Induction and expression of abnormal involuntary movements is related to the duration of dopaminergic stimulation in 6-OHDA-lesioned rats

Dyskinesia induction in Parkinson's disease (PD) appears less marked with long-acting dopamine agonists than with short-acting L-Dopa, but the relationship to duration of drug action is unknown. It is also unclear whether the duration of drug action affects the expression of established dyskinesia. This study compared the ability of L-Dopa and four dopamine agonists of different duration of action to induce abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA)-lesioned rats, and their ability to express established AIMs following prior exposure to L-Dopa. 6-OHDA-lesioned rats were treated with saline, L-Dopa/benserazide, apomorphine, ropinirole, pramipexole or pergolide once daily for 15 days. Repeated administration of the short-acting dopamine agonists, apomorphine (duration 80 min) and ropinirole (duration 90 min) induced marked axial, limb and orolingual AIMs at peak effect. L-Dopa (duration 100 min) produced moderate AIMs at peak effect, while administration of the long-acting dopamine agonists, pramipexole (duration 150 min) and pergolide (duration 240 min) resulted in mild AIMs. In rats primed to exhibit severe AIMs following repeated L-Dopa administration, acute administration of apomorphine, ropinirole and L-Dopa induced severe AIMs. By contrast, pramipexole and pergolide evoked only mild-moderate AIMs. Again, there was a negative correlation between duration of effect and the severity of AIMs expressed. These studies show that both the induction and expression of AIMs in 6-OHDA-lesioned rats are related to the duration of action of dopaminergic drugs. These findings suggest that continuous dopaminergic stimulation could be used both to avoid dyskinesia induction and to improve motor function in late-stage PD when troublesome dyskinesia is evident.     

Striatal synaptic changes in experimental parkinsonism: role of NMDA receptor trafficking in PSD

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of dopaminergic terminals from substantia nigra pars compacts, which leads to the motor symptoms observed in this disorder. L-Dopa administration represents the most effective therapeutic treatment of PD, but the development of disabling dyskinetic movements is a dramatic consequence of the treatment. The organization and functional interactions of glutamate receptors within the striatum appear to be crucial both in the pathogenesis of PD and in the development of dyskinesia. At the molecular level, it has become increasingly evident that the glutamatergic NMDA receptor complex is a dynamic structure that is involved in the regulation of corticostriatal long-term synaptic changes, which is altered in experimental PD and in dyskinesia.     

Arc interacts with microtubules/microtubule-associated protein 2 and attenuates microtubule-associated protein 2 immunoreactivity in the dendrites

Arc, activity-regulated cytoskeleton-associated gene, is an immediate early gene, and its expression is regulated by a variety of stimuli, such as electric stimulation and methamphetamine. The function of Arc, however, is unknown. To explore this function, we carried out expression experiments by transfecting green fluorescent protein (GFP)-Arc constructs or by using a protein transduction system in hippocampal cultured neurons. We found that the overexpression of Arc as well as Arc induction by seizure in vivo decreased microtubule-associated protein 2 (MAP2) staining in the dendrites by immunocytochemistry, although MAP2 content was not changed on Western blot. Furthermore, Arc interacted with newly polymerized microtubules and MAP2, leading to blocking of the epitope of MAP2. The data suggest that Arc increased by synaptic activities would trigger dendritic remodeling by interacting with cytoskeletal proteins.     

Arc in synaptic plasticity: from gene to behavior

The activity-regulated cytoskeletal (Arc) gene encodes a protein that is critical for memory consolidation. Arc is one of the most tightly regulated molecules known: neuronal activity controls Arc mRNA induction, trafficking and accumulation, and Arc protein production, localization and stability. Arc regulates synaptic strength through multiple mechanisms and is involved in essentially every known form of synaptic plasticity. It also mediates memory formation and is implicated in multiple neurological diseases. In this review, we will discuss how Arc is regulated and used as a tool to study neuronal activity. We will also attempt to clarify how its molecular functions correspond to its requirement in various forms of plasticity, discuss Arc's role in behavior and disease, and highlight critical unresolved questions.     

