Motor Dyskinesias Research Articles

Dopamine D2 agonist priming in intact and dopamine-lesioned rats.

Receptor priming is a recently discovered phenomenon by which receptor agonists produce abrupt and long-lived supersensitization of receptors. Induction of dopamine (DA) D2 receptor supersensitivity by the agonist quinpirole was discovered approximately 15 years ago, and was found to occur consistently if rats were treated repeatedly at daily or weekly or monthly intervals with low or high doses of quinpirole. In this review we summarize and discuss some of the major studies that underlie DA D2 receptor supersensitivity, describe behavioral processes that are known to be altered by DA D2 receptor supersensitivity, and discuss the importance of DA innervation on expression of enhanced behaviors. DA D2 receptor supersensitivity represents one of the neural mechanisms implicated in psychiatric disorders. Also, DA D2 receptor supersensitivity and increased DA D3 receptor expression are associated with motor dyskinesias, as in L-DOPA-treated Parkinson's disease patients. An understanding of receptor priming, a knowledge of the types of behavioral expression associated with DA D2 receptor supersensitivity, and an understanding of mechanisms associated with receptor supersensitization, can lead to improvements in the treatments of psychiatric and neurological disorders.

Clinical aspects of Parkinson disease

Parkinson disease is a slowly progressive neurodegenerative disorder with a varied clinical picture and a variable rate of progression. Recently, there have been some studies conducted to assess the diagnostic accuracy and other clinical aspects of the disease. In the absence of a biomarker the clinical diagnosis is imprecise. This leads to a significant number of misdiagnoses, especially in early disease. Assessment of the clinical features suggests that an accuracy of 90% may be the highest that can be expected using current diagnostic criteria. In addition to bradykinesia, which is a core symptom, different types of tremors occur. Whereas the rest tremor is characteristic, action tremor, re-emergent tremor and orthostatic tremor may occur in Parkinson disease. Symptomatic treatments are quite effective in early disease but clinical course is complicated by the appearance of motor fluctuations and dyskinesias in more advanced disease. Non-motor complications, such as cognitive, psychiatric and autonomic problems, become bothersome and disabling in some patients.

Advances in the pharmacological management of Parkinson disease.

Numerous advances have taken place in the pharmacological management of Parkinson disease (PD) in recent years. Some of the more clinically relevant will be discussed in the text that follows. New drugs have been developed to treat or prevent the motor fluctuations and dyskinesias that occur frequently with the continuous use of levodopa. Such drugs include the catechol-O-methyl-transferase (COMT) inhibitors, such as tolcapone and entecapone, and new dopamine (DA) agonists with long half lives such as cabergoline, pramipexole or ropirinole. Also new, atyical, antipsychotics have appeared which have revolutionized the treatment of PD since they allow us to control hallucinations and other psychotic behaviour without worsening of motor function. Finally preliminary reports suggest that cholinesterase inhibitors, such as rivastigmine, can be usefull in the management of cognitive impairment in PD, one of the most difficult clinical problems encountered in the management of this neurodegenerative disorder.

A six-month multicentre, double-blind, bromocriptine-controlled study of the safety and efficacy of ropinirole in the treatment of patients with Parkinson's disease not optimally controlled by L-dopa.

To compare the safety and efficacy of ropinirole and bromocriptine as adjunct therapy in patients with Parkinson's disease (PD) not optimally controlled by L-dopa. A randomised, double-blind trial in which 555 patients were assigned to three treatment groups according to the level of daily dosage of L-dopa, presence of motor fluctuations, and use of dopamine agonist before study entry. Patient response was defined as at least a 20% reduction in daily L-dopa dose plus: for patients with no prior treatment and no motor fluctuations, a 20% reduction in UPDRS motor score; for patients with motor fluctuations, a 20% reduction in time spent "off"; and for patients already taking an agonist, an improvement on the CGI scale. Safety assessments showed no significant differences in the two treatment groups for patients without prior dopamine-agonist therapy. In the group of patients with prior dopamine-agonist therapy, more patients reported adverse events in the ropinirole group (90% versus 79%, p < 0.001). The proportions of responders tended to be higher in ropinirole groups compared with bromocriptine groups and, in the subgroup with motor fluctuations, this difference was statistically significant (9.1% versus 0.0%, respectively; p < 0.05). Both drugs were well tolerated. In patients receiving a relatively high dose of L-dopa and requiring the addition of a dopamine agonist to control motor fluctuations or dyskinesias, ropinirole was significantly more effective than bromocriptine.

