raclopride and Parkinsonian-Disorders

Although pure cerebellar ataxia is usually emphasized as the characteristic clinical feature of spinocerebellar ataxia type 6 (SCA6), parkinsonism has been repeatedly described in patients with genetically confirmed SCA6.. We conducted a positron emission tomography study using a combination of [. Most patients had somewhat decreased dopaminergic function, and this decrease was significant in the caudate nucleus. In addition, one SCA6 patient with parkinsonism had whole striatal dysfunction of both dopamine synthesis and dopamine D2 receptor function.. The pathology of SCA6 may not be restricted to the cerebellum, but may also be distributed across various regions, including in both presynaptic and postsynaptic dopaminergic neurons to some degree. Patients with SCA6 may show apparent parkinsonism after the progression of neurodegeneration.

Topics: Dopamine; Humans; Parkinsonian Disorders; Positron-Emission Tomography; Raclopride; Spinocerebellar Ataxias

A growing body of evidence indicates that impairment of the ubiquitin-proteasome (UPS) system in the substantia nigra (SN) plays an important role in the pathogenesis of Parkinson's disease (PD). The aim of our study was to compare two unilateral rat models, one produced by intranigral administration of the UPS inhibitor lactacystin or the other induced by 6-OHDA, in terms of their effect on the amphetamine- and apomorphine-induced rotational behavior, striatal dopamine (DA) D1 and D2 receptor sensitivity and tissue levels of DA and its metabolites. We found that these models did not differ in the intensity of ipsilateral rotations induced by amphetamine. In contrast, apomorphine produced contralateral rotations only in 6-OHDA-lesioned rats, and, depending on the dose, it induced either no or moderate ipsilateral rotations in the lactacystin-lesioned group. In addition, lactacystin induced a strong reduction in the tissue DA level and its metabolites in the lesioned striatum and SN when measured three weeks after the administration which was aggravated six weeks post-lesion, reaching the level comparable to the 6-OHDA group. Binding of [3H]raclopride to D2 receptors was increased in the lesioned striatum in both investigated (PD) models six weeks after lesion. In turn, binding of [3H]SCH23390 to the striatal D1 receptors was not changed in the lactacystin group but was increased bilaterally in the 6-OHDA group. The present results add a new value to the study of DA receptor sensitivity and are discussed in the context of the validity of the lactacystin model as a suitable model of Parkinson's disease.

Topics: Acetylcysteine; Amphetamine; Animals; Apomorphine; Benzazepines; Central Nervous System Stimulants; Corpus Striatum; Dopamine; Dopamine Agents; Dose-Response Relationship, Drug; Functional Laterality; Male; Motor Activity; Oxidopamine; Parkinsonian Disorders; Pars Compacta; Raclopride; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Rotation

Many current therapies target G protein coupled receptors (GPCR), transporters, or ion channels. In addition to directly targeting these proteins, disrupting the protein-protein interactions that localize or regulate their function could enhance selectivity and provide unique pharmacologic actions. Regulators of G protein signaling (RGS) proteins, especially RGS4, play significant roles in epilepsy and Parkinson's disease. Thiadiazolidinone (TDZD) inhibitors of RGS4 are nanomolar potency blockers of the biochemical actions of RGS4 in vitro. Here, we demonstrate the substantial selectivity (8- to >5000-fold) of CCG-203769 for RGS4 over other RGS proteins. It is also 300-fold selective for RGS4 over GSK-3β, another target of this class of chemical scaffolds. It does not inhibit the cysteine protease papain at 100 μM. CCG-203769 enhances Gαq-dependent cellular Ca(2+) signaling in an RGS4-dependent manner. TDZD inhibitors also enhance Gαi-dependent δ-OR inhibition of cAMP production in SH-SY-5Y cells, which express endogenous receptors and RGS4. Importantly, CCG-203769 potentiates the known RGS4 mechanism of Gαi-dependent muscarinic bradycardia in vivo. Furthermore, it reverses raclopride-induced akinesia and bradykinesia in mice, a model of some aspects of the movement disorder in Parkinson's disease. A broad assessment of compound effects revealed minimal off-target effects at concentrations necessary for cellular RGS4 inhibition. These results expand our understanding of the mechanism and specificity of TDZD RGS inhibitors and support the potential for therapeutic targeting of RGS proteins in Parkinson's disease and other neural disorders.

