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Molecules (Basel, Switzerland) Jan 2020Huntington's disease (HD) is a fatal neurodegenerative disease caused by a CAG expansion mutation in the gene. As a result, intranuclear inclusions of mutant huntingtin... (Review)
Review
Huntington's disease (HD) is a fatal neurodegenerative disease caused by a CAG expansion mutation in the gene. As a result, intranuclear inclusions of mutant huntingtin protein are formed, which damage striatal medium spiny neurons (MSNs). A review of Positron Emission Tomography (PET) studies relating to HD was performed, including clinical and preclinical data. PET is a powerful tool for visualisation of the HD pathology by non-invasive imaging of specific radiopharmaceuticals, which provide a detailed molecular snapshot of complex mechanistic pathways within the brain. Nowadays, radiochemists are equipped with an impressive arsenal of radioligands to accurately recognise particular receptors of interest. These include key biomarkers of HD: adenosine, cannabinoid, dopaminergic and glutamateric receptors, microglial activation, phosphodiesterase 10 A and synaptic vesicle proteins. This review aims to provide a radiochemical picture of the recent developments in the field of HD PET, with significant attention devoted to radiosynthetic routes towards the tracers relevant to this disease.
Topics: Biomarkers; Brain; Cannabinoid Receptor Agonists; Carbon Radioisotopes; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Fluorine Radioisotopes; GABA Antagonists; Humans; Huntington Disease; Microglia; Phosphodiesterase Inhibitors; Positron-Emission Tomography; Purinergic P1 Receptor Antagonists; Radiopharmaceuticals
PubMed: 31979301
DOI: 10.3390/molecules25030482 -
Journal of Pain Research 2021It has been suggested that reward system dysfunction may account for emotion and pain suffering in migraine. However, there is a lack of evidence whether the altered...
PURPOSE
It has been suggested that reward system dysfunction may account for emotion and pain suffering in migraine. However, there is a lack of evidence whether the altered reward system connectivity is directly associated with clinical manifestations, including negative affect and ictal pain severity and, at the molecular level, the dopamine (DA) D2/D3 receptors (D2/3Rs) signaling implicated in encoding motivational and emotional cues.
PATIENTS AND METHODS
We acquired resting-state functional MRI from interictal episodic migraine (EM) patients and age-matched healthy controls, as well as positron emission tomography (PET) with [C]raclopride, a selective radiotracer for DA D2/3Rs, from a subset of these participants. The nucleus accumbens (NAc) was seeded to measure functional connectivity (FC) and DA D2/3Rs availability based on its essential involvement in pain-related aversive/reward functions. Associations of the brain measures with positive/negative affect and ictal pain severity were also assessed.
RESULTS
Compared with controls, the EM group showed weaker right NAc connectivity with areas implicated in pain and emotional regulation, such as the amygdala, rostral anterior cingulate cortex, hippocampus, and thalamus; but showed stronger left NAc connectivity with the dorsolateral prefrontal cortex and lingual gyrus. Moreover, among the altered NAc connectivities, only right NAc-amygdala connectivity was inversely correlated with DA D2/3Rs availability in migraine patients (diagnostic group-by-D2/3Rs interaction p < 0.007). At a clinical level, such weaker NAc-amygdala connectivity was associated with lower interictal positive affect and greater ictal pain severity over the head and facial extension area (pain area and intensity number summation, PAINS).
CONCLUSION
Together, our findings suggest that altered reward system connectivity, specifically between the NAc and amygdala, might be affected by endogenous DA D2/3Rs signaling, and such process might be a neural mechanism that underlies emotional and pain suffering in episodic migraineurs.
PubMed: 33727857
DOI: 10.2147/JPR.S296540 -
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 -
Translational Psychiatry May 2021Obesity is a growing burden to health and the economy worldwide. Obesity is associated with central µ-opioid receptor (MOR) downregulation and disruption of the...
