raclopride and Movement-Disorders

A crucial role of corticostriatal dopaminergic networks in cognitive and motor processes has been well established but largely unexplored in Alzheimer's disease (AD). The study investigated the relationship between striatal DA (D(2)) receptor availability and specific aspects of cognitive (sustained visual attention, spatial planning, word recognition) and motor (speed and dexterity) function in 24 people with mild to moderate AD. In vivo dopamine DA (D(2)) receptor availability was determined with [(11)C] raclopride (RAC) positron emission tomography (PET). Imaging data were analysed using both region of interest (ROI) and voxel-based approaches. Higher [(11)C] RAC binding was associated with increased motor speed and, paradoxically, poorer attentional performance. These findings are broadly consistent with previously conducted studies in healthy older adults and would suggest that the use of DA (D(2)) receptor agonists as an adjunctive treatment strategy in AD may have dissociable effects upon cognitive function.

Topics: Alzheimer Disease; Attention; Binding, Competitive; Brain Chemistry; Brain Mapping; Cognition; Cognition Disorders; Corpus Striatum; Disability Evaluation; Dopamine; Dopamine Agonists; Dopamine Antagonists; Movement; Movement Disorders; Neuropsychological Tests; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2

The ability of primate embryonic stem (ES) cells to differentiate into dopamine (DA)-synthesizing neurons has raised hopes of creating novel cell therapies for Parkinson's disease (PD). As the primary purpose of cell transplantation in PD is restoration of dopaminergic neurotransmission in the striatum, in vivo assessment of DA function after grafting is necessary to achieve better therapeutic effects. A chronic model of PD was produced in two cynomolgus monkeys (M-1 and M-2) by systemic administration of neurotoxin. Neural stem cells (NSCs) derived from cynomolgus ES cells were implanted unilaterally in the putamen. To evaluate DA-specific functions, we used multiple [(11)C]-labeled positron emission tomography (PET) tracers, including [beta-(11)C]L-3,4-dihydroxyphenylalanine (L-[beta-(11)C]DOPA, DA precursor ligand), [(11)C]-2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane ([(11)C]beta-CFT, DA transporter ligand) and [(11)C]raclopride (D(2) receptor ligand). At 12 weeks after grafting NSCs, PET demonstrated significantly increased uptake of L-[beta-(11)C]DOPA (M-1:41%, M-2:61%) and [(11)C]beta-CFT (M-1:31%, M-2:36%) uptake in the grafted putamen. In addition, methamphetamine challenge in M-2 induced reduced [(11)C]raclopride binding (16%) in the transplanted putamen, suggesting release of DA. These results show that transplantation of NSCs derived from cynomolgus monkey ES cells can restore DA function in the putamen of a primate model of PD. PET with multitracers is useful for functional studies in developing cell-based therapies against PD.

Topics: Animals; Carbon Radioisotopes; Cells, Cultured; Cocaine; Disease Models, Animal; Dopamine; Dopamine Agents; Embryonic Stem Cells; Levodopa; Macaca fascicularis; Methamphetamine; Movement Disorders; Neurons; Parkinson Disease; Positron-Emission Tomography; Putamen; Raclopride; Tyrosine 3-Monooxygenase

Dopamine is known to regulate several behavioral phenomena, including sensorimotor gating and aspects of motor activity. The roles of dopamine D1 and D2 receptors in these behaviors have been documented in the rat literature, but few reports exist on their role in mice. We used dopamine transporter (DAT) (-/-) mice to examine the behavioral consequences of a chronically hyperdopaminergic state, challenging them with the preferential dopamine D2 receptor antagonist raclopride and D1 receptor antagonist SCH23390. At baseline, DAT (-/-) mice exhibited deficient sensorimotor gating as measured by prepulse inhibition (PPI) of the startle response, exhibited nonfocal preservative patterns of locomotion, and were hyperactive in a novel environment. Pretreatment with raclopride significantly increased PPI in the DAT (-/-) mice, whereas SCH23390 had no significant effect. Blockade of D2 receptors did not affect the predominantly straight patterns of motor behavior produced by the DAT (-/-) mice, but antagonism of D1 receptors significantly attenuated the preservative patterns, producing more of a meandering behavior seen in the DAT (+/+) control mice. Both D1 and D2 receptor antagonists decreased the hyperactivity seen in the DAT (-/-) mice. These findings support the role of the D2, but not the D1, receptor in the modulation of PPI in mice. Furthermore, D1 receptor activation appears to be the critical substrate for the expression of preservative patterns of motor behavior, whereas both D1 and D2 receptors appear to regulate the amount of motor activity.

