Treatment of Parkinson disease commonly includes levodopa and dopamine agonists; however, the interaction of these 2 drugs is poorly understood.
To examine the effects of a dopamine agonist on the motor response to levodopa.
Double-blind, randomized, placebo-controlled, crossover clinical trial.
Ambulatory academic referral center.
Thirteen patients with idiopathic Parkinson disease taking levodopa and experiencing motor fluctuations and dyskinesia.
Eligible individuals were randomly assigned to receive pramipexole dihydrochloride or placebo for 4 weeks followed by a 2-hour intravenous levodopa infusion on consecutive days at 2 rates and with blinded assessments. They were then crossed over to the alternate oral therapy for 4 weeks followed by levodopa infusion and reassessment.
Main Outcome Measures
Change in finger-tapping speed, measured using the area under the curve (AUC) for finger taps per minute across time; peak finger-tapping speed; duration of response; time to “ON” (defined as a 10% increase in finger-tapping speed above baseline); walking speed; and dyskinesia AUC.
Pramipexole with levodopa infusion increased finger-tapping speed beyond the change in baseline by a mean (SE) of 170 (47.2) per minute×minutes (P=.006) and more than doubled the AUC for finger-tapping speed. Pramipexole increased peak finger-tapping speed by a mean (SE) of 18 (8.5) taps per minute (P=.02) and improved mean (SE) walking speed (15.9 [0.70] vs 18.9 [0.70] seconds, P=.004). Pramipexole prolonged duration of response after levodopa infusion and shortened time to ON. Pramipexole increased mean (SE) baseline dyskinesia scores (26.0 [5.85] vs 12.1 [5.85] points, P = .05) and peak dyskinesia scores with levodopa infusion.
Pramipexole augmented the motor response to levodopa beyond a simple additive effect and increased the severity of levodopa-induced dyskinesia. When considering a combination of these therapies, an appropriate balance should be maintained regarding gain of motor function vs worsening of dyskinesia.
clinicaltrials.gov Identifier: NCT00666653
Objectives: To assess the efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with advanced Parkinson's disease previously reliant on apomorphine as their main antiparkinsonian medication.
Methods: Seven patients with motor fluctuations despite optimal medical treatment given as predominantly apomorphine infusion (n=6), or intermittent apomorphine injections (n=1) underwent bilateral STN DBS using frameless stereotactic surgery. Standard assessments of parkinsonism and motor fluctuations, using Unified Parkinson's Disease Rating Scale (UPDRS) were performed before and six months after surgery. Assessments were performed both on and off medication, and postoperative with the stimulators switched on and off.
Results: Bilateral STN DBS improved motor scores (UPDRS III) by 61% when off medication (p<0.05). Clinical fluctuations (UPDRS IV items 36–39) were reduced by 46.2% (p<0.05). Total daily apomorphine dose was reduced by 68.9% (p<0.05) and apomorphine infusion via a pump was no longer required in four patients. There were no operative complications. Two patients required treatment for hallucinations postoperatively but there was no significant change in mini-mental state examination.
Conclusions: In patients with advanced Parkinson's disease, previously reliant on apomorphine, bilateral STN DBS is an effective treatment to reduce motor fluctuations and enable a reduction in apomorphine use.
The motor responses of 14 patients with Parkinson's disease (six previously untreated and eight chronically receiving levodopa) with pronounced asymmetry in the severity of motor signs between the left and right sides of the body were studied. The effects of a short (60 minutes) and a long (16-22 hours) intravenous levodopa infusion as well as of subcutaneous apomorphine (1-6 mg bolus) were assessed. Four different tapping tests were used to measure motor function. For all pharmacological tests, the more affected side showed a shorter response duration, increased latency, and greater response magnitude than the less affected side. These differences were more pronounced in those patients receiving chronic levodopa treatment. As apomorphine is not dependent on dopamine storage capacity, these findings suggest that postsynaptic mechanisms play an important part in the origin of motor fluctuations in Parkinson's disease.