Levodopa or dopamine agonists, or deprenyl as initial treatment for Parkinson's disease. A randomized multicenter study.

Objectives: levodopa improves the quality of life in parkinsonian patients, however long term response is compromised by the emergence of motor fluctuations and dyskinesias. The aim of this study was to compare the occurrence of motor fluctuations and dyskinesias in previously untreated patients assigned to receive levodopa, a dopamine agonist or deprenyl.Thirty-five neurological departments in Italian hospitals participated in this randomized open trial. Patients with Parkinson's disease, who required the initiation of an effective antiparkinsonian treatment, were randomly assigned to receive levodopa, dopamine agonists or deprenyl. The end-points were motor dyskinesias and motor fluctuations occurring in a median follow-up period of about 3years.After a median follow-up of 34months, motor fluctuations and dyskinesias were less frequent in patients assigned to a dopamine agonist or deprenyl than in patients assigned to levodopa (relative risk [RR] 0.5, 95% confidence interval [95% CI] 0.3-0.8, and RR=0.6, 95% CI 0.3-0.9, respectively), but dopamine agonists were less effective and less well tolerated than levodopa. The lower frequency of motor fluctuations in patients assigned to deprenyl was no longer statistically significant when prognostic predictors were considered in a multivariable analysis. Long-term mortality did not differ in the three arms of the study. Dopamine agonists and deprenyl can be considered as an alternative to levodopa for starting treatment in Parkinson's disease patients. However, on clinical grounds, only small advantages are expected over the traditional therapy initiation with levodopa.

Review: Bromocriptine may be beneficial in delaying motor complications and dyskinesias in Parkinson disease

Review: Bromocriptine may be beneficial in delaying motor complications and dyskinesias in Parkinson disease

Amantadine infusion in treatment of motor fluctuations and dyskinesias in Parkinson's disease

Efficiency and safety of amantadine sulfate (AMS) infusions were investigated in late stage complications of Parkinson's disease (PD). In an open-label study, 21 PD patients suffering from motor fluctuations and/or dyskinesias were administered AMS infusions (PK-Merz, 400 mg per day) during seven days. Oral AMS treatment followed. Significant improvement of UPDRS motor scores was observed between day 0 and day 7, remaining improved until day 21. Based on patients' diary notes, both severity and occurrence of hypokinetic "off" state significantly decreased (from 6.6 to 3.1 hours, p < 0.001, average "off" time per day) as well as dopaminergic-induced dyskinesias (from 2.5 to 1.3 hours, p < 0.05, average duration of dyskinesias per day). AMS infusions followed by oral administration appeared as a safe method for improvement of both motor fluctuations and dyskinesias in advanced PD. In advantage to simple oral therapy, AMS infusions allowed fast introduction of a profound and durable treatment effect.

The early treatment of Parkinson's disease: levodopa, dopamine agonists or both.

Much has been written about the pharmacologic management of Parkinson's disease (PD) because of an expanding arsenal of antiparkinson drugs and our quest to alter the natural history of disease. Choice of initial therapy may prove fundamental to a treatment strategy that maximizes symptomatic control while minimizing the chances for long-term complications such as motor fluctuations and dyskinesias. Dopamine agonists (DA) have assumed a primary role in the early therapy of PD because of their antiparkinson effectiveness and low propensity to induce fluctuations and dyskinesias. Four available DA in the United States and an array of recent studies supporting their utility in early PD have shaped current PD management. Moreover, DA have neuroprotective properties in vivo. Nevertheless, levodopa remains the most effective drug for symptomatic control in PD. There is conflicting evidence regarding the putative neurotoxicity of levodopa and the mechanisms for levodopa-related motor fluctuations are not entirely known. Clinicians must therefore weigh the available evidence as they initiate therapy in PD. Clearly, both DA and levodopa will remain essential components of the early management of PD.

