RESUMO
Sensorimotor adaptation is thought to involve a remapping of the kinematic and kinetic parameters associated with movements performed within a changing environment. Patients with Parkinson's disease (PD) are known to be affected on this type of learning process, although the specific role of dopamine depletion in these deficits has not yet been elucidated. The present study was an attempt to clarify whether dopamine depletion in PD may directly affect the capacity to internally reorganize the visuomotor remapping of a distorted environment. Fourteen PD patients were tested twice, while they were treated and while they were withdrawn from their regular levodopa treatment. Fourteen control subjects were also enrolled and tested twice. Two parallel forms of the Computed Mirror Pointing Task (CMPT), requiring making a reaching movement in a visually transformed environment (mirror inversion), were administered to each participant. Each of them had to perform 40 trials at each of the 2 testing sessions. At each trial, sensorimotor adaptation was evaluated by the initial direction angle (IDA), which reflects the direction of movement before any visually guided readjustment. Results revealed no IDA difference at baseline, between control subject and PD patients, whether they were treated or not. In all group, IDA values at that time were large, reflecting a tendency to make movements according to the real life visuomotor mapping (based on the natural direct vision). However, striking differences appeared during sensorimotor learning, in that IDA reduction along trials was poorer in patient not treated with levodopa than both control subjects and the same PD patient treated with levodopa. No difference was observed between the treated PD patients and control subjects. Given that IDA is thought to reflect the internal representation of the visuomotor mapping, it is concluded that dopamine depletion in PD would affects sensorimotor adaptation, in that it facilitates old and poorly adapted movements (real life mapping), instead of new and more adapted ones (mirror transformed mapping).
Assuntos
Adaptação Fisiológica/fisiologia , Dopamina/metabolismo , Levodopa/uso terapêutico , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Desempenho Psicomotor/fisiologia , Adaptação Fisiológica/efeitos dos fármacos , Idoso , Dopamina/deficiência , Feminino , Humanos , Levodopa/farmacologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Estimulação Luminosa/métodos , Desempenho Psicomotor/efeitos dos fármacosRESUMO
Results obtained in patients with schizophrenia have shown that antipsychotic drugs may induce motor learning deficits correlated with the striatal type-2 dopamine receptors (D(2)R) occupancy. Other findings suggest that the role of the striatum in motor learning could be related to a process of "chunking" discrete movements into motor sequences. We therefore hypothesized that a D(2)R blocking substance, such as raclopride, would affect motor learning by specifically disrupting the grouping of movements into sequences. Two monkeys were first trained to perform a baseline-overlearned sequence (Seq. A) drug free. Then, a new sequence was learned (Seq. B) and the overlearned sequence was recalled OFF-drug (Seq. A recall OFF-drug). The effect of raclopride was then assessed on the learning of a third sequence (Seq. C), and on the recall of the overlearned sequence (Seq. A recall ON-drug). Results showed that performance related to the overlearned sequence remained the same in the three experimental conditions (Seq. A, Seq. A recall OFF-drug, Seq. A recall ON-drug), whether the primates received raclopride or not. On the other hand, new sequence learning was significantly affected during raclopride treatment (Seq. C), when compared with new sequence learning without the effect of any drug (Seq. B). Raclopride-induced disturbances consisted in performance fluctuations, which persisted even after many days of trials, and prevented the monkeys from reaching a stable level of performance. Further analyses also showed that these fluctuations appeared to be related to monkeys' inability to group movements into single flowing motor sequences. The results of our study suggest that dopamine is involved in the stabilization or consolidation of motor performances, and that this function would involve a chunking of movements into well-integrated sequences.