Topics: Animals; Antiparkinson Agents; Bradycardia; Calcium; Carbachol; Cell Line, Tumor; Cholinergic Agonists; Cyclic AMP; Dose-Response Relationship, Drug; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; HEK293 Cells; Humans; Male; Mice, Inbred C57BL; Motor Activity; Papain; Parkinsonian Disorders; Raclopride; Rats, Sprague-Dawley; RGS Proteins

Lesion localization based on patient's manifestation is a fundamental step in making a neurological diagnosis. However, it has been reported that diagnosticians are vulnerable to the effects of various cognitive biases during diagnostic processes.. A 69-year-old man with right-hand stiffness visited the Movement Disorder Clinic with the history of periodic limb movement syndrome and restless leg syndrome. His sensory and deep tendon reflex examination results were normal. Brain magnetic resonance imaging was normal. Corticobasal degeneration was considered as a possibility, but functional imaging studies including FP-CIT positron emission tomography were all normal. Later, cervical spine magnetic resonance imaging revealed a cervical meningioma at the C2-C3 levels and he showed tingling senses in his right ulnar 3 fingers and a hyperactive knee jerk on his right side, which were absent on the first examinations.. Insufficient clinical information (declarative shortcoming) and inherent heuristic pitfalls (procedural shortcoming) were 2 major causes of the diagnostic error. Especially, in the present case, cognitive biases from framing effects and anchoring heuristics misled the clinical reasoning during the process of localization.

Topics: Aged; Brain; Cervical Vertebrae; Diagnostic Errors; Humans; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Meningeal Neoplasms; Meningioma; Parkinsonian Disorders; Positron-Emission Tomography; Raclopride

We used positron emission tomography (PET) to assess dopaminergic and serotonergic terminal density in three subjects carrying a mutation in the DCT1 gene, two clinically affected with Perry syndrome.. All subjects had brain imaging using 18F-6-fluoro-l-dopa (FDOPA, dopamine synthesis and storage), (+)-11C-dihydrotetrabenazine (DTBZ, vesicular monoamine transporter type 2), and 11C-raclopride (RAC, dopamine D2/D3 receptors). One subject also underwent PET with 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB, serotonin transporter).. FDOPA-PET and DTBZ-PET in the affected individuals showed a reduction of striatal tracer uptake. Also, RAC-PET showed higher uptake in these area. DASB-PET showed significant uptake changes in left orbitofrontal cortex, bilateral anterior insula, left dorsolateral prefrontal cortex, left orbitofrontal cortex, left posterior cingulate cortex, left caudate, and left ventral striatum.. Our data showed evidence of both striatal dopaminergic and widespread cortical/subcortical serotonergic dysfunctions in individuals carrying a mutation in the DCTN1 gene.

Topics: Adult; Aniline Compounds; Corpus Striatum; Depression; Dopamine; Dynactin Complex; Fluorine Radioisotopes; Humans; Hypoventilation; Microtubule-Associated Proteins; Middle Aged; Mutation; Parkinsonian Disorders; Positron-Emission Tomography; Raclopride; Serotonin; Sulfides; Tetrabenazine; Tomography, Emission-Computed