OBJECTIVES—Despite the recent introduction of new
peroral drugs as well as neurosurgical methods for Parkinson's
disease, treatment of late stage parkinsonian patients remains
difficult and many patients become severely handicapped because of
fluctuations in their motor status. Injections and infusions of
apomorphine has been suggested as an alternative in the treatment of
these patients, but the number of studies describing the effects of
such a treatment over longer time periods is still limited. The
objective was to investigate the therapeutic response and range of side
effects during long term treatment with apomorphine in advanced
METHODS—Forty nine patients (30 men, 19 women; age
range 42-80 years) with Parkinson's disease were treated for 3 to 66 months with intermittent subcutaneous injections or continuous
infusions of apomorphine.
RESULTS—Most of the patients experienced a long
term symptomatic improvement. The time spent in "off" was
significantly reduced from 50 to 29.5% with injections and from 50 to
25% with infusions of apomorphine. The quality of the remaining
"off" periods was improved with infusion treatment, but was
relatively unaffected by apomorphine injections. The overall frequency
and intensity of dyskinesias did not change. The therapeutic effects of
apomorphine were stable over time. The most common side effect was
local inflammation at the subcutaneous infusion site,
whereas the most severe were psychiatric side effects occurring in 44%
of the infusion and 12% of the injection treated patients.
CONCLUSION—Subcutaneous apomorphine is a highly
effective treatment which can substantially improve the symptomatology
in patients with advanced stage Parkinson's disease over a prolonged
period of time.
OBJECTIVES—To determine whether continous waking
day dopaminergic stimulation with the dopamine agonist apomorphine can
reduce levodopa induced dyskinesias in Parkinson's disease
METHODS—19 patients with severe unpredictable
refractory motor fluctuations and functionally disabling levodopa
induced dyskinesias were treated with continuous subcutaneoius
apomorphine monotherapy for a minimum duration of 2.7 years
RESULTS—A mean 65% reduction in dyskinetic
severity and a mean 85% reduction in frequency and duration occurred.
On discontinuing levodopa a concomitant reduction in off period time
was also seen (35% of waking day "off" reduced to 10%)
CONCLUSION—Continuous waking day dopaminergic
stimulation with apomorphine reset the threshold for dyskinesias and
led to a pronounced reduction in their frequency.
Apomorphine should be considered as a less invasive alternative to
pallidotomy or deep cerebral stimulation in controlling levodopa
induced interdose dose dyskinesias.
Auditory event related potentials (ERPs) and visual evoked potentials (VEPs) were recorded from eight patients with Parkinson's disease, before and after a single dose of apomorphine. To assess the treatment effects, the patients' motor state, Benton visual retention test (BVRT), and digit span tests were also examined. After apomorphine, although motor performance improved, the ERP latencies were delayed and the N2-P3 ERP amplitude was significantly diminished by comparison with pretreatment values. These data suggest that apomorphine induces, besides its motor effects in patients with Parkinson's disease, a slowing down of cognitive processing. Preferential stimulation of dopamine autoreceptors in mesocortical and mesolimbic systems may represent a neural mechanism for these effects. Also, the posttreatment BVRT rotation errors significantly increased, suggesting an apomorphine induced impairment of visuospatial perception.
Continuous infusion of levodopa or apomorphine provide constant dopaminergic stimulations are good alternatives to deep brain stimulation to control motor fluctuations in patients with advanced Parkinson’s disease (PD). Apomorphine provides motor benefit similar to dopamine, but its long-term use is limited by compliance, mostly injection site skin reactions. Administration of levodopa/carbidopa by continuous duodenal infusion allows replacement of all oral medications and permits achievement of a satisfactory therapeutic response paralleled by a reduction in motor complication severity. However, this procedure is more invasive than apomorphine as it requires a percutaneous endoscopic gastrostomy Clinical experience with infusions shows that continuous dopaminergic stimulation of dopaminergic medications reduces dyskinesia and widens the therapeutic window in advanced PD.