Assuntos
Antagonistas de Dopamina/efeitos adversos , Transtornos da Memória/induzido quimicamente , Movimento/efeitos dos fármacos , Racloprida/efeitos adversos , Receptores de Dopamina D2/fisiologia , Aprendizagem Seriada/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Cebus , Rememoração Mental/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacosRESUMO
Motor skills, once learned, need to be consolidated over time in order to become resistant to disruption or interference. In some instances, the consolidation phase can also include spontaneous gains in performance even in the absence of further rehearsal on a motor task. Clinical and behavioral evidence suggest that N-methyl-D-aspartate (NMDA)-receptor activity is required for motor learning acquisition and behavioral synaptic plasticity. However, the involvement of NMDA receptors in motor consolidation, leading to stabilization of the recently formed motor memory, has not yet been assessed in humans. To address this issue, we used post-training administration of amantadine, a low-affinity NMDA-receptor channel blocker. In a double-blind design, 200 mg of amantadine or a matching placebo was given orally to two different groups of 11 healthy young volunteers each. The subjects were tested twice 24 h apart, using a motor adaptation paradigm consisting of an eight-target-pointing task. Comparison of the mean performance levels on this task revealed that subjects in both groups improved their performance levels significantly on Day 2 compared to Day 1, regardless of the treatment administered. Our data indicate that amantadine failed to block motor learning consolidation in subjects that had already learned the motor adaptation task. Thus, although required in some stages (e.g. acquisition) of motor memory processes, the present results suggest that NMDA-receptor activation may not be essential for consolidation of motor adaptation in humans.
Assuntos
Amantadina/farmacologia , Dopaminérgicos/farmacologia , Memória/efeitos dos fármacos , Destreza Motora , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Adaptação Fisiológica , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , PlacebosAssuntos
Agonistas de Dopamina/farmacologia , Atividade Motora/efeitos dos fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/metabolismo , Receptores Dopaminérgicos/metabolismo , Aminoquinolinas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Benzazepinas/farmacologia , Cabergolina , Modelos Animais de Doenças , Ergolinas/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Bombas de Infusão Implantáveis , Macaca fascicularis , Pulsoterapia , RNA Mensageiro/análise , Receptores Dopaminérgicos/genética , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3RESUMO
This study was designed to assess the effects of bromocriptine, a dopamine D2 receptor agonist, on sleep bruxism. Seven otherwise healthy patients with severe and frequent sleep bruxism participated in this randomized, double-blind, placebo-controlled study. The study used a crossover design that included 2 weeks of active treatment or placebo with a washout period of 1 week. To further evaluate whether bromocriptine influences striatal D2 receptor binding, we used iodine-123-iodobenzamide single photon emission computed tomography (SPECT) under both placebo and bromocriptine regimens. Bromocriptine did not reduce the frequency of episodes of bruxism during sleep (mean +/- SEM, 9.0 +/- 1.0 and 9.6 +/- 1.5 bruxism episodes per hour for placebo and bromocriptine, respectively) or the amplitude of masseter muscle contractions (root mean square values, 48.2 +/- 15.5 microV and 46.9 +/- 12.7 microV for placebo and bromocriptine, respectively). SPECT also failed to reveal that either treatment had any influence on striatal D2 binding (values for total binding in counts/pixel, 1.80 [1.72-1.93] and 1.79 [1.56-1.87] for placebo and bromocriptine, respectively). This study shows that a nightly dose of bromocriptine does not exacerbate or reduce sleep bruxism motor activity.
Assuntos
Bromocriptina/uso terapêutico , Bruxismo/tratamento farmacológico , Agonistas de Dopamina/uso terapêutico , Adulto , Bromocriptina/efeitos adversos , Estudos Cross-Over , Agonistas de Dopamina/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Sono/efeitos dos fármacos , Fases do Sono/efeitos dos fármacosRESUMO
We investigated the effect of MPTP-induced lesion of the substantia nigra pars compacta (SNpc) dopaminergic neurons on GABA(B) receptors in the basal ganglia of mice and monkeys using receptor autoradiography and in situ hybridization. The extent of the lesion was measured with striatal catecholamine content, striatal binding of (125)I-RTI-121 to dopamine transporter (DAT), and DAT expression in the SNpc. GABA(B) receptors in mice brain were evaluated using (3)H-CGP54626 and its expression was measured with oligonucleotides probes targeting the mRNAs of GABA(B(1a+b)), GABA(B(1a)), GABA(B(1b)), GABA(B(2)) subunits. In monkeys, (125)I-CGP64213 and selective probes for GABA(B(1a+b)) and GABA(B(2)) mRNAs were used. In mice, dopamine content, (125)I-RTI-121 binding, and DAT expression were reduced by 44%, 40%, and 39% after a dose of 40 mg/kg of MPTP and 74%, 70%, and 34% after 120 mg/kg of MPTP, respectively. In monkeys, dopamine content and DAT expression were decreased by more than 90% and 80%, respectively. In the striatum and the subthalamic nucleus, GABA(B) receptors were unchanged following MPTP in both species. In the SNpc of mice, MPTP (120 mg/kg) induced a significant decrease of (3)H-CGP54626 binding (-10%) and of the expression of GABA(B(1a+b)) mRNA (-13%). The decrease of the expression of GABA(B(1a+b)) mRNA was correlated with dopamine content, (125)I-RTI-121 binding and DAT expression. In MPTP-treated monkeys, (125)I-CGP64213 binding (-40%), GABA(B(1a+b)) mRNA (-69%) and GABA(B(2)) mRNA (-66%) were also significantly decreased in the SNpc. Our results suggest that MPTP-induced denervation is associated with a decrease of GABA(B) receptors restricted to the SNpc. These observations may be relevant to the pathophysiology of motor disorders involving dysfunction of the basal ganglia such as Parkinson disease.