Spatial exploration induces ARC, a plasticity-related immediate-early gene, only in calcium/calmodulin-dependent protein kinase II-positive principal excitatory and inhibitory neurons of the rat forebrain

Active behavior, such as exploring a novel environment, induces the expression of the immediate-early gene Arc (activity-regulated cytoskeletal associated protein, or Arg 3.1) in many brain regions, including the hippocampus, neocortex, and striatum. Arc messenger ribonucleic acid and protein are localized in activated dendrites, and Arc protein is required for the maintenance of long-term potentiation and memory consolidation. Although previous evidence suggests that Arc is expressed in neurons, there is no direct demonstration that only neurons can express Arc. Furthermore, there is no characterization of the main neuronal types that express Arc. The data reported here show that behavior- or seizure-induced Arc expression in the hippocampus, primary somatosensory cortex, and dorsal striatum of rats colocalizes only with neuronal (NeuN-positive) and not with glial (GFAP-positive) cells. Furthermore, Arc was found exclusively in non-GABAergic alpha-CaMKII-positive hippocampal and neocortical neurons of rats that had explored a novel environment. Some GAD65/67-positive neurons in these regions were observed to express Arc, but only after a very strong stimulus (electroconvulsive seizure). In the dorsal striatum, spatial exploration induced Arc only in GABAergic and alpha-CaMKII-positive neurons. Combined, these results show that although a very strong stimulus (seizure) can induce Arc in a variety of neurons, behavior induces Arc in the CaMKII-positive principal neurons of the hippocampus, neocortex, and dorsal striatum. These results, coupled with recent in vitro findings of interactions between Arc and CaMKII, are consistent with the hypothesis that Arc and CaMKII act as plasticity partners to promote functional and/or structural synaptic modifications that accompany learning.     

Long-term potentiation in the rat dentate gyrus is associated with enhanced Arc/Arg3.1 protein expression in spines, dendrites and glia

Electron microscopic immunocytochemical methods were used to determine the localization, subcellular distribution and expression of activity-regulated cytoskeletal protein (Arc/Arg3.1) in dentate gyrus after unilateral induction of long-term potentiation (LTP) in the perforant pathway of anaesthetized rats. At 2 h post-induction, immunoreaction product was visible in the dentate gyrus in both the granule cell and molecular layers. Arc expression was higher in the potentiated than the unstimulated contralateral hemisphere. Single-section electron microscopy analysis in unstimulated tissue and in tissue prepared 2 and 4 h after LTP induction showed Arc immunoreactivity (Arc-IR) in dendrites, dendritic spines and glia. Arc-IR was associated with synaptic and non-synaptic plasma membrane apposed to axon terminals and with cytoplasmic organelles, including the cytoskeleton. Arc-IR was also present in neuronal perikarya and there was occasional labelling of nuclei and axons. At 2 h post-LTP induction, there were significant increases in Arc-IR within the granule cell and molecular layers of the dentate gyrus and particularly within the middle molecular layer relative to the inner and outer molecular layers. This increase in Arc expression 2 h after LTP induction was blocked by the N-methyl-D-aspartate receptor antagonist (RS)-3-2-carboxypiperazin-4-yl-propyl-1-phosphonic acid. In animals killed 4 h after LTP induction, Arc expression had declined and differences between the potentiated and unpotentiated hemispheres were no longer significant. Our data provide ultrastructural evidence for a transient LTP-associated increase in the expression of Arc protein in the middle molecular layer of the dentate gyrus, with preferential targeting to dendrites, dendritic spines and glia.     