Obesity is a growing burden to health and the economy worldwide. Obesity is associated with central µ-opioid receptor (MOR) downregulation and disruption of the interaction between MOR and dopamine D receptor (DR) system in the ventral striatum. Weight loss recovers MOR function, but it remains unknown whether it also recovers aberrant opioid-dopamine interaction. Here we addressed this issue by studying 20 healthy non-obese and 25 morbidly obese women (mean BMI 41) eligible for bariatric surgery. Brain MOR and DR availability were measured using positron emission tomography (PET) with [C]carfentanil and [C]raclopride, respectively. Either Roux-en-Y gastric bypass or sleeve gastrectomy was performed on obese subjects according to standard clinical treatment. 21 obese subjects participated in the postoperative PET scanning six months after bariatric surgery. In the control subjects, MOR and DR availabilities were associated in the ventral striatum (r = .62) and dorsal caudate (r = .61). Preoperatively, the obese subjects had disrupted association in the ventral striatum (r = .12) but the unaltered association in dorsal caudate (r = .43). The association between MOR and DR availabilities in the ventral striatum was recovered (r = .62) among obese subjects following the surgery-induced weight loss. Bariatric surgery and concomitant weight loss recover the interaction between MOR and DR in the ventral striatum in the morbidly obese. Consequently, the dysfunctional opioid-dopamine interaction in the ventral striatum is likely associated with an obese phenotype and may mediate excessive energy uptake. Striatal opioid-dopamine interaction provides a feasible target for pharmacological and behavioral interventions for treating obesity.
Topics: Analgesics, Opioid; Bariatric Surgery; Dopamine; Female; Humans; Obesity, Morbid; Positron-Emission Tomography; Receptors, Dopamine D2; Weight Loss
PubMed: 33934103
DOI: 10.1038/s41398-021-01370-2 -
Neuropathology and Applied Neurobiology Feb 2023CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in...
AIMS
CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia.
METHODS
The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride.
RESULTS
CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice.
CONCLUSIONS
Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.
Topics: Humans; Mice; Animals; Adolescent; Mice, Transgenic; Cytochrome P-450 CYP2C19; Ataxia; Cerebellum; Cerebellar Diseases; Neurodegenerative Diseases; Atrophy; Disease Models, Animal
PubMed: 36536486
DOI: 10.1111/nan.12867 -
Neuropsychopharmacology : Official... Apr 2020Impaired cognitive flexibility in visual reversal-learning tasks has been observed in a wide range of neurological and neuropsychiatric disorders. Although both human...
Impaired cognitive flexibility in visual reversal-learning tasks has been observed in a wide range of neurological and neuropsychiatric disorders. Although both human and animal studies have implicated striatal D-like and D-like receptors (D2R; D1R) in this form of flexibility, less is known about the contribution they make within distinct sub-regions of the striatum and the different phases of visual reversal learning. The present study investigated the involvement of D2R and D1R during the early (perseverative) phase of reversal learning as well as in the intermediate and late stages (new learning) after microinfusions of D2R and D1R antagonists into the nucleus accumbens core and shell (NAcC; NAcS), the anterior and posterior dorsomedial striatum (DMS) and the dorsolateral striatum (DLS) on a touchscreen visual serial reversal-learning task. Reversal learning was improved after dopamine receptor blockade in the nucleus accumbens; the D1R antagonist, SCH23390, in the NAcS and the D2R antagonist, raclopride, in the NAcC selectively reduced early, perseverative errors. In contrast, reversal learning was impaired by D2R antagonism, but not D1R antagonism, in the dorsal striatum: raclopride increased errors in the intermediate phase after DMS infusions, and increased errors across phases after DLS infusions. These findings indicate that D1R and D2R modulate different stages of reversal learning through effects localised to different sub-regions of the striatum. Thus, deficits in behavioral flexibility observed in disorders linked to dopamine perturbations may be attributable to specific D1R and D2R dysfunction in distinct striatal sub-regions.