Assuntos
Gânglios da Base/metabolismo , Cocaína/análogos & derivados , Dopamina/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Transtornos Parkinsonianos/metabolismo , Receptores de GABA-B/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Gânglios da Base/fisiopatologia , Benzoatos/metabolismo , Cocaína/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina , Relação Dose-Resposta a Droga , Feminino , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organofosforados/metabolismo , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , RNA Mensageiro/metabolismo , Ensaio Radioligante , Receptores de GABA-B/genética , Substância Negra/metabolismo , Substância Negra/fisiopatologia , Núcleo Subtalâmico/metabolismo , Núcleo Subtalâmico/fisiopatologiaRESUMO
The MPTP monkey is a well-characterized animal model of parkinsonism and provides an exceptional tool for the study of dyskinesias induced by dopamine-like agents. Several such agents have been tested during the past 15 years, and it has been found that the duration of action of these compounds is the most reliable variable with which to predict their dyskinesiogenic profile. It is proposed that L-dopa-induced dyskinesias represent a form of pathological learning caused by chronic pulsatile (nonphysiological) stimulation of dopamine receptors, which activates a cascade of molecular and biochemical events. These events include defective regulation of Fos proteins that belong to the deltaFosB family, increased expression of neuropeptides, and defective GABA- and glutamate-mediated neurotransmission in the output structures of the basal ganglia.
Assuntos
Antiparkinsonianos/efeitos adversos , Gânglios da Base/efeitos dos fármacos , Agonistas de Dopamina/efeitos adversos , Discinesia Induzida por Medicamentos/metabolismo , Levodopa/efeitos adversos , Transtornos Parkinsonianos/metabolismo , Receptores Dopaminérgicos/efeitos dos fármacos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Antiparkinsonianos/administração & dosagem , Gânglios da Base/metabolismo , Modelos Animais de Doenças , Agonistas de Dopamina/administração & dosagem , Haplorrinos , Levodopa/administração & dosagem , Inibição Neural , Neuropeptídeos/metabolismo , Transtornos Parkinsonianos/induzido quimicamente , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de GABA/metabolismo , Receptores de Glutamato/metabolismo , Transdução de SinaisRESUMO
Much evidence indicates that abnormal GABA neurotransmission may be implicated in the pathophysiology of Parkinson's disease (PD) and dopaminomimetic-induced dyskinesias (DID). In this study, autoradiography using (125)I-CGP 64213 was performed to investigate GABA(B) receptor density in the brain of control monkeys as well as monkeys with MPTP-induced nigrostriatal depletion. Three MPTP monkeys received pulsatile administrations of the D1 dopamine (DA) receptor agonist (SKF 82958) whereas a long-acting D2 DA receptor agonist (cabergoline) was given to another three animals. SKF 82958 treatment relieved parkinsonian symptoms but two of three animals developed DID. Cabergoline induced a comparable motor benefit effect without persistent DID. (125)I-CGP 64213 binding to GABA(B) receptors was heterogeneous throughout the brain with the highest levels in the medial habenula of the thalamus. MPTP induced a decrease (-40%) of (125)I-CGP 64213 binding to GABA(B) receptors in the substantia nigra pars compacta (SNpc) and an increase (+29%) in the internal segment of the globus pallidus (GPi). This increase in the GPi was not affected by SKF 82958 but partly reversed by cabergoline. No change was seen in the striatum, the thalamus, the external segment of the globus pallidus, and the substantia nigra pars reticulata following MPTP and dopaminomimetic treatments. The changes of GABA(B) receptors observed in the SNpc and in the GPi suggest that alteration of GABA(B) receptors may play a role in the pathophysiology of PD and DID.