Parkinson’s disease; Infusion; Apomorphine; Levodopa; Carbidopa; Duodopa; DBS
OBJECTIVES--To evaluate the contribution of postsynaptic changes to motor fluctuations, three groups of parkinsonian patients with differing responses to treatment were acutely challenged with two dopaminergic drugs-apomorphine and levodopa-having different mechanisms of action. METHODS--Forty two patients with Parkinson's disease (14 untreated, eight with a stable response to levodopa, and 20 with levodopa induced motor fluctuations) were challenged on two consecutive days with apomorphine and levodopa. The latency, duration, and magnitude of motor response was measured. RESULTS--A progressive shortening of mean latency after levodopa challenge was found passing from the untreated to the stable and fluctuating groups; the difference between untreated and fluctuating patients was statistically significant (P < 0.01). Response duration after levodopa challenge was similar in untreated and stable patients, whereas it showed a significant shortening in patients with motor fluctuations (P < 0.05 v both untreated and stable patients). When subcutaneous apomorphine was given, untreated patients had a longer response duration than those who had developed motor fluctuations (P < 0.05). Although baseline disability was significantly greater in the fluctuating patients than in the untreated and stable patients, the severity of residual parkinsonian signs after both apomorphine and levodopa challenge was similar for all three groups; as a result, the degree of improvement in parkinsonian signs after dopaminergic stimulation was substantially greater in more advanced than in early cases. Linear regression analysis also indicated that latency and duration after apomorphine challenge did not significantly correlate with those after levodopa challenge, whereas magnitude of response to apomorphine showed a strong positive correlation with that after levodopa challenge (r = 0.9, P < 0.001). CONCLUSION--The progressive shortening of motor response after both apomorphine and levodopa suggests that pharmacodynamic factors play an important part in determining the duration of motor response and argue against altered central pharmacokinetics of levodopa being principally responsible for the on-off effect. The widening response amplitude and increasing off phase disability occurring during disease progression are also critical factors in determining the appearance of motor fluctuations.
Administering manganese chloride (Mn) to rats on postnatal day (PD) 1–21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as persistent increases in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1–21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., “autoreceptor” doses) of apomorphine (0.06 and 0.12 mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired.
Manganese; Apomorphine; DOPA accumulation; Autoreceptors; Ontogeny; Dorsal striatum
Apomorphine is a potent dopamine agonist at both D1 and D2 receptors and has been used successfully for treating the 'on/off' phenomenon in Parkinson's disease. We report our experience with apomorphine in treating the 'on/off' phenomenon in L-dopa responsive idiopathic Parkinson's disease. Thirteen such patients were commenced on apomorphine infusions. Their mean age was 69 (range 53-80) years and the mean duration of the disease was 15 (range 6-28) years. The clinical response to apomorphine was good in four patients, fair in two, unchanged in five and worse in two. Activities of daily living improved in six, were unchanged in five and worse in two. When the response was poor or showed no change, apomorphine was discontinued. In addition, apomorphine was also discontinued in three patients who had had a fair/good response but suffered side effects of hallucinations, delusions and psychosis, lack of cooperation or found the pump inconvenient. Apomorphine was continued in only three patients out of 13.
Long-term dopamine replacement therapy with L-DOPA in Parkinson’s disease often leads to the development of abnormal involuntary movements known as L-DOPA-induced dyskinesia. Growing evidence suggests that following dopamine cell loss, serotonin neurons acting as surrogates for dopaminergic processes, take up L-DOPA, convert it to dopamine and release it in an unregulated fashion that precipitates dyskinesia. While most studies have focused on serotonin 5-HT1 receptor stimulation as an anti-dyskinetic strategy, targeting serotonin transporter modulation of dopamine activity has been overlooked. Therefore, in the current study, selective serotonin reuptake inhibitors were tested for their ability to reduce L-DOPA- and apomorphine-induced dyskinesia. In experiments 1 and 2, hemi-parkinsonian rats were primed with L-DOPA until stable dyskinesia developed. Rats in experiment 1 were administered the selective serotonin reuptake inhibitors paroxetine, citalopram or fluoxetine, followed by L-DOPA. Abnormal involuntary movements and forepaw adjusting steps were recorded to determine the effects of these compounds on dyskinesia and motor performance, respectively. Brains were collected on the final test day, after which striatal and raphe monoamines were examined via high performance liquid chromatography. In experiment 2, dyskinesias were measured after selective serotonin reuptake inhibitors and apomorphine. Serotonin reuptake inhibitors dose-dependently attenuated L-DOPA- but not apomorphine-induced dyskinesia, while preserving L-DOPA efficacy. Neurochemically, serotonin transporter inhibition enhanced striatal and raphe serotonin levels and reduced its turnover, indicating a potential mechanism of action. The present results support targeting serotonin transporters to improve Parkinson’s disease treatment and provide further evidence for the role of the serotonin system in L-DOPA’s effects.