Sustained cabergoline treatment reverses levodopa-induced dyskinesias in parkinsonian monkeys

The pathophysiology of L-Dopa-induced dyskinesias (LID), a common problem after long-term use of L-dopa in the treatment of Parkinson's disease (PD), is not completely understood. Oscillations in L-Dopa concentrations in the brain are believed to be responsible, at least in part, for their pathogenesis. This study was aimed at verifying whether chronic administration of cabergoline, a long-acting dopamine D2-like receptor agonist, can reverse established LID. Four MPTP-treated cynomolgus monkeys with long-standing and stable parkinsonian syndrome and reproducible dyskinesias to L-Dopa, were used in this study. We compared the antiparkinsonian and dyskinetic responses of L-Dopa methyl ester (62.5 mg and 125 mg), given with benserazide (50 mg) (L-Dopa/benserazide), administered before and after a 6-week period during which the animals were treated only by daily administration of cabergoline (doses ranging from 0.125 to 0.185 mg/kg, subcutaneous). During cabergoline treatment, the monkeys initially showed marked dyskinesias, which were reduced significantly after 4 weeks of treatment. However, there was no tolerance to its antiparkinsonian effect. L-Dopa/benserazide given 4 days after cabergoline withdrawal produced a significant antiparkinsonian effect, but dyskinesias were dramatically reduced compared to what had been seen before chronic cabergoline treatment. The duration of the L-Dopa response was not increased after chronic administration of cabergoline. Our data suggest that sustained dopamine D2 receptor stimulation could be of value when trying to reduce or to reverse LID in patients with fluctuating advanced PD.     

Reduction of dyskinesia and induction of akinesia induced by morphine in two Parkinsonian patients with severe sciatica

Summary. In two patients with Parkinson's disease and L-Dopa induced dyskinesia we administered morphine orally to alleviate lumboradicular pain unresponsive to any other form of treatment. Besides an alleviation of the pain both patients showed a decrease in dyskinetic movements at very low doses of morphine and an increase in akinesia at higher doses. This observation indicates a modulation of basal ganglia output by morphine with the possibility of reducing L-Dopa induced dyskinesia in patients treated with morphine for pain. Received September 24, 1998; accepted February 3, 1999     

Continuous transdermal dopaminergic stimulation in advanced Parkinson's disease

The objective of the study was to determine the safety and efficacy of increasing doses of Rotigotine CDS in patients with advanced Parkinson's disease. The development of motor complications in Parkinson's disease has been linked to intermittent stimulation of dopamine receptors. Continuous, noninvasive, dopaminergic stimulation has not been available to date. Rotigotine CDS is a lipid-soluble D2 dopamine agonist in a transdermal delivery system that could fill this void. This inpatient study consisted of a 2-week dose escalation phase followed by a 2-week dose maintenance phase at the highest dose (80 cm2). Each individual's L-Dopa dose was back-titrated as feasible. The primary outcome measure was L-Dopa dose, and secondary outcome measures included early morning "off"-L-Dopa Unified Parkinson's Disease Rating Scale motor scores by a blinded evaluator and motor fluctuation data obtained from patient diaries ("on" without dyskinesia, "on" with dyskinesia, and "off"). Seven of 10 subjects provided data that could be evaluated. There were two administrative dropouts, and one individual was eliminated from the study because of recrudescence of hallucinations. The median daily L-Dopa dose decreased from 1,400 to 400 mg (p = 0.018, Wilcoxon test). Unified Parkinson's Disease Rating Scale motor scores were unchanged. Although diary variables improved in most individuals, only the reduction in "off" time attained statistical significance. Adverse effects were mild and consisted mainly of dopaminergic side effects and local skin reactions. The data suggest that Rotigotine CDS is an effective treatment for advanced Parkinson's disease and permits patients to substantially lower L-Dopa doses without loss of antiparkinsonian efficacy. Full-scale controlled clinical trials are warranted. In addition to potential therapeutic benefits, this drug can be used to test the hypothesis that continuous dopaminergic stimulation from the initiation of Parkinson's disease therapy will limit the development of motor complications.     