Assuntos
Benzoatos/metabolismo , Encéfalo/metabolismo , Antagonistas GABAérgicos/metabolismo , Compostos Organofosforados/metabolismo , Doença de Parkinson Secundária/metabolismo , Receptores de GABA-B/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Antiparkinsonianos/farmacologia , Autorradiografia , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Gânglios da Base/patologia , Benzazepinas/farmacologia , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Cabergolina , Corpo Estriado/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Esquema de Medicação , Discinesia Induzida por Medicamentos/metabolismo , Ergolinas/farmacologia , Feminino , Antagonistas de Receptores de GABA-B , Injeções Subcutâneas , Radioisótopos do Iodo , Macaca fascicularis , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/tratamento farmacológico , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Tálamo/efeitos dos fármacos , Tálamo/metabolismo , Tálamo/patologiaRESUMO
A series of experiments were performed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism for the purpose of understanding the mechanism of dopaminergic dyskinesias. Dyskinesias can be induced in this model by de novo treatment with levodopa, or selective D1 or D2 agonists, provided the drugs are short acting and administered in the pulsatile mode. Biochemical analysis of the brains revealed several alterations in dopamine receptor-binding and messenger RNA message following denervation and dopaminergic treatment, but none that clearly correlated with the presence of dyskinesias. On the other hand, gamma-aminobutyric acid (GABA)A binding was increased in the internal segment of the globus pallidus of dyskinetic MPTP monkeys. This was observed consistently and could be associated with an exaggerated response to GABAergic inhibitory inputs in this strategic structure. Increased preproenkephalin message was also found to correlate with dyskinesias and may be linked to changes in GABA receptors. Treatments that caused dyskinesias induced, in the striatum, chronic Fos proteins of the deltaFosB family which, when coupled with Jun-D, form AP-1 complexes that can affect several genes, including enkephalin and N-methyl-D-aspartate receptor. We suggest that levodopa-induced dyskinesias represent a form of pathological learning, which results from deficient gating of glutamatergic inputs to the striatum by dopamine.
Assuntos
Química Encefálica/genética , Dopaminérgicos/efeitos adversos , Discinesia Induzida por Medicamentos/genética , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Animais , Química Encefálica/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , HumanosRESUMO
OBJECTIVE: To evaluate the contribution of amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) glutamate receptors to the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias. BACKGROUND: Motor fluctuations and dyskinesias reflect, in part, altered function of glutamate receptors of the NMDA subtype. The possible role of AMPA receptors, however, has not yet been examined. METHODS: The authors compared the ability of an AMPA agonist (CX516) and a noncompetitive AMPA antagonist (LY300164) to alter parkinsonian symptoms and levodopa-induced dyskinesia in MPTP-lesioned monkeys. Eight levodopa-treated parkinsonian monkeys received rising doses of each drug, first in monotherapy and then in combination with low-, medium-, and high-dose levodopa. RESULTS: CX516 alone, as well as when combined with low-dose levodopa, did not affect motor activity but induced dyskinesia. Moreover, following injection of the higher doses of levodopa, it increased levodopa-induced dyskinesia by up to 52% (p < 0.05). LY300164 potentiated the motor activating effects of low-dose levodopa, increasing motor activity by as much as 86% (p < 0.05), and that of medium-dose levodopa as much as 54% (p < 0.05). At the same time, LY300164 decreased levodopa-induced dyskinesia by up to 40% (p < 0.05). CONCLUSIONS: AMPA receptor upregulation may contribute to the expression of levodopa-induced dyskinesia. Conceivably, noncompetitive AMPA receptor antagonists could be useful, alone or in combination with NMDA antagonists, in the treatment of PD, by enhancing the antiparkinsonian effects of levodopa without increasing and possibly even decreasing levodopa-induced dyskinesia.