Interventions to achieve tonic exposure to levodopa: delaying or preventing the onset of motor complications.

Variations in levodopa delivery and subsequent dopamine exposure may lead to motor fluctuations and dyskinesias in patients with Parkinson's disease, as the therapeutic window for levodopa narrows with disease progression. Long-term exposure to the oscillations in levodopa-derived dopamine also is suggested to cause postsynaptic changes within the dopaminergic system, leading to further reductions in the drug's efficacy. The need to extend the actions of levodopa led to the development of the catechol-O-methyltransferase (COMT) inhibitors, which are the newest agents introduced to manage the symptoms of Parkinson's disease. Entacapone and tolcapone are two potent, selective, and reversible COMT inhibitors that effectively augment levodopa's pharmacokinetics by increasing area under the plasma concentration versus time curve and plasma elimination half-life without significantly affecting peak levodopa concentrations. This enhanced pharmacokinetic effect results in marked improvements in patients' clinical response. In patients experiencing end-of-dose wearing-off, the addition of either entacapone or tolcapone led to improvements in "on" time, "off" time, and the Unified Parkinson's Disease Rating Scale scoring system, even though many patients already were receiving optimum dosages of various other antiparkinsonian drugs. In patients with stable responses to long-term levodopa, addition of tolcapone significantly reduced the onset of motor fluctuations. These data, combined with the potential for delaying the onset of motor fluctuations, suggest that COMT inhibition may enhance levodopa's short- and long-term efficacy.

The role of dorsal striatal GABA A receptors in dopamine agonist-induced behavior and neuropeptide gene expression

The purpose of this study was to investigate whether GABA A receptors in the dorsal striatum regulate basal or stimulant-induced behaviors. Correspondingly, the question of possible GABA A receptor control of neuropeptide mRNA expression in nigrostriatal neurons was addressed. The GABA A receptor antagonist, bicuculline, was unilaterally or bilaterally microinjected into the dorsal striatum of rats in a series of 3 studies. In the first study, unilateral administration of 10–50 ng/μl of bicuculline did not alter behavior. However, 250 ng/μl bicuculline produced motor dyskinesias and/or seizures. In the second study, 100 ng/μl bicuculline administered unilaterally prior to saline or amphetamine treatment, produced mild twitching in 61% of rats but did not affect amphetamine (2.5 mg/kg, i.p.)-induced behavioral activity, specifically rearing and sniffing. In the third study, 75 ng/μl of bicuculline was administered unilaterally or bilaterally into the striatum in two separate experiments. Administration of bicuculline either unilaterally or bilaterally produced mild transient twitching of the forelimbs but did not affect behaviors induced by the selective D 1 receptor agonist SKF-82958 (0.5 mg/kg, s.c.). Three hours after unilateral bicuculline administration, the brains were removed and processed for quantitative in situ hybridization. Bicuculline did not significantly affect the basal or SKF-82958-induced increase in preprodynorphin or substance P mRNA expression in striatonigral neurons on the side of injection. These data suggest that blockade of GABA A receptors in the dorsal striatum does not affect dopamine agonist-stimulated behaviors or neuropeptide mRNA expression in striatonigral neurons in the rat striatum.

Neuroleptic discontinuation syndromes.

The existence of discontinuation syndromes following treatment with neuroleptic (antipsychotic) drugs was first outlined in the mid-1960s but the effects of such syndromes have been neglected since then. We have pursued evidence for the existence and nature of discontinuation syndromes following neuroleptics through reports of difficulties following the use of dopamine blocking anti-emetics, the use of chlorpromazine to treat tuberculosis, the use of antidepressant-neuroleptic combinations in affective disorders, the occurrence of tardive syndromes and studies designed to establish the existence of discontinuation syndromes in schizophrenia. Combined these bodies of data point strongly to the existence of discontinuation syndromes after cessation of treatment with neuroleptics which may involve features other than motor dyskinesias. There is at present little evidence on the relative frequency of such syndromes or predisposing factors. The area needs research input to establish the nature of the syndromes that may result, their frequency, predisposing factors and best methods of treatment.

