raclopride and Parkinson-Disease--Secondary

The prevalence of both parkinsonian signs and Parkinson's disease (PD) per se increases with age. Although the pathophysiology of PD has been studied extensively, less is known about the functional changes taking place in the basal ganglia circuitry with age. To specifically address this issue, 3 groups of rhesus macaques were studied: normal middle-aged animals (used as controls), middle-aged animals with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, and aged animals (>20 years old) with declines in motor function. All animals underwent the same behavioral and pharmacologic magnetic resonance imaging (phMRI) procedures to measure changes in basal ganglia function in response to dopaminergic drug challenges consisting of apomorphine administration followed by either a D1 (SCH23390) or a D2 (raclopride) receptor antagonist. Significant functional changes were predominantly seen in the external segment of the globus pallidus (GPe) in aged animals and in the striatum (caudate nucleus and putamen) in MPTP-lesioned animals. Despite significant differences seen in the putamen and GPe between MPTP-lesioned versus aged animals, a similar response profile to dopaminergic stimulations was found between these 2 groups in the internal segment of the GP. In contrast, the pharmacologic responses seen in the control animals were much milder compared with the other 2 groups in all the examined areas. Our phMRI findings in MPTP-lesioned parkinsonian and aged animals suggest that changes in basal ganglia function in the elderly may differ from those seen in parkinsonian patients and that phMRI could be used to distinguish PD from other age-associated functional alterations in the brain.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Aging; Animals; Apomorphine; Basal Ganglia; Benzazepines; Diagnosis, Differential; Dopamine Agents; Female; Macaca mulatta; Magnetic Resonance Imaging; Motor Activity; Parkinson Disease, Secondary; Raclopride

L-DOPA is more effective than direct dopamine (DA) agonists in relieving the motor deficits in Parkinson's disease. Using in vivo recording, we compared the effect of l-DOPA and the direct DA agonist apomorphine on DA neurons in rat substantia nigra (SN). L-DOPA (50-100 mg/kg i.v.) decreased the firing rate as well as the variability and slow oscillation (SO) of firing. All effects were blocked by raclopride and mimicked by quinpirole, suggesting that they are mediated through D2-like receptors. Autoreceptor-selective doses of apomorphine (5-20 μg/kg i.v.) also inhibited all three parameters. The magnitude of the inhibition, however, was significantly greater than that induced by L-DOPA. Neither L-DOPA nor apomorphine had a consistent effect on SN local field potentials (LFPs). The GABA agonist muscimol, known to preferentially inhibit SN non-DA neurons, consistently inhibited the SO in both DA cell firing and LFPs. These results suggest that SN LFPs mainly reflect the synaptic potentials in non-DA neurons, and L-DOPA and apomorphine, unlike muscimol, affect DA neurons primarily through DA autoreceptors. DA autoreceptor activation is known to hyperpolarize DA cells by increasing the membrane conductance to K(+). This increase in membrane conductance would shunt synaptic input to DA neurons, thereby decreasing the variability and SO in DA cell firing. The low potency of L-DOPA to inhibit DA cell firing and reduce their responses to synaptic input may partially account for its superior therapeutic efficacy in Parkinson's disease compared with apomorphine and other direct DA agonists.

Topics: Animals; Apomorphine; Dopamine; Dopamine Agents; Dopamine Agonists; Dopamine Antagonists; Electrophysiological Phenomena; Evoked Potentials; GABA Agonists; Levodopa; Male; Muscimol; Neurons; Parkinson Disease, Secondary; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Substantia Nigra

Our previous study regarding the changes of D(2) receptor in nigrostriatal dopamine system at an early stage (4 weeks after lesion) indicated a different functional activity of striatal D(2) receptor between two different rat parkinsonian models, lesioning with 6-hydroxydopamine in the striatum and in the medial forebrain bundle (MFB). In the present study, we further examined binding of D(2) receptor as well as pre-synaptic dopamine transporter (DAT) at later stages (6 months after lesion) both in the striatal and MFB lesion models. The D(2) receptor binding in MFB model at 6 months after lesion was significantly lower than that at 4 weeks after lesion, albeit it was still higher than the normal side. The D(2) receptor binding in striatal model was decreased to the same extent at both 4 weeks and 6 months after lesion. DAT binding decreased at 6 months after lesion, more profound in MFB model, and the degree of reduction was not different from that at 4 weeks after lesion. These findings indicated different dynamic processes of the D(2) receptor and DAT during a longer time observation in the striatal and MFB lesion models. The dynamic changes of D(2) receptor activity after lesion should be considered when selecting 6-hydroxydopamine-induced rat parkinsonian models.

