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Nature Communications Jan 2019To date, the spatiotemporal release of specific neurotransmitters at physiological levels in the human brain cannot be detected. Here, we present a method that relates...
To date, the spatiotemporal release of specific neurotransmitters at physiological levels in the human brain cannot be detected. Here, we present a method that relates minute-by-minute fluctuations of the positron emission tomography (PET) radioligand [11C]raclopride directly to subsecond dopamine release events. We show theoretically that synaptic dopamine release induces low frequency temporal variations of extrasynaptic extracellular dopamine levels, at time scales of one minute, that can evoke detectable temporal variations in the [11C]raclopride signal. Hence, dopaminergic activity can be monitored via temporal fluctuations in the [11C]raclopride PET signal. We validate this theory using fast-scan cyclic voltammetry and [11C]raclopride PET in mice during chemogenetic activation of dopaminergic neurons. We then apply the method to data from human subjects given a palatable milkshake and discover immediate and-for the first time-delayed food-induced dopamine release. This method enables time-dependent regional monitoring of stimulus-evoked dopamine release at physiological levels.
Topics: Animals; Brain; Dopamine; Eating; Electric Stimulation; Electrodes; Female; Humans; Male; Mice; Models, Biological; Neurons; Positron-Emission Tomography; Raclopride; Radioligand Assay; Temporal Lobe; Time Factors
PubMed: 30659189
DOI: 10.1038/s41467-018-08143-4 -
The Journal of Clinical Endocrinology... Sep 2021Activity in the dopaminergic pathways of the brain is highly sensitive to body weight and metabolic states. Animal studies show that dopamine neurons are important... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Activity in the dopaminergic pathways of the brain is highly sensitive to body weight and metabolic states. Animal studies show that dopamine neurons are important targets for the metabolic hormone insulin with abolished effects in the insulin-resistant state, leading to increases in body weight and food intake. In humans, the influence of central acting insulin on dopamine and effects of their interplay are still elusive.
RESEARCH DESIGN AND METHODS
We investigated whether central administered insulin influences dopaminergic activity in striatal regions and whole-brain neural activity. Using a positron emission tomography (PET)/magnetic resonance imaging (MRI) hybrid scanner, we simultaneously performed [11C]-raclopride-PET and resting-state functional MRI in 10 healthy normal-weight men after application of intranasal insulin or placebo on 2 separate days in a randomized, placebo-controlled, blinded, crossover trial.
RESULTS
In response to central insulin compared with placebo administration, we observed greater [11C]-raclopride binding potential in the bilateral ventral and dorsal striatum. This suggests an insulin-induced reduction in synaptic dopamine levels. Resting-state striatal activity was lower 15 and 30 minutes after nasal insulin compared with placebo. Functional connectivity of the mesocorticolimbic circuitry associated with differences in dopamine levels: individuals with a stronger insulin-induced effect on dopamine levels showed a stronger increase in functional connectivity 45 minutes after intranasal insulin.
CONCLUSIONS
This study indicates that central insulin modulates dopaminergic tone in the striatum, which may affect regional brain activity and connectivity. Our results deepen the understanding of the insulin-dopamine interaction and the complex network that underlies the regulation of whole-body metabolism.
Topics: Administration, Intranasal; Adult; Brain; Corpus Striatum; Cross-Over Studies; Dopamine; Healthy Volunteers; Humans; Insulin; Magnetic Resonance Imaging; Male; Neural Pathways; Positron-Emission Tomography; Single-Blind Method
PubMed: 34131733
DOI: 10.1210/clinem/dgab410 -
Journal of Neural Engineering Apr 2021To explore the viability of developing a computer-aided diagnostic system for Parkinsonian syndromes using dynamic [C]raclopride positron emission tomography (PET) and...
To explore the viability of developing a computer-aided diagnostic system for Parkinsonian syndromes using dynamic [C]raclopride positron emission tomography (PET) and T1-weighted magnetic resonance imaging (MRI) data.The biological heterogeneity of Parkinsonian syndromes renders their statistical classification a challenge. The unique combination of structural and molecular imaging data allowed different classifier designs to be tested. Datasets from dynamic [C]raclopride PET and T1-weighted MRI scans were acquired from six groups of participants. There were healthy controls (CTRL= 15), patients with Parkinson's disease (PD= 27), multiple system atrophy (MSA= 8), corticobasal degeneration (CBD= 6), and dementia with Lewy bodies (DLB= 5). MSA, CBD, and DLB patients were classified into one category designated as atypical Parkinsonism (AP). The distribution volume ratio (DVR) kinetic parameters obtained from the PET data were used to quantify the reversible tracer binding to D2/D3 receptors in the subcortical regions of interest (ROI). The grey matter (GM) volumes obtained from the MRI data were used to quantify GM atrophy across cortical, subcortical, and cerebellar ROI.The classifiers CTRL vs PD and CTRL vs AP achieved the highest balanced accuracy combining DVR and GM (DVR-GM) features (96.7%, 92.1%, respectively), followed by the classifiers designed with DVR features (93.3%, 88.8%, respectively), and GM features (69.6%, 86.1%, respectively). In contrast, the classifier PD vs AP showed the highest balanced accuracy (78.9%) using DVR features only. The integration of DVR-GM (77.9%) and GM features (72.7%) produced inferior performances. The classifier CTRL vs PD vs AP showed high weighted balanced accuracy when DVR (80.5%) or DVR-GM features (79.9%) were integrated. GM features revealed poorer performance (59.5%).This work was unique in its combination of structural and molecular imaging features in binary and triple category classifications. We were able to demonstrate improved binary classification of healthy/diseased status (concerning both PD and AP) and equate performance to DVR features in multiclass classifications.