Extending levodopa action: COMT inhibition.

Degradation of levodopa in the periphery is known to be associated with motor fluctuations and dyskinesia in Parkinson's disease (PD) patients. The enzyme catechol-O-methyltransferase (COMT) is responsible for much of this degradation. Therefore, inhibiting COMT activity is one method of extending the action of levodopa. The new nitrocatechol-type COMT inhibitors entacapone, nitecapone, and tolcapone inhibit COMT in the periphery; tolcapone also inhibits COMT activity centrally. COMT inhibitors increase patients' duration of response to levodopa and reduce response fluctuations. Administration may prolong levodopa-induced dyskinesia, but peak-dose dyskinesia does not appear to increase. To reduce dyskinesia, the total daily dose of levodopa can be reduced.

Current and emerging drug therapies in the management of Parkinson's disease.

Recent advances in pharmacology are changing the therapy of Parkinson's disease (PD). The development of a sustained-release carbidopa-levodopa formulation, of new dopamine agonists, and of a new class of drugs, COMT inhibitors, is not only providing new therapeutic options but is also changing our understanding of the development of long-term complications, such as motor fluctuations and dyskinesias. We begin this supplement with perspective on the development of PD therapy thus far with a history of the use of levodopa and dopamine agonists in PD. Since almost …

Drug treatment of Parkinson's disease in the 1990s. Achievements and future possibilities.

Advances in the medical treatment of Parkinson's disease have improved the disability related to complications of long term levodopa therapy, including motor fluctuations, dyskinesias and neuropsychiatric toxicity. A range of new dopamine agonists are in various stages of preclinical and clinical development. Cabergoline appears to be effective in improving moderate motor fluctuations, and a number of dopamine partial agonists that can act as either agonists or antagonists depending on the degree of denervation and receptor sensitivity are being investigated. Apomorphine represents a significant advance in the treatment of well developed motor fluctuations in selected patients who are able to master the technique of subcutaneous administration. The catecholamine-O-methyl transferase inhibitors are proving useful in phase III studies in the management of patients with moderate motor fluctuations. A role for glutamate antagonists is supported by animal and early clinical data, although the poor therapeutic index associated with the currently available nonselective, noncompetitive glutamate antagonists has prompted a search for more selective antagonists with less toxicity. The management of levodopa-induced dyskinesias remains a major therapeutic challenge. Some reports of dopamine partial agonists, selective D2 receptor antagonists and atypical antipsychotics being useful await confirmation. Neuropsychiatric toxicity probably remains the major dose-limiting adverse effect of levodopa and is a major reason for parkinsonian patients being admitted to nursing homes. The development of new atypical antipsychotics with improved therapeutic indices, along with the possible use of serotonergic antagonists, may improve management of this difficult problem. The challenge will be to fit these new forms of treatment into our present range of available drugs and to assess their relative role within the emerging framework of functional neurosurgery for parkinsonian disability.

The relationship between diabetes mellitus and Parkinson's disease.

It has been reported that 50% to 80% of patients with Parkinson's disease have abnormal glucose tolerance which may be further exacerbated by levodopa therapy. Little is known about the impact of chronic hyperglycemia on the severity of the motor manifestations and the course of the disease as well as its impact on the efficacy of levodopa or other dopaminergic drugs. This issue, which has been largely ignored, is of clinical relevance since animal studies indicate that chronic hyperglycemia decreases striatal dopaminergic transmission and increases the sensitivity of postsynaptic dopamine receptors. In addition, evidence from experimental animal studies indicates that diabetic rats are resistant to the locomotor and behavioral effects of the dopamine agonist amphetamine. The resistance to the central effects of amphetamine is largely restored with chronic insulin therapy. In the present communication, I propose that in Parkinson's disease diabetes may exacerbate the severity of the motor disability and attenuate the therapeutic efficacy of levodopa or other dopaminergic agents as well as increase the risk of levodopa-induced motor dyskinesias. Thus, it is advocated that Parkinsonian patients should be routinely screened for evidence of glucose intolerance and that if found aggressive treatment of the hyperglycemia may improve the response to levodopa and potentially diminish the risk of levodopa-induced motor dyskinesias.