The Immediate Early Gene Arc Is Not Required for Hippocampal Long-Term Potentiation

Memory consolidation is thought to occur through protein synthesis-dependent synaptic plasticity mechanisms such as long-term potentiation (LTP). Dynamic changes in gene expression and epigenetic modifications underlie the maintenance of LTP. Similar mechanisms may mediate the storage of memory. Key plasticity genes, such as the immediate early gene Arc, are induced by learning and by LTP induction. Mice that lack Arc have severe deficits in memory consolidation, and Arc has been implicated in numerous other forms of synaptic plasticity, including long-term depression and cell-to-cell signaling. Here, we take a comprehensive approach to determine if Arc is necessary for hippocampal LTP in male and female mice. Using a variety of Arc knock-out (KO) lines, we found that germline Arc KO mice show no deficits in CA1 LTP induced by high-frequency stimulation and enhanced LTP induced by theta-burst stimulation. Temporally restricting the removal of Arc to adult animals and spatially restricting it to the CA1 using Arc conditional KO mice did not have an effect on any form of LTP. Similarly, acute application of Arc antisense oligodeoxynucleotides had no effect on hippocampal CA1 LTP. Finally, the maintenance of in vivo LTP in the dentate gyrus of Arc KO mice was normal. We conclude that Arc is not necessary for hippocampal LTP and may mediate memory consolidation through alternative mechanisms.SIGNIFICANCE STATEMENT The immediate early gene Arc is critical for maintenance of long-term memory. How Arc mediates this process remains unclear, but it has been proposed to sustain Hebbian synaptic potentiation, which is a key component of memory encoding. This form of plasticity is modeled experimentally by induction of LTP, which increases Arc mRNA and protein expression. However, mechanistic data implicates Arc in the endocytosis of AMPA-type glutamate receptors and the weakening of synapses. Here, we took a comprehensive approach to determine if Arc is necessary for hippocampal LTP. We find that Arc is not required for LTP maintenance and may regulate memory storage through alternative mechanisms.     

The acute antiparkinsonian and antidyskinetic effect of AFQ056, a novel metabotropic glutamate receptor type 5 antagonist, in L-Dopa-treated parkinsonian monkeys

Overactivity of glutamatergic transmission has been implicated in Parkinson's disease (PD) and levodopa (L-Dopa)-induced dyskinesias. Striatal metabotropic glutamate receptors type 5 (mGluR5) are abundant and provide specific targets to modulate glutamatergic activity. This study investigated the acute effects of the novel mGluR5 antagonist AFQ056 on motor behavior in L-Dopa-treated monkeys with a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion to model PD. Six Macaca fascicularis MPTP monkeys were treated repeatedly with L-Dopa; this treatment increased their locomotion and reduced their parkinsonian scores, but also induced dyskinesias. When AFQ056 (doses of 5, 25, 125 or 250mg/kg) was administered one hour prior to a high dose of L-Dopa, the antiparkinsonian activity of L-Dopa was maintained as measured with locomotion and antiparkinsonian scores, whereas dyskinesias were significantly reduced at 25, 125 and 250mg/kg AFQ056 for peak dyskinesia score and at 125 and 250mg/kg for the 1h peak period of dyskinesia score. Administration of AFQ056 one hour before L-Dopa led to peak or elevated plasma AFQ056 concentrations occurring close to L-Dopa peak-dose dyskinesias. We next investigated AFQ056 25mg/kg combined with a low dose of L-Dopa. The antiparkinsonian activity of L-Dopa was increased as measured with locomotion, while dyskinesias remained low at these doses. Our results show a beneficial motor effect of AFQ056 with L-Dopa in MPTP monkeys. This supports the therapeutic use of an mGluR5 antagonist to restore normal glutamatergic neurotransmission in PD and decrease dyskinesias.     