Abnormal involuntary movements; Dopamine; Parkinson’s disease; Selective serotonin reuptake inhibitors
The on-off phenomenon is an almost invariable consequence of sustained levodopa treatment in patients with Parkinson's disease. Phases of immobility and incapacity associated with depression alternate with jubilant thaws. Both pharmacokinetic and pharmacodynamic factors are involved in its pathogenesis, but evidence is presented to indicate that the importance of levodopa handling has been underestimated and that progressive reduction in the storage capacity of surviving nigrostriatal dopamine terminals is not a critical factor. Re-distribution of levodopa dosage which may mean smaller, more frequent doses, or larger less frequent increments, may be helpful in controlling oscillations in some patients. Dietary protein restriction, the use of selegiline hydrochloride and bromocriptine may also temporarily improve motor fluctuations. New approaches to management include the use of subcutaneous apomorphine, controlled-release preparations of levodopa with a peripheral dopa decarboxylase inhibitor and the continuous intra-duodenal administration of levodopa.
The effect, therapeutic dose range, and pharmacokinetics of apomorphine, given as subcutaneous injections by a single use pen, were evaluated in the treatment of off phenomena in 22 patients with idiopathic Parkinson's disease. At study entry a placebo controlled apomorphine test was performed, and apomorphine doses were then individually titrated (mean 3.4 (range 0.8-6.0) mg) and compared with placebo in a double blind cross over phase. With apomorphine compared with placebo the mean daily duration of off periods was reduced by 51% as assessed by the patients and by 58% as assessed by the staff. The severity of off periods was also significantly reduced. The effect was unchanged after a maintenance phase of eight weeks. At study termination 13 of 14 patients were able to inject themselves and 11 of 14 patients found that their feeling of freedom had increased. The most common adverse events were nausea, subcutaneous nodules, and increased frequency of involuntary movements. Pharmacokinetics were linear and did not change with repeat dosing. The tmax ranged from five to 45 minutes (16 patients). It is concluded that pen injected apomorphine is a valuable treatment for patients with advanced Parkinson's disease with on-off phenomena.
Overexpression of α-synuclein causes familial Parkinson’s disease and abnormal aggregates of the protein are present in sporadic cases of the disease. We have examined the behavioral effects of direct and indirect dopaminergic agonists in transgenic mice expressing human α-synuclein under the Thy-1 promoter (Thy1-aSyn, alpha-synuclein overexpressor), which exhibit progressive impairments in behavioral tests sensitive to nigrostriatal dopamine dysfunction. Male Thy1-aSyn and wild-type mice received vehicle, benserazide/L-DOPA (25 mg/kg, i.p.), high (2 mg/kg, s.c.) and low doses (0.125, 0.25, 0.5 mg/kg, s.c.) of apomorphine, and amphetamine (5 mg/kg, i.p.), beginning at 3 months of age, and were tested on the challenging beam, spontaneous activity, pole test, and gait. L-DOPA had a paradoxical effect and worsened the deficits in Thy1-aSyn mice compared with controls, whereas the high dose of apomorphine only produced few deficits above those already present in Thy1-aSyn. In contrast to wild-type mice, Thy1-aSyn mice did not show amphetamine-induced stereotypies. The results indicate that chronic overexpression of α-synuclein led to abnormal pharmacological responses in mice.
sensorimotor function; Parkinson’s disease; amphetamine; apomorphine; L-DOPA
The clinical condition of advanced Parkinson's disease (PD) patients is often complicated by motor fluctuations and dyskinesias which are difficult to control with available oral medications.
To compare clinical and neuropsychological 12 month outcome following subcutaneous apomorphine infusion (APO) and chronic deep brain stimulation of the subthalamic nucleus (STN‐DBS) in advanced PD patients.