Stem cell therapy in the nervous system aims to replace the lost neurons and provide functional recovery. However, it is imperative that we understand the in vivo behaviour of these cells post-implantation. We report visualisation of iron oxide labelled bone marrow-derived stem cells (BMSCs) implanted into the striatum of hemi-parkinsonian rats by magnetic resonance imaging (MRI). Functional efficacy of the donor cells was monitored in vivo using the positron emission tomography (PET) radioligand [11C]raclopride. The cells were visible for 28 days by in vivo MRI. BMSCs provided functional recovery demonstrated by a decreased binding of [11C]raclopride. Although, histology confirmed the persistence of donor cells, no tyrosine hydroxylase positive cells were present. This suggests that BMSCs may have a limited paracrine effect and influence functional recovery. We demonstrate, using multimodal imaging, that we can not only track BMSCs but also establish their effects in a pre-clinical model of Parkinson's disease.

Topics: Adult Stem Cells; Animals; Antipsychotic Agents; Carbon Isotopes; Diagnostic Imaging; Disease Models, Animal; Glial Fibrillary Acidic Protein; Indoles; Magnetic Resonance Imaging; Male; Oxidopamine; Parkinsonian Disorders; Positron-Emission Tomography; Raclopride; Rats; Rats, Sprague-Dawley; Stem Cell Transplantation; Time Factors; Tyrosine 3-Monooxygenase

We used positron emission tomography (PET) to measure the earliest change in dopaminergic synapses and glial cell markers in a chronic, low-dose MPTP non-human primate model of Parkinson's disease (PD). In vivo levels of dopamine transporters (DAT), vesicular monoamine transporter-type 2 (VMAT2), amphetamine-induced dopamine release (AMPH-DAR), D2-dopamine receptors (D2R) and translocator protein 18 kDa (TSPO) were measured longitudinally in the striatum of MPTP-treated animals. We report an early (2 months) decrease (46%) of striatal VMAT2 in asymptomatic MPTP animals that preceded changes in DAT, D2R, and AMPH-DAR and was associated with increased TSPO levels indicative of a glial response. Subsequent PET studies showed progressive loss of all pre-synaptic dopamine markers in the striatum with expression of parkinsonism. However, glial cell activation did not track disease progression. These findings indicate that decreased VMAT2 is a key pathogenic event that precedes nigrostriatal dopamine neuron degeneration. The loss of VMAT2 may result from an association with alpha-synuclein aggregation induced by oxidative stress. Disruption of dopamine sequestration by reducing VMAT2 is an early pathogenic event in the dopamine neuron degeneration that occurs in the MPTP non-human primate model of PD. Genetic or environmental factors that decrease VMAT2 function may be important determinants of PD.

Topics: Animals; Autoradiography; Brain; Carbon Isotopes; Carrier Proteins; Cocaine; Disease Models, Animal; Dopamine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Glial Fibrillary Acidic Protein; Isoquinolines; Male; Neurons; Papio anubis; Parkinsonian Disorders; Positron-Emission Tomography; Raclopride; Tetrabenazine; Tyrosine 3-Monooxygenase; Vesicular Monoamine Transport Proteins