Repeated administration of the monoamine reuptake inhibitor BTS 74 398 induces ipsilateral circling in the 6-hydroxydopamine lesioned rat without sensitizing motor behaviours

BTS 74 398 (1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio)ethanone monocitrate) is a monoamine reuptake inhibitor that reverses motor deficits in MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmosets without provoking established dyskinesia. However, it is not known whether BTS 74 398 primes the basal ganglia for dyskinesia induction. In this study, the ability of BTS 74 398 to sensitize 6-hydroxydopamine (6-OHDA)-lesioned rats for the production of abnormal motor behaviours and the induction of striatal DeltaFosB were determined in comparison with l-3,4-dihydroxyphenylalanine methyl ester (L-dopa). Acute administration of BTS 74 398 induced a dose-dependent ipsilateral circling response in unilaterally 6-OHDA-lesioned rats whereas L-dopa produced dose-dependent contraversive rotation. The ipsilateral circling response to BTS 74 398 did not alter during 21 days of administration. In contrast, L-dopa treatment for 21 days caused a marked increase in rotational response. Repeated administration of both L-dopa and BTS 74 398 increased general motor activity and stereotypic behaviour. In L-dopa-treated rats, orolingual, locomotive, forelimb and axial abnormal movements developed whereas BTS 74 398 produced only locomotion with a side bias but no other abnormal movements. Sensitization of circling responses and the development of abnormal movements in 6-OHDA-lesioned rats have been associated with the potential of dopaminergic drugs to induce dyskinesia. Furthermore, striatal DeltaFosB immunoreactivity, shown to correlate with dyskinesia induction, was increased by L-dopa but was unaffected by repeated BTS 74 398 administration. The lack of such changes following repeated BTS 74 398 treatment suggests that it may be an effective antiparkinsonian therapy that is unlikely to produce involuntary movements.     

GDNF reverses priming for dyskinesia in MPTP-treated, L-DOPA-primed common marmosets

Parkinson's disease (PD) is associated with a progressive loss of dopamine neurons in the substantia nigra and degeneration of dopaminergic terminals in the striatum. Although L-DOPA treatment provides the most effective symptomatic relief for PD it does not prevent the progression of the disease, and its long-term use is associated with the onset of dyskinesia. In rodent and primate studies, glial cell line-derived neurotrophic factor (GDNF) may prevent 6-OHDA- or MPTP-induced nigral degeneration and so may be beneficial in the treatment of PD. In this study, we investigate the effects of GDNF on the expression of dyskinesia in L-DOPA-primed MPTP-treated common marmosets, exhibiting dyskinesia. GDNF or saline was administered by two intraventricular injections, 4 weeks apart, to MPTP-treated, L-DOPA-treated common marmosets primed to exhibit dyskinesia. Prior to GDNF or saline administration, all animals displayed marked dyskinesia when treated with L-DOPA. GDNF administration produced a significant improvement in motor disability and, following the second injection of GDNF, a significant improvement in the locomotor activity was observed. Following the administration of L-DOPA there was a greater reversal of disability and a reduction in the intensity of L-DOPA-induced dyskinesia in GDNF-treated animals compared to saline-treated controls. However, there was no significant difference in L-DOPA's ability to increase locomotor activity between GDNF-treated and saline-treated animals. GDNF treatment caused a significant increase in the number of tyrosine hydroxylase-positive neurons in the substantia nigra, but no change in [(3)H]mazindol binding to dopamine terminals was found in the striatum of GDNF-treated animals compared to saline-treated controls. In GDNF-treated animals a small but significant reduction in enkephalin mRNA was observed in the caudate nucleus but not in the putamen or the nucleus accumbens. Substance P mRNA expression was equally reduced in the caudate nucleus and the putamen of the GDNF-treated animals but not in the nucleus accumbens. Intraventricular administration of GDNF improved MPTP-induced disability and reversed dopamine cell loss in the substantia nigra. GDNF also diminished L-DOPA-induced dyskinesia, which may relate to its ability to partly restore nigral dopaminergic transmission or to modify the activity of striatal output pathways.     