Assuntos
Benzodiazepinas/farmacologia , Dioxóis/farmacologia , Discinesia Induzida por Medicamentos/tratamento farmacológico , Doença de Parkinson Secundária/tratamento farmacológico , Piperidinas/farmacologia , Receptores de AMPA/agonistas , Receptores de AMPA/antagonistas & inibidores , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Benzodiazepinas/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Discinesia Induzida por Medicamentos/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Levodopa/administração & dosagem , Macaca fascicularis , Masculino , Atividade Motora/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Índice de Gravidade de DoençaRESUMO
As part of a larger study, polysomnographic and audiovisual data were recorded over 2 nights in 41 subjects with a clinical diagnosis of sleep bruxism (SB). Electromyographic (EMG) events related to SB were scored according to standard criteria (Lavigne et al. J Dent Res 1996;75:546-552). Post hoc analysis revealed that rapid shock-like contractions with the characteristics of myoclonus in the jaw muscles were observed in four subjects. EMG bursts characterized as myoclonus were significantly shorter in duration than bursts classified as SB. None of the subjects had any history of myoclonus while awake. Myoclonic episodes were more frequent in sleep stages 1 and 2 than in REM. Half of the episodes contained one or two contractions whereas the other half had three or more repetitive contractions. SB and myoclonus coexisted in one subject. To rule out sleep epilepsy, full electroencephalogram montage was done in three subjects and no epileptic spikes were noted. Our results suggest that approximately 10% of subjects clinically diagnosed as SB could present oromandibular myoclonus during sleep.
Assuntos
Epilepsias Mioclônicas/diagnóstico , Mandíbula , Bruxismo do Sono/diagnóstico , Sono REM/fisiologia , Adulto , Diagnóstico Diferencial , Eletroencefalografia , Eletromiografia , Feminino , Humanos , Masculino , Polissonografia/métodosAssuntos
Corpo Estriado/fisiopatologia , Agonistas de Dopamina/efeitos adversos , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/fisiopatologia , Levodopa/efeitos adversos , Vias Neurais/fisiopatologia , Substância Negra/fisiopatologia , Animais , Ligação Competitiva , Corpo Estriado/metabolismo , Dopamina/metabolismo , Agonistas de Dopamina/farmacocinética , Globo Pálido/metabolismo , Haplorrinos , Humanos , Levodopa/farmacocinética , Vias Neurais/metabolismo , Neurônios/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores de GABA/metabolismo , Substância Negra/metabolismoRESUMO
While dopamine agonists are still traditionally used as adjunct medications to improve performance and smooth out motor response complications in advanced levodopa-treated Parkinson's disease, they are increasingly used in monotherapy or early in combination with levodopa particularly in patients under 65 years of age. Long-term studies using bromocriptine showed efficacy in lowering the cumulative levodopa dose and reducing the early incidence of levodopa-related motor response complications. New dopamine agonists have recently shown efficacy as adjunct medications in short-term trials. While we now have more options to fit our individual patients' needs and tolerance, it is important to view the new agonists in the light of the results obtained with ergot derivatives. In this article, the rationale for use and efficacy profile of the ergolines are briefly reviewed.