Patients with advanced PD and medically untreatable fluctuations underwent either APO (13 patients) or STN‐DBS (12 patients). All patients were clinically (UPDRS‐III, AIMS, 12 h on‐off daily) and neuropsychologically (MMSE, Hamilton‐17 depression, NPI) evaluated at baseline and at 12 months. APO was discontinued at night.
At 12 months APO treatment (74.78±24.42 mg/day) resulted in significant reduction in off time (−51%) and no change in AIMS. Levodopa equivalent medication doses were reduced from 665.98±215 mg/day at baseline to 470±229 mg/day. MMSE, NPI, and Hamilton depression scores were unchanged. At 12 months STN‐DBS resulted in significant clinical improvement in terms of reduction in daily off time (−76%) and AIMS (−81%) as well as levodopa equivalent medication doses (980±835 to 374±284 mg/day). Four out of 12 patients had stopped oral medications. MMSE was unchanged (from 28.6±0.3 to 28.4±0.6). Hamilton depression was also unchanged, but NPI showed significant worsening (from 6.58±9.8 to 18.16±10.2; p<0.02). Category fluency also declined.
Both APO and STN‐DBS resulted in significant clinical improvement in complicated PD. STN‐DBS resulted in greater reduction in dopaminergic medications and provided 24 h motor benefit. However, STN‐DBS, unlike APO, appears to be associated with significant worsening on NPI resulting from long term behavioral problems in some patients.
apomorphine; deep brain stimulation of the subthalamic nucleus; neuropsychology; Parkinson's disease; STN‐DBS
The aims of this study were to assess the effects of the dopamine agonist apomorphine on experimental pain models in healthy subjects and to explore the possible association between these effects and a common polymorphism within the dopamine transporter gene. Healthy volunteers (n = 105) participated in this randomized double-blind, placebo-controlled, cross-over trial. Heat pain threshold and intensity, cold pain threshold, and the response to tonic cold pain (latency, intensity, and tolerance) were evaluated before and for up to 120 min after the administration of 1.5 mg apomorphine/placebo. A polymorphism (3′-UTR 40-bp VNTR) within the dopamine transporter gene (SLC6A3) was investigated. Apomorphine had an effect only on tolerance to cold pain, which consisted of an initial decrease and a subsequent increase in tolerance. An association was found between the enhancing effect of apomorphine on pain tolerance (120 min after its administration) and the DAT-1 polymorphism. Subjects with two copies of the 10-allele demonstrated significantly greater tolerance prolongation than the 9-allele homozygote carriers and the heterozygote carriers (p = 0.007 and p = 0.003 in comparison to the placebo, respectively). In conclusion, apomorphine administration produced a decrease followed by a genetically associated increase in cold pain tolerance.
We have evaluated the use of silica–dopamine reservoirs synthesized by the sol–gel approach with the aim of using them in the treatment of Parkinson’s disease, specifically as a device for the controlled release of dopamine in the striatum. Theoretical calculations illustrate that dopamine is expected to assume a planar structure and exhibit weak interactions with the silica surface.
Several samples were prepared by varying the wt% of dopamine added during the hydrolysis of tetraethyl orthosilicate. The silica–dopamine reservoirs were characterized by N2 adsorption, scanning and transmission electron microscopy, and Fourier transform infrared spectroscopy. The in vitro release profiles were determined using ultraviolet visible absorbance spectroscopy. The textural analyses showed a maximum value for the surface area of 620 m2/g nanostructured silica materials. The stability of dopamine in the silica network was confirmed by infrared and 13C-nuclear magnetic resonance spectroscopy. The reservoirs were evaluated by means of apomorphine-induced rotation behavior in hemiparkisonian rats.
The in vitro dopamine delivery profiles indicate two regimes of release, a fast and sustained dopamine delivery was observed up to 24 hours, and after this time the rate of delivery became constant. Histologic analysis of formalin-fixed brains performed 24–32 weeks after reservoir implantation revealed that silica–dopamine implants had a reddish-brown color, suggesting the presence of oxidized dopamine, likely caused by the fixation procedure, while implants without dopamine were always translucent.