Baclofen in tardive dyskinesia patients maintained on neuroleptics

Several short-term trials of baclofen for tardive dyskinesia have yielded conflicting results. We evaluated 33 patients maintained on a constant dose of neuroleptic during a randomized 6-week double-blind placebo-controlled trial, followed by a 6-week open-label trial. During the double-blind part, 67% of baclofen-treated patients and 47% of placebo-treated patients showed a reduction of 25% or more in their original dyskinesia score on the abnormal involuntary movement scale. In the open-labeled part, we further evaluated seven of nine baclofen responders and nine of nine placebo nonresponders. We found a 77% baclofen response rate for the original placebo nonresponders, a loss of efficacy in 23% of the original baclofen responders, and an attenuation of response in others. Patients with major depressive disorders were poorer responders to baclofen than those with schizophrenia. Side effects were infrequent and reversible, but dose limiting in several instances. Although baclofen may help some cases of mild tardive dyskinesia, its efficacy may attenuate with long-term administration.     

Functional integration of new neurons into hippocampal networks and poststroke comorbidities following neonatal stroke in mice

Stroke in the developing brain is an important cause of chronic neurological morbidities including neurobehavioral dysfunction and epilepsy. Here, we describe a mouse model of neonatal stroke resulting from unilateral carotid ligation that results in acute seizures, long-term hyperactivity, spontaneous lateralized circling behavior, impaired cognitive function, and epilepsy. Exploration-dependent induction of the immediate early gene Arc (activity-regulated cytoskeleton associated protein) in hippocampal neurons was examined in the general population of neurons versus neurons that were generated ∼ 1 week after the ischemic insult and labeled with bromodeoxyuridine. Although Arc was inducible in a network-specific manner after severe neonatal stroke, it was impaired, not only in the ipsilateral injured but also in the contralateral uninjured hippocampi when examined 6 months after the neonatal stroke. Severity of both the stroke injury and the acquired poststroke epilepsy negatively correlated with Arc induction and new neuron integration into functional circuits in the injured hippocampi.     

Continuous administration of rotigotine to MPTP-treated common marmosets enhances anti-parkinsonian activity and reduces dyskinesia induction

Rotigotine is a novel, non-ergoline dopamine D₃/D₂/D₁-receptor agonist for the treatment of Parkinson's disease that can be continuously delivered by the transdermal route to provide stable plasma levels. Continuous drug delivery should reduce the risk of dyskinesia induction in comparison to pulsatile dopaminergic treatment. Thus the aim of the study was to compare the reversal of motor disability and induction of dyskinesia produced by continuous compared to pulsatile rotigotine administration in MPTP-treated common marmosets. The study also investigated whether pulsatile or continuous rotigotine administration in combination with l-DOPA prevented l-DOPA-induced dyskinesia. Animals were treated for 28 days with vehicle or pulsatile (twice daily) or continuous delivery of rotigotine (via an osmotic minipump). Subsequently, l-DOPA was then co-administered for a further 28 days. Animals were assessed for locomotor activity, motor disability and dyskinesia induction. The study showed that both continuous and pulsatile administration of rotigotine improved motor deficits and normalized motor function in MPTP-treated monkeys. However, continuous rotigotine delivery reduced dyskinesia expression compared to pulsatile treatment. Both pulsatile and continuous rotigotine administration produced less dyskinesia than administration of l-DOPA alone. The addition of l-DOPA to either pulsatile or continuous rotigotine treatment resulted in the induction of marked dyskinesia similar to that produced by treatment with l-DOPA alone. These data further support the hypothesis that continuous delivery of a dopaminergic agent reduces the risk of dyskinesia induction. However, continuous rotigotine administration did not prevent l-DOPA from inducing dyskinesia suggesting that l-DOPA may induce dyskinesia by mechanisms different from dopamine agonist drugs.     