Assuntos
Agonistas de Dopamina/uso terapêutico , Ergolinas/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Animais , Antiparkinsonianos/uso terapêutico , Quimioterapia Combinada , Humanos , Levodopa/uso terapêutico , Fármacos Neuroprotetores/uso terapêuticoRESUMO
The antiparkinsonian and antidyskinetic profile of two N-methyl-D-aspartate (NMDA) receptor antagonists, a competitive antagonist, (R)-4-oxo-5-phosphononorvaline (MDL 100,453), and a novel noncompetitive allosteric site antagonist, 4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piper idi ne (Co 101244/PD 174494), was assessed in six levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine-lesioned parkinsonian monkeys. The effects on motor function of these two drugs, alone and in combination with levodopa, were then correlated with NMDA subtype selectivity and apparent affinity for four diheteromeric NMDA receptor subunit combinations expressed in Xenopus oocytes. MDL 100, 453 (300 mg/kg s.c.) by itself increased global motor activity (p =. 0005 versus vehicle) and administered 15 min after a low dose of levodopa/benserazide s.c., MDL 100,453 (50, 300 mg/kg s.c.) showed dose-dependent potentiation of antiparkinsonian responses and also produced dyskinesias. Following injection of a fully effective dose of levodopa, MDL 100,453 (300 mg/kg s.c.) also produced a 25% increase in mean dyskinesia score (p =.04). In contrast, Co 101244 did not change motor activity by itself and only showed a tendency to potentiate the antiparkinsonian response when given in combination with a low dose of levodopa, which did not attain statistical significance. However, with a high dose of levodopa, Co 101244 (0.1, 1 mg/kg s.c.) displayed antidyskinetic effects (67 and 71% reduction, respectively) while sparing levodopa motor benefit. In vitro, MDL 100,453 was an NMDA glutamate-site antagonist, with approximately 5- to 10-fold selectivity for the NR1A/NR2A subtype combination (K(b) = 0.6 microM) versus NR1A in combination with 2B, 2C, or 2D. In contrast, the allosteric site antagonist Co 101244 showed approximately 10,000-fold selectivity for the NR1A/NR2B (IC(50) = 0.026 microM) versus the other three subunit combinations tested. Taken together, the data suggest that the NR2 subunit selectivity profile of NMDA receptor antagonists can play an important role in predicting behavioral outcome and offer more evidence that NR2B-selective NMDA receptor antagonists may be useful agents in the treatment of Parkinson's disease.
Assuntos
Antiparkinsonianos/farmacologia , Dopaminérgicos/farmacologia , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/farmacologia , Intoxicação por MPTP , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/classificação , Animais , Dopaminérgicos/toxicidade , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Macaca fascicularis , Masculino , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/fisiopatologia , Ratos , Receptores de N-Metil-D-Aspartato/biossíntese , Receptores de N-Metil-D-Aspartato/genética , Valina/análogos & derivados , Valina/farmacologia , Xenopus laevisRESUMO
OBJECTIVE: To examine the effect of 17beta-estradiol on the severity of the cardinal signs of PD in postmenopausal women. BACKGROUND: Although the impact of estrogens on the manifestations of PD has not been subjected to rigorous study, their use is generally thought to be associated with a detrimental antidopaminergic effect. METHODS: A double-blind, placebo-controlled, two-arm crossover study of high-dose transdermal 17beta-estradiol was conducted in eight postmenopausal women with mild to moderate PD, all but one of whom exhibited levodopa-induced dyskinesias. Patients were randomized initially to either hormonal treatment or placebo for 2 weeks, followed by a 2-week washout period, and then another 2-week crossover treatment period. Active treatment employed four skin patches each releasing 0.1 mg of estradiol daily, replaced every 2 to 3 days. RESULTS: After 10 days of treatment a significant reduction was observed in the antiparkinsonian threshold dose of IV levodopa. Mean duration and magnitude of the antiparkinsonian response to threshold or high doses of levodopa were unchanged, and dyskinesia scores were unaltered during 17beta-estradiol treatment compared with placebo. No worsening in "on" time or motor ratings with estrogen treatment was documented. CONCLUSIONS: 17beta-estradiol appears to display a slight prodopaminergic (or antiparkinsonian) effect without consistently altering dyskinesias. Standard postmenopausal replacement therapy with transdermal 17beta-estradiol is likely to be well tolerated by many female parkinsonian patients.