The major finding of the study was that intrastriatal silica–dopamine implants reversed the rotational asymmetry induced by apomorphine, a dopamine agonist, in hemiparkinsonian rats. No dyskinesias or other motor abnormalities were observed in animals implanted with silica or silica–dopamine.
Parkinson’s disease; silica-dopamine; controlled drug release; central nervous system; reservoirs
Dysfunction of brain dopamine systems is involved in various neuropsychiatric disorders. Challenge studies with dopamine receptor agonists have been performed to assess dopamine receptor functioning, classically using the release of growth hormone (GH) from the hindbrain as primary outcome measure. The objective of the current study was to assess dopamine receptor functioning at the forebrain level.
Fifteen healthy male volunteers received apomorphine sublingually (2 mg), subcutaneously (0.005 mg/kg), and placebo in a balanced, double-blind, cross-over design. Outcome measures were plasma GH levels, performance on an AX continuous performance test, and prepulse inhibition of the acoustic startle. The relation between central outcome measures and apomorphine levels observed in plasma and calculated in the brain was modeled using a two-compartmental pharmacokinetic-pharmacodynamic analysis.
After administration of apomorphine, plasma GH increased and performance on the AX continuous performance test deteriorated, particularly in participants with low baseline performance. Apomorphine disrupted prepulse inhibition (PPI) on high-intensity (85 dB) prepulse trials and improved PPI on low intensity (75 dB) prepulse trials, particularly in participants with low baseline PPI. High cognitive performance at baseline was associated with reduced baseline sensorimotor gating. Neurophysiological measures correlated best with calculated brain apomorphine levels after subcutaneous administration.
The apomorphine challenge test appears a useful tool to assess dopamine receptor functioning at the forebrain level. Modulation of the effect of apomorphine by baseline performance levels may be explained by an inverted U-shape relation between prefrontal dopamine functioning and cognitive performance, and mesolimbic dopamine functioning and sensorimotor gating. Future apomorphine challenge tests preferentially use multiple outcome measures, after subcutaneous administration of apomorphine.
Electronic supplementary material
The online version of this article (doi:10.1007/s00213-009-1686-1) contains supplementary material, which is available to authorized users.
Dopamine; Apomorphine; Cognition; Prepulse inhibition; Neuroendocrine
See Borgkvist et al. (doi:10.1093/brain/awu150) for a scientific commentary on this article.
D2 autoreceptors and L-type calcium channels are both implicated in Parkinson’s disease, but how they interact is unclear. Dragicevic et al. reveal that L-type calcium channels can modulate D2-autoreceptor responses via the neuronal calcium sensor NCS-1. This dopamine-dependent signalling network is altered in Parkinson’s disease and could represent a therapeutic target.
Dopamine midbrain neurons within the substantia nigra are particularly prone to degeneration in Parkinson’s disease. Their selective loss causes the major motor symptoms of Parkinson’s disease, but the causes for the high vulnerability of SN DA neurons, compared to neighbouring, more resistant ventral tegmental area dopamine neurons, are still unclear. Consequently, there is still no cure available for Parkinson’s disease. Current therapies compensate the progressive loss of dopamine by administering its precursor l-DOPA and/or dopamine D2-receptor agonists. D2-autoreceptors and Cav1.3-containing L-type Ca2+ channels both contribute to Parkinson’s disease pathology. L-type Ca2+ channel blockers protect SN DA neurons from degeneration in Parkinson’s disease and its mouse models, and they are in clinical trials for neuroprotective Parkinson’s disease therapy. However, their physiological functions in SN DA neurons remain unclear. D2-autoreceptors tune firing rates and dopamine release of SN DA neurons in a negative feedback loop through activation of G-protein coupled potassium channels (GIRK2, or KCNJ6). Mature SN DA neurons display prominent, non-desensitizing somatodendritic D2-autoreceptor responses that show pronounced desensitization in PARK-gene Parkinson’s disease mouse models. We analysed surviving human SN DA neurons from patients with Parkinson’s disease and from controls, and detected elevated messenger RNA levels of D2-autoreceptors and GIRK2 in Parkinson’s disease. By electrophysiological