Sustained synergism by chronic caffeine of the motor control deficit produced by midazolam.

To evaluate the effects of chronic caffeine on the impairment of discriminative fine motor control produced by midazolam, rats were trained to hold a force transducer steady to deliver food pellets. Chronic, daily doses of midazolam (3 mg/kg SC) led to a stable level of motor impairment. Chronic caffeine (20 mg/kg IP) alone usually produced a more moderate deficit or, for one animal, no deficit. Combined, chronic administration of these doses yielded a sustained synergism in motor performance impairment, which contrasted with the antagonism usually found between the benzodiazepines and methylxanthines when performance is evaluated by psychomotor tests not requiring fine motor control. The observed synergism was not explicable in terms of measured disposition of the drugs. The synergistic production of fine motor dyskinesia by the concurrent administration of caffeine and midazolam may be relevant to the triggering of anxiety attacks by caffeine observed in panic disorder patients.

Locus coeruleus-pineal melatonin interactions and the pathogenesis of the "on-off" phenomenon associated with mood changes and sensory symptoms in Parkinson's disease.

The "on-off" phenomenon has been reported to occur in more than 50% of patients with Parkinson's disease after 5 years of treatment with levodopa. Several recent studies have reported an association between the "on-off" phenomenon, concurrent mood changes and sensory symptoms in patients with Parkinson's disease. In these reports, "off" was associated with exacerbation of depression, anxiety and sensory symptoms, while "on" was accompanied by normalization of mood with occasional elation and attenuation in the severity of the sensory symptoms. These observations suggest that the biological mechanisms of the "on-off" interact with mechanisms regulating mood and sensory functions. The "on-off" phenomenon may be related to primary degenerative changes in the locus coeruleus (LC). The emergence of mood changes and sensory symptoms associated with the "on-off" may be facilitated by deregulation of LC-pineal melatonin functions. Administration of noradrenergic agents may be beneficial in attenuating the severity of the motor dyskinesias of the "on-off" while serotonergic drugs alone or in combination with melatonin-release enhancing agents may be useful in the management of the mood changes and sensory symptoms.

Spinal cord stimulation for spasticity.

After the dramatic improvement of multiple sclerosis patients reported by Cook and Weinstein (1973), spinal cord stimulation (SCS) for the relief of spasticity and motor dyskinesias has been applied to a large number of patients. However, the overall effectiveness of this treatment has been a subject of considerable debate, some authors even reaching the conclusion that the observed results can be explained in terms of a placebo effect (Rosen and Barsoum 1979). In this review we will try to answer the question which is most important from the patient’s point of view: (1) What is the effect of SCS on spasticity and accompanying motor impairment? We will also examine the data which are available with respect to the following questions which are important for the physician: (2) Is there a difference between the effect of SCS in MS patients, who have a fluctuating clinical course, and patients with other conditions, such as cerebral palsy, trauma, and cerebellar atrophies, in which the clinical course is either stabilized or progressive?

L-Dopa Treatment and Parkinson's Disease

Seventeen years after its introduction, L-dopa, now administered in combination with a peripheral dopa decarboxylase inhibitor remains the most effective palliative remedy for Lewy body Parkinson's disease. A therapeutic effect to large doses is so consistent that alternative diagnoses should be considered in any patient with a Parkinsonian syndrome who fails completely to respond. Despite improving the quality of life, it probably does not influence appreciably the reduced life expectancy in Parkinson's disease and the long-term therapeutic response is frequently marred by drug-induced oscillations in motor performance, dyskinesias and psychotoxicity. Experimental studies using continuous intravenous infusions of L-dopa in order to obtain constant plasma levels suggests that additional refinements in management may be achieved by the design of a practical controlled delivery system, and prototype pumps and sustained release formulations are already under evaluation.