Topics: Animals; Behavior, Animal; Benzazepines; Carrier Proteins; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dopamine Plasma Membrane Transport Proteins; Female; Heterozygote; Homozygote; Hyperkinesis; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Membrane Glycoproteins; Membrane Transport Proteins; Mice; Mice, Knockout; Motor Activity; Movement Disorders; Nerve Tissue Proteins; Neural Inhibition; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Reflex, Startle; Sex Factors

The aim of the study was to assess the contribution of central dopaminergic and glutamatergic systems to the age-dependent loss of motor functions in rats. Rats of three age groups were compared: young (3-5-month-old), middle-aged (20-21-month-old) and old (29-31-month-old). The obtained results showed an age-dependent decline in the electromyographic (EMG) resting and reflex activities in the gastrocnemius and tibialis anterior muscles, as well as in the T-maze performance. Although these disturbances were accompanied with significant age-dependent decreases in the binding to NMDA, AMPA and dopamine D2 receptors, and a decline in the number of nigral dopamine neurons, they were significantly correlated with the loss of the binding to NMDA receptors only. The reduction in T-maze performance with aging was additionally correlated with a decrease in motor functions (EMG activity). The study suggests a crucial role of the loss of NMDA receptors in age-dependent motor disabilities, as well as in disturbances measured in the T-maze.

Topics: Aging; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Ankle Joint; Biomarkers; Biomechanical Phenomena; Brain Mapping; Cell Count; Dizocilpine Maleate; Dopamine; Electromyography; Female; Glutamic Acid; Learning Disabilities; Maze Learning; Movement Disorders; Muscle, Skeletal; Nerve Tissue Proteins; Pliability; Psychomotor Performance; Raclopride; Rats; Rats, Wistar; Reaction Time; Receptors, AMPA; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; Substantia Nigra; Tyrosine 3-Monooxygenase

Dyskinesias are usually seen in Parkinson's disease (PD) patients after several years of L-dopa therapy. Their presence has been attributed to supersensitivity of striatal D1 and D2 receptors. We have used PET to assess striatal D2 receptor binding in untreated PD patients and striatal D1 and D2 binding in L-dopa-treated PD patients. Untreated patients showed a 14% increase in mean D2 receptor binding in the putamen contralateral to the more affected limbs (p < 0.02). Treated patients were segregated into subgroups according to the presence or absence of dyskinesias. There were no differences in mean caudate and putamen D1 and D2 binding between dyskinetic and nondyskinetic patients, matched for duration of clinical disease. Both dyskinetic and nondyskinetic PD subgroups showed a similar 16% reduction of mean caudate D2 binding (p < 0.01) with normal D2 binding in putamen. Mean caudate and putamen D1 binding potentials of both subgroups were reduced by 10% compared with those of controls, though this trend did not reach significance. Putamen D1 binding, however, showed a negative correlation with duration and L-dopa treatment (p < 0.03). These findings suggest that, while exposure of PD patients to L-dopa may be associated with reductions in caudate D2 and caudate and putamen D1 receptor, dyskinesias are unlikely to result from alterations in striatal dopamine receptor binding.

Topics: Adult; Aged; Carbon Radioisotopes; Corpus Striatum; Female; Humans; Levodopa; Male; Middle Aged; Movement Disorders; Parkinson Disease; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides

Selective D1 and D2 dopamine (DA) antagonists and agonists were given to 4 Cebus monkeys who had previously received haloperidol treatment for 4 years. SCH 23390 (a selective D1 antagonist) and raclopride (a selective D2 antagonist) induced identical syndromes consisting of dystonia and oral dyskinesia. Biperiden (an anticholinergic drug) and LY 171555 (a selective D2 agonist) completely antagonized the dystonia and dyskinesia induced by SCH 23390 as well as raclopride. The combined treatment with LY 171555 and SCH 23390 (but not LY 171555 and raclopride) caused pronounced sedation. LY 171555 induced repetitive movements of head, legs and trunk, but no oral dyskinesia. SKF 38393 (a partial D1 agonist) caused slight sedation, minimal oral dyskinesia and a significant reduction in D2 agonist-induced repetitive movements.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Antipsychotic Agents; Benzazepines; Biperiden; Cebus; Dystonia; Ergolines; Haloperidol; Male; Movement Disorders; Quinpirole; Raclopride; Receptors, Dopamine; Salicylamides; Stereotyped Behavior