Topics: Gray Matter; Humans; Magnetic Resonance Imaging; Parkinson Disease; Parkinsonian Disorders; Positron-Emission Tomography; Raclopride
PubMed: 33848996
DOI: 10.1088/1741-2552/abf772 -
The Journal of Neuroscience : the... Sep 2021Acetaldehyde (ACD), the first metabolite of ethanol, is implicated in several of ethanol's actions, including the reinforcing and aversive effects. The neuronal...
Acetaldehyde (ACD), the first metabolite of ethanol, is implicated in several of ethanol's actions, including the reinforcing and aversive effects. The neuronal mechanisms underlying ACD's aversive effect, however, are poorly understood. The lateral habenula (LHb), a regulator of midbrain monoaminergic centers, is activated by negative valence events. Although the LHb has been linked to the aversive responses of several abused drugs, including ethanol, little is known about ACD. We, therefore, assessed ACD's action on LHb neurons in rats. The results showed that intraperitoneal injection of ACD increased cFos protein expression within the LHb and that intra-LHb infusion of ACD induced conditioned place aversion in male rats. Furthermore, electrophysiological recording in brain slices of male and female rats showed that bath application of ACD facilitated spontaneous firing and glutamatergic transmission. This effect of ACD was potentiated by an aldehyde dehydrogenase (ALDH) inhibitor, disulfiram (DS), but attenuated by the antagonists of dopamine (DA) receptor (DAR) subtype 1 (SCH23390) and subtype 2 (raclopride), and partly abolished by the pretreatment of DA or DA reuptake blocker (GBR12935; GBR). Moreover, application of ACD initiated a depolarizing inward current () and enhanced the hyperpolarizing-activated currents in LHb neurons. Bath application of Rp-cAMPs, a selective cAMP-PKA inhibitor, attenuated ACD-induced potentiation of EPSCs and Finally, bath application of ZD7288, a selective blocker of hyperpolarization-activated cyclic nucleotide-gated channels, attenuated ACD-induced potentiation of firing, EPSCs, and These results show that ACD exerts its aversive property by exciting LHb neurons via multiple cellular mechanisms, and new treatments targeting the LHb may be beneficial for alcoholism. Acetaldehyde (ACD) has been considered aversive peripherally and rewarding centrally. However, whether ACD has a central aversive property is unclear. Here, we report that ACD excites the lateral habenula (LHb), a brain region associated with aversion and negative valence, through multiple cellular and molecular mechanisms. Intra-LHb ACD produces significant conditioned place aversion. These results suggest that ACD's actions on the LHb neurons might contribute to its central aversive property and new treatments targeting the LHb may be beneficial for alcoholism.
Topics: Acetaldehyde; Animals; Avoidance Learning; Disulfiram; Dopamine Antagonists; Dopamine Uptake Inhibitors; Glutamic Acid; Habenula; Male; Neurons; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Synaptic Transmission
PubMed: 34326141
DOI: 10.1523/JNEUROSCI.2913-20.2021 -
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 Nov 2015Dopamine and opioid neurotransmitter systems share many functions such as regulation of reward and pleasure. μ-Opioid receptors (MOR) modulate the mesolimbic dopamine...
Dopamine and opioid neurotransmitter systems share many functions such as regulation of reward and pleasure. μ-Opioid receptors (MOR) modulate the mesolimbic dopamine system in ventral tegmental area and striatum, key areas implicated in reward. We hypothesized that dopamine and opioid receptor availabilities correlate in vivo and that this correlation is altered in obesity, a disease with altered reward processing. Twenty lean females (mean BMI 22) and 25 non-binge eating morbidly obese females (mean BMI 41) underwent two positron emission tomography scans with [(11)C]carfentanil and [(11)C]raclopride to measure the MOR and dopamine D2 receptor (DRD2) availability, respectively. In lean subjects, the MOR and DRD2 availabilities were positively associated in the ventral striatum (r=0.62, p=0.003) and dorsal caudate nucleus (r=0.62, p=0.004). Moreover, DRD2 availability in the ventral striatum was associated with MOR availability in other regions of the reward circuitry, particularly in the ventral tegmental area. In morbidly obese subjects, this receptor interaction was significantly weaker in ventral striatum but unaltered in the caudate nucleus. Finally, the association between DRD2 availability in the ventral striatum and MOR availability in the ventral tegmental area was abolished in the morbidly obese. The study demonstrates a link between DRD2 and MOR availabilities in living human brain. This interaction is selectively disrupted in mesolimbic dopamine system in morbid obesity. We propose that interaction between the dopamine and opioid systems is a prerequisite for normal reward processing and that disrupted cross-talk may underlie altered reward processing in obesity.
Topics: Adult; Body Mass Index; Caudate Nucleus; Female; Fentanyl; Humans; Middle Aged; Obesity; Positron-Emission Tomography; Putamen; Raclopride; Receptors, Dopamine D2; Receptors, Opioid, mu; Reward; Ventral Striatum
PubMed: 26260431
DOI: 10.1016/j.neuroimage.2015.08.001 -
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