Topics: Animals; Corpus Striatum; Dopamine; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Immunohistochemistry; Male; Medial Forebrain Bundle; Oxidopamine; Parkinson Disease, Secondary; Positron-Emission Tomography; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Sympatholytics; Tyrosine 3-Monooxygenase

In the present studies, the effect of paeoniflorin (PF), one of the main compounds extracted from Paeoniae radix, in alleviating the neurological impairment following unilateral striatal 6-hydroxydopamine (6-OHDA) lesion was examined in Sprague-Dawley rats. Sub-chronic PF (2.5, 5 and 10 mg/kg, s.c., twice daily for 11 days) administration dose-dependently reduced apomorphine (APO)-induced rotation, suggesting that PF had an ameliorative effect on the 6-OHDA-induced neurological impairment. Notably, PF had no direct action on dopamine D(1) receptor or dopamine D(2) receptor indicated by the competitive binding experiments. These results suggest that PF, an active component of Paeoniae radix, might provide an opportunity to introduce a non-dopaminergic management of Parkinson's disease.

Topics: Animals; Apomorphine; Behavior, Animal; Benzazepines; Benzoates; Binding, Competitive; Bridged-Ring Compounds; Dopamine Agonists; Dopamine Antagonists; Glucosides; Hydroxydopamines; In Vitro Techniques; Male; Membranes; Microinjections; Monoterpenes; Neostriatum; Parkinson Disease, Secondary; Raclopride; Rats; Rats, Sprague-Dawley; Stereotyped Behavior

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Carbon Radioisotopes; Clozapine; Corpus Striatum; Dopamine Antagonists; Female; Humans; Male; Olanzapine; Parkinson Disease, Secondary; Pirenzepine; Psychiatric Status Rating Scales; Raclopride; Radioligand Assay; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tomography, Emission-Computed

In rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion in the nigrostriatal pathway, methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity (FLI) not only in the striatum on the intact side but also in the substantia nigra pars reticulata (SNr) on the lesioned side. The methamphetamine-induced hyperexpression of FLI in the SNr on the lesioned side was suppressed by pretreatment with either dopamine D1 receptor antagonist SCH-23390 (0.5 mg/kg, i.p.), D2 receptor antagonist raclopride (2 mg/kg, i.p.) or N-methyl-d-aspartate receptor antagonist MK-801 (1 mg/kg, i.p.), which was concomitant with inhibition of the methamphetamine-induced rotational behavior of each antagonist. However, the hyperexpression of FLI in the SNr was not suppressed by intrastriatal grafts of fetal ventral mesencephalon which could suppress the methamphetamine-induced rotation completely. These results indicate that opposite hemispheric asymmetries in FLI are induced by methamphetamine in the striatum and the SNr in the 6-OHDA rats. It is suggested that the FLIs in the two discrete sites are activated independently by different mechanisms, and furthermore, different neuronal pathways are involved in the methamphetamine-induced rotation and Fos expression in the SNr of 6-OHDA rats.

Topics: Animals; Behavior, Animal; Benzazepines; Brain Chemistry; Brain Tissue Transplantation; Corpus Striatum; Disease Models, Animal; Dizocilpine Maleate; Dopamine Agents; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Female; Mesencephalon; Methamphetamine; Neurons; Oxidopamine; Parkinson Disease, Secondary; Proto-Oncogene Proteins c-fos; Raclopride; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Rotation; Salicylamides; Substantia Nigra; Sympatholytics; Tyrosine 3-Monooxygenase

