thus, it is unclear whether the preponderance of evidence supports the theory that [ C]-(+)-PHNO is more sensitive to displacement by amphetamine in humans than [ C]-raclopride. In order to clarify these issues, we conducted a comparative meta-analysis summarizing the effects of amphetamine on [ C]-raclopride and [ C]-(+)-PHNO binding in healthy humans. Our analysis indicates that amphetamine given at 0.3 mg/kg, p.o. does not reliably reduce [ C]-raclopride binding in the caudate. Second, the greater sensitivity of [ C]-(+)-PHNO is evidenced at 0.5 mg/kg, p.o., but not at lower doses of amphetamine. Third, our analysis suggests that [ C]-(+)-PHNO may be roughly 1.5 to 2.5 times more sensitive to displacement by amphetamine than [ C]-raclopride in healthy persons. We recommend that future displacement studies with these radiotracers employ 0.5 mg/kg, p.o. of amphetamine with a dose, post-scan interval of at least 3 hr. Using this dose of amphetamine, [ C]-raclopride studies should employ at least n = 34 participants per group, while [ C]-(+)-PHNO studies should employ at least n = 6 participants per group, in order to be sufficiently powered (80%) to detect changes in radiotracer binding within the caudate.
Topics: Amphetamine; Dopamine; Dopamine Agonists; Humans; Oxazines; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2
PubMed: 33471400
DOI: 10.1002/syn.22195 -
Synapse (New York, N.Y.) Jan 2023The brain plays a major role in controlling the desire to eat. This meta-analysis aimed to assess the association between dopamine receptor (DR) availability and... (Meta-Analysis)
Meta-Analysis
The brain plays a major role in controlling the desire to eat. This meta-analysis aimed to assess the association between dopamine receptor (DR) availability and dopamine transporter (DAT) availability, measured using positron emission tomography, and obesity. We performed a systematic search of MEDLINE (from inception to November 2020) and EMBASE (from inception to November 2020) for articles published in English using the keywords "dopamine receptor," "dopamine transporter," "obesity," and "neuroimaging." Body mass index (BMI) and the corresponding binding potential (BP ) were extracted from figures in each study using Engauge Digitizer, version 12.1, and plotted for radiopharmaceuticals and regions of interest (ROIs). Five studies involving 119 subjects with DR and five studies including 421 subjects with DAT were eligible for inclusion in this study. In overweight or obese subjects with BMI of 25 kg/m or higher, DR availability from C-Racloprie was negatively associated with BMI. However, DR availability from C-PHNO was positively associated with BMI. DAT ratio was calculated after dividing DAT availabilities of overweight/obese BMI with mean DAT availabilities of normal BMI. The association between DAT ratio and BMI was not significant regardless of radiopharmaceuticals. In conclusion, dopamine plays a main role in the reward system with regard to obesity. Overweight and obese subjects had negative association between DR availability from C-Raclopride and BMI. However, the association of DR availability with BMI was dependent on radiopharmaceuticals. DAT availability did not show the significant relationship with BMI regardless of radiopharmaceuticals.
Topics: Humans; Dopamine Plasma Membrane Transport Proteins; Radiopharmaceuticals; Overweight; Obesity; Receptors, Dopamine D2
PubMed: 36099576
DOI: 10.1002/syn.22254 -
NeuroImage May 2022Head motion during PET scans causes image quality degradation, decreased concentration in regions with high uptake and incorrect outcome measures from kinetic analysis...