Degeneration of dopaminergic neurons of the substantia nigra pars compacta is a cardinal feature of Parkinson's disease (PD). Although uncertain, the pathology has been suggested to derive from a malfunction of the complex interaction between dopaminergic and metabotropic glutamate receptors (mGluRs). To further address this issue, we investigated the imaging profile and expression of dopamine D(2) receptors and mGluRs in a classic parkinsonian rodent model induced by the toxin 6-hydroxydopamine.. Adult male Sprague-Dawley rats (250-300 g) received a stereotaxic injection of 8 mug/2 muL of 6-hydroxydopamine (n = 6) or saline solution (n = 4) in the right medial forebrain bundle. Small-animal PET was performed on all rats 4 wk after the surgical procedure to assess dopamine transporter (DAT) status using (11)C-2beta-carbomethoxy-3beta-(4-fluorophenyl)-tropane (CFT), as well as dopamine D(2) receptor and mGluR(5) modulation using (11)C-raclopride and 2-(11)C-methyl-6-(2-phenylethynyl)-pyridine ((11)C-MPEP), respectively. Behavioral studies were also conducted 6 wk after lesioning by d-amphetamine challenge. Immunohistochemistry and Western blotting were carried out at 8 wk after lesioning to confirm dopamine fiber, neuronal loss, and level of striatal mGluR(5) expression.. PET images showed decreased (11)C-CFT binding on the lesioned side, including the structures of the striatum, hippocampus, and cortex, compared with the contralateral intact side. Interestingly, dopamine D(2) receptors and mGluR(5) upregulation were observed in the right striatum, hippocampus, and cortex, using (11)C-raclopride and (11)C-MPEP, respectively. A negative correlation was also found between the percentage change in mGluR(5) expression and DAT function. Finally, tyrosine hydroxylase immunoreactivity confirmed both dopamine fiber loss (t test, P < 0.01) and neuronal loss (t test, P < 0.01) on the lesioned side. These changes were accompanied by a strongly enhanced mGluR(5) expression in the right striatum of the lesioned side analyzed by Western plot.. These findings support the existence of compensatory mechanisms in nigrostriatal dopamine degeneration and provide new insights that help further dissect some of the pathways underlying neurodegeneration. In addition, these results reconfirm that PET is a valuable tool for multilevel receptor studies, significantly contributing to the understanding of pathogenic mechanisms and ultimately opening new avenues in the study of neuroprotective approaches toward PD.

Topics: Animals; Carbon Radioisotopes; Cocaine; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Hippocampus; Immunohistochemistry; Male; Nerve Degeneration; Neurons; Oxidopamine; Parkinsonian Disorders; Positron-Emission Tomography; Pyridines; Raclopride; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Dopamine D2; Receptors, Metabotropic Glutamate; Substantia Nigra; Tyrosine 3-Monooxygenase

Human retinal pigment epithelial (hRPE) cells produce L-dopa, are easily harvested and expanded in culture, and, attached to microcarriers, can survive in the brain without immunosuppression. Studies in rats, primates, and parkinsonian patients have demonstrated that striatally implanted hRPE cells attached to gelatin microcarriers (RPE-GM) are able to improve parkinsonian symptoms and are well tolerated for extended periods. In moderately to severely impaired monkeys with bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced parkinsonism receiving a unilateral RPE-GM implant in the putamen, there was a 39% improvement in clinical scores over the first 2 months post-implant. Positron emission tomography (PET) with [18F]fluoro-L-dopa (FDOPA) showed increased accumulation in the implanted putamen and a concomitant decrease in [11C]raclopride binding in the same area, suggesting increased dopamine release compared to the contralateral putamen. We report the first in vivo visualization of hRPE cells and their effects, implicating a dopaminergic mechanism of action.

Topics: Animals; Binding, Competitive; Dihydroxyphenylalanine; Disease Models, Animal; Dopamine; Female; Humans; Macaca fascicularis; Macaca mulatta; Male; Parkinsonian Disorders; Pigment Epithelium of Eye; Putamen; Raclopride; Radioligand Assay; Recovery of Function; Tomography, Emission-Computed; Treatment Outcome; Up-Regulation

The ligand-receptor binding potential determined by PET studies at high ligand-specific radioactivity reflects both the receptor density and ligand-receptor affinity. This ambiguity has been resolved by various methods based on the administration of multiple unlabeled ligand concentrations. The authors aimed to implement and refine an approach to multiple ligand concentration receptor assay that combined maximum simplicity and a minimum of assumptions and model dependence that would nonetheless reliably distinguish density from affinity effects. The approach uses administration by bolus followed by infusion to obtain a true equilibrium between bound ligand and the other components of the ligand concentration, and does not require measurements of ligand in blood plasma. Four approaches to the optimization of the desired density and affinity parameters from the measured equilibrium data were implemented and compared in the analysis of raclopride studies performed in both normal control and MPTP-lesioned nonhuman primates. The authors conclude that the method is simple enough for routine use and yet reliable enough to apply in ongoing studies of both chronic and acute drug effects in the dopamine system.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Kinetics; Ligands; Macaca mulatta; Male; Models, Neurological; Parkinsonian Disorders; Protein Binding; Raclopride; Receptors, Dopamine D2; Reference Values