Topics: Animals; Discrimination, Psychological; Male; Neostriatum; Nucleus Accumbens; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Reversal Learning; Visual Perception
PubMed: 31940660
DOI: 10.1038/s41386-020-0612-4 -
Proceedings of the National Academy of... Jan 2021The link between synaptic plasticity and reorganization of brain activity in health and disease remains a scientific challenge. We examined this question in Parkinson's...
The link between synaptic plasticity and reorganization of brain activity in health and disease remains a scientific challenge. We examined this question in Parkinson's disease (PD) where functional up-regulation of postsynaptic D receptors has been documented while its significance at the neural activity level has never been identified. We investigated cortico-subcortical plasticity in PD using the oculomotor system as a model to study reorganization of dopaminergic networks. This model is ideal because this system reorganizes due to frontal-to-parietal shifts in blood oxygen level-dependent (BOLD) activity. We tested the prediction that functional activation plasticity is associated with postsynaptic dopaminergic modifications by combining positron emission tomography/functional magnetic resonance imaging to investigate striatal postsynaptic reorganization of dopamine D receptors (using C-raclopride) and neural activation in PD. We used covariance (connectivity) statistics at molecular and functional levels to probe striato-cortical reorganization in PD in on/off medication states to show that functional and molecular forms of reorganization are related. D binding across regions defined by prosaccades showed increased molecular connectivity between both caudate/putamen and hyperactive parietal eye fields in PD in contrast with frontal eye fields in controls, in line with the shift model. Concerning antisaccades, parietal-striatal connectivity dominated in again in PD, unlike frontal regions. Concerning molecular-BOLD covariance, a striking sign reversal was observed: PD patients showed negative frontal-putamen functional-molecular associations, consistent with the reorganization shift, in contrast with the positive correlations observed in controls. Follow-up analysis in off-medication PD patients confirmed the negative BOLD-molecular correlation. These results provide a link among BOLD responses, striato-cortical synaptic reorganization, and neural plasticity in PD.
Topics: Aged; Brain Mapping; Case-Control Studies; Caudate Nucleus; Dopamine; Dopamine Antagonists; Female; Frontal Lobe; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuronal Plasticity; Neurons; Oxygen; Parietal Lobe; Parkinson Disease; Positron-Emission Tomography; Putamen; Raclopride; Receptors, Dopamine D2; Saccades; Synapses
PubMed: 33431672
DOI: 10.1073/pnas.2013962118 -
Reproductive Medicine and Biology 2022In humans, catecholamines (including dopamine) have been identified in semen and fallopian tubes, while dopamine D2 receptors (D2DR) are found in the sperm midpiece...
PURPOSE
In humans, catecholamines (including dopamine) have been identified in semen and fallopian tubes, while dopamine D2 receptors (D2DR) are found in the sperm midpiece region. How dopamine dose affects human sperm function and whether dopamine treatment is useful in assisted reproductive technology is unclear.
METHODS
Sperm samples were obtained from patients with normal semen parameters undergoing fertility treatment. We investigated the effects of dopamine treatment on tyrosine phosphorylation and sperm motility. Sperm motility was analyzed using the computer-assisted sperm analysis (CASA) system.
RESULTS
This study revealed that various dopamine concentrations (0.1-100 μM) did not increase sperm tyrosine phosphorylation. Progressive motility increased substantially when treated with high concentrations of dopamine (10 and 100 μM) and was blocked by raclopride (a D2DR antagonist). After 24-h sperm culture, the addition of 10 μM dopamine significantly increased curvilinear velocity and amplitude of lateral head displacement, which are indicators of hyperactivation.
CONCLUSION
Dopamine did not affect tyrosine phosphorylation, but increased sperm motility. High concentrations of dopamine were more effective to accelerate sperm motility in cases where sperm motile capacity was low.
PubMed: 36310655
DOI: 10.1002/rmb2.12482 -
Journal of Neurophysiology Jul 2022Abnormalities of auditory steady-state responses (ASSRs) and the effects of antipsychotic drugs on ASSRs have been investigated in patients with schizophrenia. It is...