Assuntos
Antiparkinsonianos/uso terapêutico , Estradiol/uso terapêutico , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Administração Cutânea , Idoso , Estudos Cross-Over , Preparações de Ação Retardada , Método Duplo-Cego , Estradiol/administração & dosagem , Estradiol/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Pós-MenopausaRESUMO
The effect of various chronic dopaminergic treatments in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys on the brain gamma-aminobutyric acid type A (GABA(A)) /benzodiazepine receptor complex and GABA content was investigated in order to assess the GABAergic involvement in dopaminomimetic-induced dyskinesia. Three MPTP monkeys received for one month pulsatile administrations of the D1 dopamine (DA) receptor agonist SKF 82958 whereas three others received the same dose of SKF 82958 by continuous infusion. A long acting D2 DA receptor agonist, cabergoline, was given to another three animals. Untreated MPTP as well as naive control animals were also included. Pulsatile SKF 82958 relieved parkinsonian symptoms but was also associated with dyskinesia in two of the three animals whereas animals treated continuously with SKF 82958 remained as untreated MPTP monkeys. Chronic cabergoline administration improved motor response with no persistent dyskinesia. MPTP treatment induced a decrease of 3H-flunitrazepam binding in the medial anterior part of caudate-putamen and an increase in the internal segment of globus pallidus (GPi) which was in general unchanged by pulsatile or continuous SKF 82958 administration. Throughout the striatum, binding of 3H-flunitrazepam remained reduced in MPTP monkeys treated with cabergoline but was not significantly lower than untreated MPTP monkeys. Moreover, cabergoline treatment reversed the MPTP-induced increase in 3H-flunitrazepam binding in the GPi. GABA concentrations remained unchanged in the striatum, external segment of globus pallidus and GPi following MPTP denervation. Pulsatile but not continuous SKF 82958 administration decreased putamen GABA content whereas cabergoline treatment decreased caudate GABA. No alteration in GABA levels were observed in the GPe and GPi following the experimental treatments. These results suggest that: (1) D2-like receptor stimulation with cabergoline modulates GABA(A) receptor density in striatal subregions anatomically related to associative cortical afferent and (2) the absence of dyskinesia in dopaminomimetic-treated monkeys might be associated with the reversal of the MPTP-induced upregulation of the GABA(A)/benzodiazepine receptor complex in the Gpi.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Gânglios da Base/metabolismo , Benzazepinas/farmacologia , Agonistas de Dopamina/farmacologia , Ergolinas/farmacologia , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Autorradiografia , Gânglios da Base/efeitos dos fármacos , Cabergolina , Denervação , Feminino , Flunitrazepam/farmacocinética , Macaca fascicularis , Ovariectomia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Receptores de GABA-A/efeitos dos fármacos , TrítioRESUMO
The contribution of dopamine D1 receptor stimulation to the motor effects of dopaminergic drugs in patients with Parkinson's disease remains undetermined. The authors of this article studied the clinical efficacy, pharmacokinetics, and tolerability of the full D1 receptor agonist dihydrexidine, (+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine hydrochloride in a double-blind, placebo-controlled trial in four patients with Parkinson's disease. Single intravenous doses were carefully titrated according to a fixed schedule ranging from 2 mg to the highest tolerated dose (or a maximum of 70 mg) infused over either 15 or 120 minutes. The only patient to achieve a plasma drug concentration greater than 100 ng/ml had a brief but definite motor improvement accompanied by choreic dyskinesias similar to the response to levodopa. Dose-limiting adverse effects, including flushing, hypotension, and tachycardia, were observed in all cases, especially with rapid infusions. No nausea or emesis occurred. Pharmacokinetic studies yielded a plasma half-life < 5 minutes. These preliminary data suggest that dihydrexidine has a marginal therapeutic window for providing an antiparkinsonian effect, although it remains uncertain how much of this effect is attributable to pure D1 receptor stimulation.