Combined effects of cabergoline and L-dopa on parkinsonism in MPTP-treated cynomolgus monkeys

Summary The behavioral effects of L-dopa or cabergoline alone were compared with those of the joint administration of the two drugs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity and dyskinesia. Cabergoline alone at 0.2mg/kg or less improved in a dose-dependent fashion the parkinsonism without inducing hyperactivity and dyskinesia following a single subcutaneous injection. L-dopa alone improved the parkinsonism, but induced hyperactivity and dyskinesia, depending on the dose applied. Doses required for 50% amelioration by L-dopa and cabergoline were 10 and 0.038mg/kg, s.c., respectively. With low doses (50%-amelioration doses), cabergoline or L-dopa alone improved the parkinsonism without induction of hyperactivity and dyskinesia, but the duration of action was brief. Cabergoline in combination with L-dopa was highly effective in improving motor disability without induction of hyperactivity and dyskinesia. Moreover, the duration of action was more prolonged with the coadministration than with the single administration of each drug. These findings suggest that the combined therapy with low doses of L-dopa and cabergoline is beneficial for treating patients with advanced Parkinson's disease.     

Pharmacokinetics and pharmacodynamics of L-Dopa after acute and 6-week tolcapone administration in patients with Parkinson's disease

Tolcapone, a central and peripheral catechol O-methyltransferase (COMT) inhibitor, reduces the conversion of L-Dopa into 3-O-methyl-Dopa (3-OMD), thus leading to more stable and sustained L-Dopa plasma levels. This study was designed to evaluate the effects of acute and 6-week tolcapone administration on L-Dopa pharmacokinetics and pharmacodynamics in Parkinson's disease (PD) patients with predictable motor fluctuations. Tapping test, walking time, and tremor, as well as L-Dopa and 3-OMD plasma levels, were assessed before and for 5 hours after the administration of a single L-Dopa dose, alone or in combination with 200 mg tolcapone, in seven patients with PD. This clinical and pharmacokinetic study was repeated after 6 weeks of tolcapone therapy (200 mg three times daily). It was observed that tolcapone, after both acute and chronic administration, prolonged the motor improvement induced by L-Dopa. As a result, at week 6 of tolcapone therapy, the daily hours spent "off" were significantly decreased. Tolcapone significantly increased the area under the curve of L-Dopa plasma levels by slowing down the elimination of L-Dopa from plasma, whereas the maximal concentration of L-Dopa was not modified. 3-OMD levels decreased significantly after acute tolcapone administration, and after 6 weeks of tolcapone therapy, they were approximately one sixth of pre-tolcapone values. The data confirm that tolcapone decreases L-Dopa clearance and prolongs motor response in PD patients with motor fluctuations, and that this effect is maintained after 6 weeks of tolcapone therapy.     

Antiparkinsonian activity and dyskinesia risk of ropinirole and L-DOPA combination therapy in drug na?ve MPTP-lesioned common marmosets (Callithrix jacchus).

De novo administration of long-acting dopamine agonists, such as ropinirole, to patients with Parkinson's disease or to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated subhuman primates produces a lower incidence of dyskinesia than occurs with L-DOPA. This study compares the intensity of dyskinesia produced by combinations of L-DOPA and ropinirole and by these drugs alone, using the MPTP-treated common marmoset model of Parkinson's disease. The objective is to determine the optimum therapeutic strategy for the long-term control of Parkinson's disease with a minimal risk of dyskinesia. MPTP-treated marmosets received either L-DOPA alone, ropinirole alone, or one of two combinations of these drugs (either L-DOPA dominant or ropinirole dominant) daily for 28 days in doses titrated to produce a similar improvement in disability and increase in locomotion. In the group receiving L-DOPA alone, there was a trend for peak dose locomotor activity to increase and the duration of drug effect to decline over the period of the study. L-DOPA alone induced marked dyskinesia over the period of treatment, in contrast to ropinirole which produced a low intensity of involuntary movements. The L-DOPA dominant combination initially produced little dyskinesia, but this became increasingly intense as the study progressed. In contrast, the ropinirole dominant combination produced no greater intensity of dyskinesia than was produced by ropinirole alone. These data suggest that in early Parkinson's disease, the use of ropinirole alone or in combination with a low-dose L-DOPA might delay the induction of dyskinesias while improving motor performance.