analysis of postnatal juvenile and adult mouse SN DA neurons in in vitro brain-slices, we observed that D2-autoreceptor desensitization is reduced with postnatal maturation. Furthermore, a transient high-dopamine state in vivo, caused by one injection of either l-DOPA or cocaine, induced adult-like, non-desensitizing D2-autoreceptor responses, selectively in juvenile SN DA neurons, but not ventral tegmental area dopamine neurons. With pharmacological and genetic tools, we identified that the expression of this sensitized D2-autoreceptor phenotype required Cav1.3 L-type Ca2+ channel activity, internal Ca2+, and the interaction of the neuronal calcium sensor NCS-1 with D2-autoreceptors. Thus, we identified a first physiological function of Cav1.3 L-type Ca2+ channels in SN DA neurons for homeostatic modulation of their D2-autoreceptor responses. L-type Ca2+ channel activity however, was not important for pacemaker activity of mouse SN DA neurons. Furthermore, we detected elevated substantia nigra dopamine messenger RNA levels of NCS-1 (but not Cav1.2 or Cav1.3) after cocaine in mice, as well as in remaining human SN DA neurons in Parkinson’s disease. Thus, our findings provide a novel homeostatic functional link in SN DA neurons between Cav1.3- L-type-Ca2+ channels and D2-autoreceptor activity, controlled by NCS-1, and indicate that this adaptive signalling network (Cav1.3/NCS-1/D2/GIRK2) is also active in human SN DA neurons, and contributes to Parkinson’s disease pathology. As it is accessible to pharmacological modulation, it provides a novel promising target for tuning substantia nigra dopamine neuron activity, and their vulnerability to degeneration.
D2-autoreceptor; isradipine; Parkinsons disease; l-DOPA; cocaine
The dopamine receptor agonist apomorphine has been used successfully to treat on-off swings in Parkinson's disease. Its value as a predictor of dopa responsiveness in idiopathic Parkinson's disease (IPD) was assessed and its potential role in differentiating IPD from the Parkinsonian plus syndromes (PPS) of multisystem atrophy, progressive supranuclear palsy and olivopontocerebellar atrophy was investigated. The response to an injection of apomorphine was observed in 20 patients with IPD and eight with PPS after being off levodopa for 12 hours. Patients were reassessed after taking levodopa for one month. Nineteen of the 20 patients (95%) with IPD showed a positive response to apomorphine and 18 (90%) to oral levodopa. In the PPS group, two patients (25%) responded to the apomorphine injection but not to oral levodopa. Apomorphine produced severe drowsiness in the PPS patients. It is suggested that the test can predict dopa responsiveness in IPD and may be of help in confirming a doubtful diagnosis. It has potential value in differentiating IPD from PPS.
Dopaminergic therapy in Parkinson's disease (PD) can improve some cognitive functions while worsening others. These opposite effects might reflect different levels of residual dopamine in distinct parts of the striatum, although the underlying mechanisms remain poorly understood. We used functional magnetic resonance imaging (fMRI) to address how apomorphine, a potent dopamine agonist, influences brain activity associated with working memory in PD patients with variable levels of nigrostriatal degeneration, as assessed via dopamine-transporter (DAT) scan. Twelve PD patients underwent two fMRI sessions (Off-, On-apomorphine) and one DAT-scan session. Twelve sex-, age-, and education-matched healthy controls underwent one fMRI session. The core fMRI analyses explored: (1) the main effect of group; (2) the main effect of treatment; and (3) linear and nonlinear interactions between treatment and DAT levels. Relative to controls, PD-Off patients showed greater activations within posterior attentional regions (e.g., precuneus). PD-On versus PD-Off patients displayed reduced left superior frontal gyrus activation and enhanced striatal activation during working-memory task. The relation between DAT levels and striatal responses to apomorphine followed an inverted-U-shaped model (i.e., the apomorphine effect on striatal activity in PD patients with intermediate DAT levels was opposite to that observed in PD patients with higher and lower DAT levels). Previous research in PD demonstrated that the nigrostriatal degeneration (tracked via DAT scan) is associated with inverted-U-shaped rearrangements of postsynaptic D2-receptors sensitivity. Hence, it can be hypothesized that individual differences in DAT levels drove striatal responses to apomorphine via D2-receptor-mediated mechanisms.