Assuntos
Agonistas de Dopamina/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Fenantridinas/uso terapêutico , Receptores de Dopamina D1/agonistas , Adulto , Agonistas de Dopamina/efeitos adversos , Agonistas de Dopamina/farmacocinética , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Atividade Motora/efeitos dos fármacos , Doença de Parkinson/metabolismo , Fenantridinas/efeitos adversos , Fenantridinas/farmacocinética , Resultado do TratamentoRESUMO
The development of a validated primate model of progressive parkinsonism is a critical step in the evaluation of drugs that might halt or slow progression of Parkinson's disease. In this pilot study, we gradually exposed 14 cynomolgus monkeys to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), at a weekly dose of 0.5 mg/kg s.c. for 10 weeks, to determine their probability of not reaching a predetermined endpoint on a disability scale by Kaplan-Meier analysis. Four other MPTP-exposed animals were coadministered the potent free radical scavenger 7-hydroxy-1-[4-(3-methoxyphenyl)-1-piperazinyl]acetylamino-2,2,4,6- tetramethylindan (OPC-14117) as a single oral daily dose of 0.6 g/kg, starting 2 weeks before MPTP initiation. The risk of reaching endpoint by week 10 was 79% and mean time before reaching endpoint was 6 weeks. Global motor activity, recorded in a subset of animals using a portable activity monitor, declined following the first MPTP dose and never recovered. Several cerebrospinal fluid indices of central monoamine metabolism collected by suboccipital puncture at 0, 5, and 10 weeks, including HVA, DOPAC, and tetrahydrobiopterin but not MHPG, were found to be "trait" markers for MPTP exposure, whereas CSF DOPAC and tetrahydrobiopterin constituted potential "state" markers for reaching endpoint. The antioxidant OPC-14117 did not protect against MPTP-induced parkinsonism. Further attempts to validate this incremental model of neurotoxin-induced parkinsonism as a predictor of patient responses to putative neuroprotective agents appear warranted.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Sequestradores de Radicais Livres/farmacologia , Indanos/farmacologia , Atividade Motora/efeitos dos fármacos , Doença de Parkinson Secundária/fisiopatologia , Piperazinas/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Animais , Biomarcadores/líquido cefalorraquidiano , Biopterinas/análogos & derivados , Biopterinas/líquido cefalorraquidiano , Modelos Animais de Doenças , Feminino , Sequestradores de Radicais Livres/sangue , Ácido Homovanílico/líquido cefalorraquidiano , Indanos/sangue , Macaca fascicularis , Masculino , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Doença de Parkinson Secundária/líquido cefalorraquidiano , Projetos Piloto , Piperazinas/sangueRESUMO
The antidyskinetic potential of the glutamate NMDA receptor channel blocker amantadine was evaluated in four levodopa-primed parkinsonian monkeys using two different regimens (1.25 or 2.5 mg/kg administered subcutaneously twice daily for 3-6 days). When administered with a relatively low dose of levodopa, amantadine produced a near-total suppression of choreiform dyskinesias and a substantial reduction in dystonic dyskinesias at the expense of a significant reduction in antiparkinsonian response. With a high dose of levodopa, amantadine had a smaller but still significant effect on dyskinesias without altering the antiparkinsonian response. These results lend support to the view that glutamate receptor-mediated mechanisms contribute to levodopa-induced dyskinesias. They also suggest that amantadine could alleviate such complications in parkinsonian patients, especially with careful dose optimization.
Assuntos
Amantadina/administração & dosagem , Antiparkinsonianos/efeitos adversos , Dopaminérgicos/administração & dosagem , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/efeitos adversos , Doença de Parkinson Secundária/tratamento farmacológico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Amantadina/efeitos adversos , Animais , Antiparkinsonianos/administração & dosagem , Dopaminérgicos/efeitos adversos , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/fisiopatologia , Injeções Subcutâneas , Levodopa/administração & dosagem , Macaca fascicularis , Exame Neurológico/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/fisiopatologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologiaRESUMO
Normal motor function is dependent on the highly regulated synthesis and release of dopamine (DA) by neurons projecting from substantia nigra to corpus striatum. Cardinal symptoms of Parkinson's disease (PD) arise as a consequence of a deficiency in striatal DA due to the progressive degeneration of this neuronal system. Under such circumstances, the subunit composition and/or phosphorylation state of glutamatergic receptors of the N-methyl-D-aspartate (NMDA) subtype expressed on the dendritic spines of medium-sized striatal neurons changes in ways that compromise motor performance. Although levodopa acts, after conversion to DA, to reverse these changes by restoring striatal dopaminergic transmission, significant differences exist between the normally functioning DA system and the restoration of function provided by standard levodopa therapy. The nonphysiologic stimulation of DA receptors on striatal spiny neurons associated with current levodopa regimens now appears to contribute to the motor response complications that ultimately affect most parkinsonian patients. Current evidence suggests that alterations in signaling systems linking dopaminergic and glutamatergic receptors within these GABAergic efferent neurons induce NMDA receptor modification. Functionally, the resultant long-term change in glutamatergic synaptic efficacy leads to alterations in spiny neuron output, favoring the appearance of motor complications. Although dopaminomimetic replacement strategies that provide more continuous DA receptor stimulation should alleviate these disabling complications, more innovative approaches to the interdiction of pathologic changes in signal transduction components or glutamate receptor sensitivity could ultimately prove safer and more effective for the treatment of all stages of PD.