Head motion during PET scans causes image quality degradation, decreased concentration in regions with high uptake and incorrect outcome measures from kinetic analysis of dynamic datasets. Previously, we proposed a data-driven method, center of tracer distribution (COD), to detect head motion without an external motion tracking device. There, motion was detected using one dimension of the COD trace with a semiautomatic detection algorithm, requiring multiple user defined parameters and manual intervention. In this study, we developed a new data-driven motion detection algorithm, which is automatic, self-adaptive to noise level, does not require user-defined parameters and uses all three dimensions of the COD trace (3DCOD). 3DCOD was first validated and tested using 30 simulation studies (F-FDG, N = 15; C-raclopride (RAC), N = 15) with large motion. The proposed motion correction method was tested on 22 real human datasets, with 20 acquired from a high resolution research tomograph (HRRT) scanner (F-FDG, N = 10; C-RAC, N = 10) and 2 acquired from the Siemens Biograph mCT scanner. Real-time hardware-based motion tracking information (Vicra) was available for all real studies and was used as the gold standard. 3DCOD was compared to Vicra, no motion correction (NMC), one-direction COD (our previous method called 1DCOD) and two conventional frame-based image registration (FIR) algorithms, i.e., FIR1 (based on predefined frames reconstructed with attenuation correction) and FIR2 (without attenuation correction) for both simulation and real studies. For the simulation studies, 3DCOD yielded -2.3 ± 1.4% (mean ± standard deviation across all subjects and 11 brain regions) error in region of interest (ROI) uptake for F-FDG (-3.4 ± 1.7% for C-RAC across all subjects and 2 regions) as compared to Vicra (perfect correction) while NMC, FIR1, FIR2 and 1DCOD yielded -25.4 ± 11.1% (-34.5 ± 16.1% for C- RAC), -13.4 ± 3.5% (-16.1 ± 4.6%), -5.7 ± 3.6% (-8.0 ± 4.5%) and -2.6 ± 1.5% (-5.1 ± 2.7%), respectively. For real HRRT studies, 3DCOD yielded -0.3 ± 2.8% difference for F-FDG (-0.4 ± 3.2% for C-RAC) as compared to Vicra while NMC, FIR1, FIR2 and 1DCOD yielded -14.9 ± 9.0% (-24.5 ± 14.6%), -3.6 ± 4.9% (-13.4 ± 14.3%), -0.6 ± 3.4% (-6.7 ± 5.3%) and -1.5 ± 4.2% (-2.2 ± 4.1%), respectively. In summary, the proposed motion correction method yielded comparable performance to the hardware-based motion tracking method for multiple tracers, including very challenging cases with large frequent head motion, in studies performed on a non-TOF scanner.
Topics: Algorithms; Brain; Humans; Image Processing, Computer-Assisted; Kinetics; Motion; Movement; Positron-Emission Tomography
PubMed: 35257856
DOI: 10.1016/j.neuroimage.2022.119031 -
BioRxiv : the Preprint Server For... Jun 2023There is now evidence from multiple Phase II clinical trials that psychedelic drugs can exert longlasting anxiolytic, anti-depressant, and anti-drug abuse (nicotine and...
There is now evidence from multiple Phase II clinical trials that psychedelic drugs can exert longlasting anxiolytic, anti-depressant, and anti-drug abuse (nicotine and ethanol) effects in patients. Despite these benefits, the hallucinogenic actions of these drugs at the serotonin 2A receptor (5-HT2AR) limit their clinical use in diverse settings. Activation of the 5-HT2AR can stimulate both G protein and β-arrestin (βArr) -mediated signaling. Lisuride is a G protein biased agonist at the 5-HT2AR and, unlike the structurally-related LSD, the drug does not typically produce hallucinations in normal subjects at routine doses. Here, we examined behavioral responses to lisuride, in wild-type (WT), βArr1-KO, and βArr2-KO mice. In the open field, lisuride reduced locomotor and rearing activities, but produced a U-shaped function for stereotypies in both βArr lines of mice. Locomotion was decreased overall in βArr1-KOs and βArr2-KOs, relative to WT controls. Incidences of head twitches and retrograde walking to lisuride were low in all genotypes. Grooming was depressed in βArr1 mice, but was increased then decreased in βArr2 animals with lisuride. Prepulse inhibition (PPI) was unaffected in βArr2 mice, whereas 0.5 mg/kg lisuride disrupted PPI in βArr1 animals. The 5-HT2AR antagonist MDL100907 failed to restore PPI in βArr1 mice, whereas the dopamine D2/D3 antagonist raclopride normalized PPI in WTs but not in βArr1-KOs. Using vesicular monoamine transporter 2 mice, lisuride reduced immobility times in tail suspension and promoted a preference for sucrose that lasted up to 2 days. Together, it appears βArr1 and βArr2 play minor roles in lisuride's actions on many behaviors, while this drug exerts anti-depressant drug-like responses without hallucinogenic-like activities.
PubMed: 37333376
DOI: 10.1101/2023.06.01.543310 -
Journal of Cerebral Blood Flow and... Sep 2020In vivo dopamine D2-receptor availability is frequently assessed with C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for C-raclopride...
In vivo dopamine D2-receptor availability is frequently assessed with C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for C-raclopride in areas with low D2 receptor densities, the ligand has been considered unreliable for measurements outside the dopamine-dense striatum. Intriguingly, recent studies show that extrastriatal C-raclopride binding potential (BP) values are (i) reliably higher than in the cerebellum (where D2-receptor levels are negligible), (ii) correlate with behavior in the expected direction, and (iii) showed good test-retest reliability in a sample of younger adults. The present work demonstrates high seven-month test-retest reliability of striatal and extrastriatal C-raclopride BP values in healthy, older adults (n = 27, age: 64-78 years). Mean C-raclopride BP values were stable between test sessions in subcortical nuclei, and in frontal and temporal cortices (p > 0.05). Across all structures analyzed, intraclass correlation coefficients were high (0.85-0.96), absolute variability was low (mean: 4-8%), and coefficients of variance ranged between 9 and 25%. Furthermore, regional C-raclopride BP values correlated with previously determined F-fallypride BP values (ρ = 0.97 and 0.92 in correlations with and without striatal values, respectively, p < 0.01) and postmortem determined D2-receptor densities (including striatum: ρ = 0.92; p < 0.001; excluding striatum: ρ = 0.75; p = 0.067). These observations suggest that extrastriatal C-raclopride measurements represent a true D2 signal.