Abnormalities of auditory steady-state responses (ASSRs) and the effects of antipsychotic drugs on ASSRs have been investigated in patients with schizophrenia. It is presumed that drugs do not directly affect ASSRs because its abnormalities are associated with schizophrenia. Therefore, to investigate the direct effect of drugs on ASSRs, we established an ASSR evaluation system for common marmosets in a naïve state. Dopamine D1 receptor stimulation (SKF-81297, 2 mg/kg ip) significantly increased evoked power (EP) at 40 Hz. The phase locking factor (PLF) was increased significantly at 20, 30, 40, and 80 Hz. However, administration of a dopamine D1 receptor antagonist (SCH-39166, 0.3 mg/kg ip) resulted in a significant decrease in EP and PLF at 30 Hz. Dopamine D2 receptor stimulation (quinpirole, 1 mg/kg im) tended to increase EP and induced power (IP) at all frequencies, and a significant difference was observed at 30 Hz IP. There was no change in PLF at all frequencies. In addition, dopamine D2 receptor blockade (raclopride, 3 mg/kg ip) reduced EP and PLF at 30 Hz. Subcutaneous administration of the serotonin dopamine antagonist, risperidone (0.3 mg/kg), tended to increase IP and decrease PLF, but not significantly. Taken together, it is possible to compare the differences in the mode of action of drugs on ASSRs using naïve nonhuman primates. We measured the effects of dopamine receptor-related compounds on ASSR in marmosets. D1 receptor stimulation increased the phase locking factor (PLF) and evoked power (EP), and reduced the induced power (IP). D2 receptor stimulation increased the IP. D1 and D2 receptor blockers reduced the PLF and EP at 30 Hz. Different modes of action of various drugs related to psychiatric disorders were evaluated by administering antipsychotic drugs to naïve marmosets.
Topics: Acoustic Stimulation; Animals; Antipsychotic Agents; Callithrix; Dopamine Antagonists; Evoked Potentials, Auditory; Humans; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 35583977
DOI: 10.1152/jn.00147.2022 -
Physics in Medicine and Biology May 2021We describe an intuitive, easy to use method called PET-ABC that enables full Bayesian statistical inference from single subject dynamic PET data. The performance of...
We describe an intuitive, easy to use method called PET-ABC that enables full Bayesian statistical inference from single subject dynamic PET data. The performance of PET-ABC was compared with weighted non-linear least squares (WNLS) in terms of reliability of kinetic parameter estimation and statistical power for model selection.Dynamic PET data based on 1-tissue and 2-tissue compartmental models were simulated with 2 noise models and 3 noise levels. PET-ABC was used to evaluate the reliability of parameter estimates under each condition. It was also used to perform model selection for a simulated noisy dataset composed of a mixture of 1- and 2-tissue compartment kinetics. Finally, PET-ABC was used to analyze a non-steady state dynamic [C] raclopride study performed on a fully conscious rat administered either 2 mg.kgamphetamine or saline 20 min after tracer injection.PET-ABC yielded posterior point estimates for model parameters with smaller variance than WNLS, as well as probability density functions indicating confidence intervals for those estimates. It successfully identified the superiority of a 2-tissue compartment model to fit the simulated mixed model data. For the drug challenge study, the post observation probability of striatal displacement of the PET signal was 0.9 for amphetamine and approximately 0 for saline, indicating a high probability of amphetamine-induced endogenous dopamine release in the striatum. PET-ABC also demonstrated superior statistical power to WNLS (0.87 versus 0.09) for selecting the correct model in a simulated ligand displacement study.PET-ABC is a simple and intuitive method that provides complete Bayesian statistical analysis of single subject dynamic PET data, including the extent to which model parameter estimates and model choice are supported by the data. Software for PET-ABC is freely available as part of thePETabcpackagehttps://github.com/cgrazian/PETabc.
Topics: Animals; Bayes Theorem; Kinetics; Positron-Emission Tomography; Probability; Rats; Reproducibility of Results
PubMed: 33882476
DOI: 10.1088/1361-6560/abfa37