Regulation of dopamine D2 receptor (D2) function plays an important role in alleviating either the motor deficits of Parkinson's disease or psychotic symptoms of schizophrenia. D2 also plays a critical role in sensorimotor gating which can be measured by monitoring the prepulse inhibition of the startle response. Alternative splicing of the D2 gene generates two isoforms, D2S and D2L. Here we investigated the role of D2S and D2L in the mechanisms of action of dopaminergic drugs, using mice lacking D2L (D2L(-/-)) but expressing D2S as a model system. We found that the typical antipsychotic raclopride was much less potent in inhibiting locomotor activity and eliciting catalepsy (or parkinsonism) in D2L(-/-) mice, whereas the atypical antipsychotic clozapine was equally effective in D2L(-/-) and wild-type mice. These suggest that the deletion of D2L diminishes drug-induced parkinsonism. Furthermore, two dopamine agonists, amphetamine and apomorphine, reduced prepulse inhibition to a similar degree in D2L(-/-) and wild-type mice. These results together suggest that D2S alone can mediate the action of clozapine and the dopamine agonist-induced disruption of prepulse inhibition. The differential binding affinities of these agents for D2S vs D2L were not sufficient to explain the divergent effects of typical vs atypical antipsychotics in D2L(-/-) mice. These findings suggest that D2S and D2L may differentially contribute to the therapeutic actions and side effects of antipsychotic agents, and may have implications for developing better antipsychotic agents.

Topics: Amphetamine; Animals; Antipsychotic Agents; Apomorphine; Clozapine; Dopamine Agonists; Dose-Response Relationship, Drug; Hallucinogens; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Parkinsonian Disorders; Protein Isoforms; Raclopride; Receptors, Dopamine D2

Topics: Age Factors; Aging; Animals; Carbon Radioisotopes; Dopamine Antagonists; Haplorhini; Parkinsonian Disorders; Raclopride; Receptors, Dopamine D2; Tomography, Emission-Computed

Studies of dopamine (DA) receptor binding in early parkinsonian patients, or in models of Parkinson's disease, have revealed a supersensitivity of the D2-like receptor subtype as compared to age-matched controls. The lack of upregulation in advanced patients is often attributed to the effects of prolonged antiparkinsonian therapy, but the impact of therapy vs. intrinsic mechanisms in untreated patients or animals with long-term lesions of the DA nigrostriatal pathway has been difficult to address. We studied, in vivo, by PET using the DA D2 receptor ligand raclopride, the status of the DA receptors in normal rhesus monkeys and those with acute (3 months) or long-term (10 years) MPTP-induced nigrostriatal lesions. Compared to age-matched controls, there was no change in raclopride binding in MPTP-treated animals without parkinsonian symptoms. There was a significant increase in raclopride binding in the putamen (but not caudate nucleus) of all the animals displaying rigidity, hypo- and bradykinesia. This increase was greater in the animals with acute lesions (32%) than with established, long-term lesions (18%). There was no correlation between the postmortem striatal DA concentrations and in vivo raclopride binding but there was a correlation between PET raclopride binding and [(3)H]raclopride binding in vitro. Complex changes in D2 receptor binding occur in various stages of parkinsonism. Antiparkinsonian therapy is unlikely to be solely responsible for the lack of upregulation found in advanced parkinsonian patients but may be a contributing factor.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Corpus Striatum; Dopamine; Dopamine Agents; Female; Macaca mulatta; Male; Parkinsonian Disorders; Putamen; Raclopride; Receptors, Dopamine D2; Tomography, Emission-Computed