Topics: Adult; Aged; Benzamides; Carbon Radioisotopes; Cerebral Cortex; Corpus Striatum; Dopamine Agonists; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Pyrrolidines; Raclopride; Radiopharmaceuticals; Receptors, Dopamine D2; Reproducibility of Results; Young Adult
PubMed: 31506011
DOI: 10.1177/0271678X19874770 -
Journal of Affective Disorders Jul 2024Depression is a chronic psychiatric disorder related to diminished dopaminergic neurotransmission. Deep brain stimulation (DBS) has shown effectiveness in treating...
BACKGROUND
Depression is a chronic psychiatric disorder related to diminished dopaminergic neurotransmission. Deep brain stimulation (DBS) has shown effectiveness in treating patients with treatment-refractory depression (TRD). This study aimed to evaluate the effect of DBS on dopamine D2 receptor binding in patients with TRD.
METHODS
Six patients with TRD were treated with bed nucleus of the stria terminalis (BNST)-nucleus accumbens (NAc) DBS were recruited. Ultra-high sensitivity [C]raclopride dynamic total-body positron emission tomography (PET) imaging was used to assess the brain D2 receptor binding. Each patient underwent a [C]raclopride PET scan for 60-min under DBS OFF and DBS ON, respectively. A simplified reference tissue model was used to generate parametric images of binding potential (BP) with the cerebellum as reference tissue.
RESULTS
Depression and anxiety symptoms improved after 3-6 months of DBS treatment. Compared with two-day-nonstimulated conditions, one-day BNST-NAc DBS decreased [C]raclopride BP in the amygdala (15.9 %, p < 0.01), caudate nucleus (15.4 %, p < 0.0001) and substantia nigra (10.8 %, p < 0.01).
LIMITATIONS
This study was limited to the small sample size and lack of a healthy control group.
CONCLUSIONS
Chronic BNST-NAc DBS improved depression and anxiety symptoms, and short-term stimulation decreased D2 receptor binding in the amygdala, caudate nucleus, and substantia nigra. The findings suggest that DBS relieves depression and anxiety symptoms possibly by regulating the dopaminergic system.
Topics: Humans; Receptors, Dopamine D2; Deep Brain Stimulation; Male; Positron-Emission Tomography; Female; Middle Aged; Depressive Disorder, Treatment-Resistant; Nucleus Accumbens; Adult; Raclopride; Septal Nuclei; Brain; Treatment Outcome
PubMed: 38657771
DOI: 10.1016/j.jad.2024.04.082 -
Frontiers in Molecular Biosciences 2023There is now evidence from multiple Phase II clinical trials that psychedelic drugs can exert long-lasting anxiolytic, anti-depressant, and anti-drug abuse (nicotine and...
There is now evidence from multiple Phase II clinical trials that psychedelic drugs can exert long-lasting anxiolytic, anti-depressant, and anti-drug abuse (nicotine and ethanol) effects in patients. Despite these benefits, the hallucinogenic actions of these drugs at the serotonin 2A receptor (5-HT2AR) limit their clinical use in diverse settings. Activation of the 5-HT2AR can stimulate both G protein and -arrestin (βArr) -mediated signaling. Lisuride is a G protein biased agonist at the 5-HT2AR and, unlike the structurally-related lysergic acid diethylamide (LSD), the drug does not typically produce hallucinations in normal subjects at routine doses. Here, we examined behavioral responses to lisuride, in wild-type (WT), βArr1-knockout (KO), and βArr2-KO mice. In the open field, lisuride reduced locomotor and rearing activities, but produced a U-shaped function for stereotypies in both βArr lines of mice. Locomotion was decreased overall in βArr1-KOs and βArr2-KOs relative to wild-type controls. Incidences of head twitches and retrograde walking to lisuride were low in all genotypes. Grooming was decreased in βArr1 mice, but was increased then decreased in βArr2 animals with lisuride. Serotonin syndrome-associated responses were present at all lisuride doses in WTs, but they were reduced especially in βArr2-KO mice. Prepulse inhibition (PPI) was unaffected in βArr2 mice, whereas 0.5 mg/kg lisuride disrupted PPI in βArr1 animals. The 5-HT2AR antagonist MDL100907 failed to restore PPI in βArr1 mice, whereas the dopamine D2/D3 antagonist raclopride normalized PPI in WTs but not in βArr1-KOs. Clozapine, SCH23390, and GR127935 restored PPI in both βArr1 genotypes. Using vesicular monoamine transporter 2 mice, lisuride reduced immobility times in tail suspension and promoted a preference for sucrose that lasted up to 2 days. Together, it appears βArr1 and βArr2 play minor roles in lisuride's actions on many behaviors, while this drug exerts anti-depressant drug-like responses without hallucinogenic-like activities.