Cognition; DAT; dopamine-agonist; fMRI; Parkinson's disease; working memory
A pharmacodynamic model is presented to describe the motor effects (tapping rate, Unified Parkinson’s Disease Rating Scale [UPDRS] Part III, and investigator-rating of ON/OFF, including dyskinesia) of levodopa (LD) in patients with advanced idiopathic Parkinson’s disease (PD) treated with immediate-release (IR) carbidopa–levodopa (CD–LD) or an extended-release (ER) formulation of CD–LD (IPX066). Twenty-seven patients participated in this open-label, randomized, single-and multiple-dose, crossover study. The pharmacodynamic models included a biophase effect site with a sigmoid Emax transduction for tapping and UPDRS and an ordered categorical model for dyskinesia. The pharmacodynamics of LD was characterized by a conduction function with a half-life of 0.59 hours for tapping rate, and 0.4 hours for UPDRS Part III and dyskinesia. The LD concentration for half-maximal effect was 1530 ng/mL, 810 ng/mL, and 600 ng/mL for tapping rate, UPDRS Part III, and dyskinesia, respectively. The sigmoidicity of the transduction was 1.53, 2.5, and 2.1 for tapping rate, UPDRS Part III, and dyskinesia, respectively. External validation of the pharmacodynamic model using tapping rate indicated good performance of the model.
IPX066; levodopa; Parkinson’s disease; pharmacodynamics
The dopamine (DA) hypothesis of schizophrenia implicates an enhancement of DA function in the pathophysiology of the disorder, at least in the genesis of positive symptoms. Accordingly, apomorphine, a directly acting DA receptor agonist, should display psychotomimetic properties. A review of the literature shows little or no evidence that apomorphine, in doses that stimulate postsynaptic DA receptors, induces psychosis in non-schizophrenic subjects or a relapse or exacerbation of psychotic symptoms in patients with schizophrenia. After a detailed review of the literature reporting psychotogenic effects of apomorphine in patients with Parkinson's disease, an interpretation of these data is difficult, in part because of several confounding factors, such as the concomitant use of drugs known to induce psychosis and the advanced state of the progressive neurological disorder. In the context of the DA hypothesis of schizophrenia, the limited ability of apomorphine to induce psychosis, in contrast to indirectly acting DA agonists that increase synaptic DA, may be explained by the relatively weak affinity of apomorphine for the D3 receptor compared with DA. Alternatively, enhancement of DA function, though necessary, may be insufficient by itself to induce psychosis.
We tested the hypothesis that dopamine-dependent motor learning mechanism underlies the long-duration response to levodopa in Parkinson disease (PD) based on our studies in a mouse model. By data-mining the motor task performance in dominant and nondominant hands of the subjects in a double-blind randomized trial of levodopa therapy, the effects of activity and dopamine therapy were examined.
We data-mined the Earlier versus Later Levodopa Therapy in Parkinson's Disease (ELLDOPA) study published in 2005 and performed statistical analysis comparing the effects of levodopa and dominance of handedness over 42 weeks.
The mean change in finger-tapping counts from baseline before the initiation of therapy to predose at 9 weeks and 40 weeks increased more in the dominant compared to nondominant hand in levodopa-treated subjects in a dose-dependent fashion. There was no significant difference in dominant vs nondominant hands in the placebo group. The short-duration response assessed by the difference of postdose performance compared to predose performance at the same visit did not show any significant difference between dominant vs nondominant hands.
Active use of the dominant hand and dopamine replacement therapy produces synergistic effect on long-lasting motor task performance during “off” medication state. Such effect was confined to dopamine-responsive symptoms and not seen in dopamine-resistant symptoms such as gait and balance. We propose that long-lasting motor learning facilitated by activity and dopamine is a form of disease modification that is often seen in trials of medications that have symptomatic effects.
Motor complications in Parkinson’s disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine.
Apomorphine; Deep brain stimulation; Duodenal levodopa infusion; Parkinson’s disease