We have studied the effects of two D2 dopamine receptor-selective compounds, (-)-OSU 6162 and raclopride, on levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmosets (Callithrix jacchus). Three monkeys developed a severe parkinsonian syndrome following administration of MPTP. In response to daily levodopa treatment the animals developed reproducible and idiosyncratic peak-dose dyskinesias. Pretreatment with (-)-OSU 6162 and raclopride, in doses increased by multiples of three, both dose-dependently relieved the levodopa-induced dyskinesias. However, in contrast to when raclopride pretreatment was given, (-)-OSU 6162 pretreatment did not induce akinesia. Our investigation suggests that (-)-OSU 6162 may be useful an an adjuvant treatment to levodopa in advanced Parkinson's disease to selectively combat levodopa-induced dyskinesias without affecting the antiparkinsonian response.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Callithrix; Carbidopa; Dopamine Antagonists; Levodopa; Male; Motor Activity; Parkinson Disease, Secondary; Piperidines; Posture; Raclopride; Salicylamides

Dihydrexidine (trans-10,11-dihydroxy5,6,6a,7,8,12b hexanhyydrobenso- [alpha]phenanthridine) is a full dopamine D1 agonist. In rhesus macaque monkeys rendered hemiparkinsonian by unilateral intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), dihydrexidine (0.15-0.9 mg/kg) elicited dose-dependent contralateral rotation. The effects of dihydrexidine were blocked by pretreatment with the D1 antagonist SCH 23390 (0.03 mg/kg), but not by the D2 antagonist raclopride (0.025 mg/kg). These results suggest a functional role for D1 receptors in stimulating motor behavior in a primate model of Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Behavior, Animal; Benzazepines; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Ergolines; Functional Laterality; Macaca mulatta; Male; Parkinson Disease, Secondary; Phenanthridines; Quinpirole; Raclopride; Receptors, Dopamine D1; Rotation; Salicylamides

Using MRI and PET, we investigated the consequences of manganese intoxication in a primate model of parkinsonism and dystonia. Three rhesus monkeys were injected intravenously with doses of 10 to 14 mg/kg of MnCl2 on seven occasions, each a week apart. Two animals became hypoactive with abnormal extended posturing in the hind limbs. These motor disturbances did not improve with administration of levodopa. In all three monkeys, T1-weighted MRI demonstrated high signal intensities in the regions of the striatum, globus pallidus, and substantia nigra. No significant changes were found on [18F]6-fluoro-L-dopa, [11C]raclopride, or [18F]fluorodeoxyglucose PET. These results are consistent with the pathologic findings, which were primarily confined to the globus pallidus, and indicate that manganese intoxication is associated with preservation of the nigrostriatal dopaminergic pathway, despite clinical evidence of parkinsonian deficits. Chronic manganese intoxication may cause parkinsonism by damaging output pathways downstream to the nigrostriatal dopaminergic pathway. This is consistent with the demonstrated lack of therapeutic response to levodopa.

Topics: Animals; Carbidopa; Corpus Striatum; Deoxyglucose; Drug Therapy, Combination; Dystonia; Fluorodeoxyglucose F18; Globus Pallidus; Glucose; Levodopa; Macaca mulatta; Magnetic Resonance Imaging; Male; Manganese Poisoning; Parkinson Disease, Secondary; Raclopride; Salicylamides; Substantia Nigra; Tomography, Emission-Computed

Striatal dopamine D2 receptor binding was studied in vivo with positron emission tomography in seven patients with early Parkinson's disease using [11C]-raclopride. The patients had unilateral symptoms and none of them had received levodopa treatment. The accumulation of [11C]-raclopride in the striatum was rapid and reached a steady state at approximately 40 min after injection. The binding of [11C]-raclopride was measured in the striatum and cerebellum: The total striatal radioactivity in both hemispheres was counted and the respective striatum/cerebellum ratios were calculated. The striatum/cerebellum ratio of [11C]-raclopride binding was significantly (p less than 0.01) increased in the hemisphere contralateral to the parkinsonian symptoms as compared with the opposite hemisphere. Thus, this study demonstrates that there is denervation supersensitivity in dopamine D2 receptor binding in early Parkinson's disease.

Topics: Adult; Aged; Corpus Striatum; Female; Humans; Male; Middle Aged; Parkinson Disease, Secondary; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Salicylamides; Tomography, Emission-Computed