PubMed: 37900918
DOI: 10.3389/fmolb.2023.1233743 -
Medical Image Analysis Dec 2021Although supervised convolutional neural networks (CNNs) often outperform conventional alternatives for denoising positron emission tomography (PET) images, they require...
Although supervised convolutional neural networks (CNNs) often outperform conventional alternatives for denoising positron emission tomography (PET) images, they require many low- and high-quality reference PET image pairs. Herein, we propose an unsupervised 3D PET image denoising method based on an anatomical information-guided attention mechanism. The proposed magnetic resonance-guided deep decoder (MR-GDD) utilizes the spatial details and semantic features of MR-guidance image more effectively by introducing encoder-decoder and deep decoder subnetworks. Moreover, the specific shapes and patterns of the guidance image do not affect the denoised PET image, because the guidance image is input to the network through an attention gate. In a Monte Carlo simulation of [F]fluoro-2-deoxy-D-glucose (FDG), the proposed method achieved the highest peak signal-to-noise ratio and structural similarity (27.92 ± 0.44 dB/0.886 ± 0.007), as compared with Gaussian filtering (26.68 ± 0.10 dB/0.807 ± 0.004), image guided filtering (27.40 ± 0.11 dB/0.849 ± 0.003), deep image prior (DIP) (24.22 ± 0.43 dB/0.737 ± 0.017), and MR-DIP (27.65 ± 0.42 dB/0.879 ± 0.007). Furthermore, we experimentally visualized the behavior of the optimization process, which is often unknown in unsupervised CNN-based restoration problems. For preclinical (using [F]FDG and [C]raclopride) and clinical (using [F]florbetapir) studies, the proposed method demonstrates state-of-the-art denoising performance while retaining spatial resolution and quantitative accuracy, despite using a common network architecture for various noisy PET images with 1/10th of the full counts. These results suggest that the proposed MR-GDD can reduce PET scan times and PET tracer doses considerably without impacting patients.
Topics: Fluorodeoxyglucose F18; Humans; Image Processing, Computer-Assisted; Neural Networks, Computer; Positron-Emission Tomography; Signal-To-Noise Ratio
PubMed: 34563861
DOI: 10.1016/j.media.2021.102226 -
Frontiers in Pharmacology 2023Experimental and clinical evidence indicates a deficit of release and function of dopamine in schizophrenia and suggests that α-adrenoceptor antagonists rescue dopamine...
Combined α- and D-receptor blockade activates noradrenergic and dopaminergic neurons, but extracellular dopamine in the prefrontal cortex is determined by uptake and release from noradrenergic terminals.
Experimental and clinical evidence indicates a deficit of release and function of dopamine in schizophrenia and suggests that α-adrenoceptor antagonists rescue dopamine deficit and improve the antipsychotic efficacy of D-receptor antagonists. In anesthetized male rats, we investigated how the blockade of α- and D-receptors by atipamezole and raclopride, respectively, modified the firing of noradrenergic neurons in the locus coeruleus (LC) and dopaminergic neurons in the ventral tegmental area (VTA). In freely moving rats, we studied how atipamezole and raclopride modified extracellular noradrenaline, dopamine, and DOPAC levels in the medial prefrontal cortex (mPFC) through microdialysis. When administered alone, atipamezole activated LC noradrenaline but not VTA dopamine cell firing. Combined with raclopride, atipamezole activated dopamine cell firing above the level produced by raclopride. Atipamezole increased extracellular dopamine to the same level, whether administered alone or combined with raclopride. In the presence of the noradrenaline transporter (NET) inhibitor, atipamezole combined with raclopride increased extracellular dopamine beyond the level produced by either compound administered alone. The results suggest that a) the D-autoreceptor blockade is required for LC noradrenaline to activate VTA cell firing; b) the level of dopamine released from dopaminergic terminals is determined by NET; c) the elevation of extracellular dopamine levels in the mPFC is the resultant of dopamine uptake and release from noradrenergic terminals, independent of dopaminergic cell firing and release; and d) LC noradrenergic neurons are an important target for treatments to improve the prefrontal deficit of dopamine in neuropsychiatric pathologies.
PubMed: 37680715
DOI: 10.3389/fphar.2023.1238115