Pierre J. Blanchet

AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys

Objective: To evaluate the contribution of amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) glutamate receptors to the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias. Background: Motor fluctuations and dyskinesias reflect, in part, altered function of glutamate receptors of the NMDA subtype. The possible role of AMPA receptors, however, has not yet been examined. Methods: The authors compared the ability of an AMPA agonist (CX516) and a noncompetitive AMPA antagonist (LY300164) to alter parkinsonian symptoms and levodopa-induced dyskinesia in MPTP-lesioned monkeys. Eight levodopa-treated parkinsonian monkeys received rising doses of each drug, first in monotherapy and then in combination with low-, medium-, and high-dose levodopa. Results: CX516 alone, as well as when combined with low-dose levodopa, did not affect motor activity but induced dyskinesia. Moreover, following injection of the higher doses of levodopa, it increased levodopa-induced dyskinesia by up to 52% (p < 0.05). LY300164 potentiated the motor activating effects of low-dose levodopa, increasing motor activity by as much as 86% (p < 0.05), and that of medium-dose levodopa as much as 54% (p < 0.05). At the same time, LY300164 decreased levodopa-induced dyskinesia by up to 40% (p < 0.05). Conclusions: AMPA receptor upregulation may contribute to the expression of levodopa-induced dyskinesia. Conceivably, noncompetitive AMPA receptor antagonists could be useful, alone or in combination with NMDA antagonists, in the treatment of PD, by enhancing the antiparkinsonian effects of levodopa without increasing and possibly even decreasing levodopa-induced dyskinesia.

Neostriatal mechanisms in Parkinson's disease

Normal motor function is dependent on the highly regulated synthesis and release of dopamine (DA) by neurons projecting from substantia nigra to corpus striatum. Cardinal symptoms of Parkinsons disease (PD) arise as a consequence of a deficiency in striatal DA due to the progressive degeneration of this neuronal system. Under such circumstances, the subunit composition and/or phosphorylation state of glutamatergic receptors of theN-methyl-D-aspartate (NMDA) subtype expressed on the dendritic spines of medium-sized striatal neurons changes in ways that compromise motor performance. Although levodopa acts, after conversion to DA, to reverse these changes by restoring striatal dopaminergic transmission, significant differences exist between the normally functioning DA system and the restoration of function provided by standard levodopa therapy. The nonphysiologic stimulation of DA receptors on striatal spiny neurons associated with current levodopa regimens now appears to contribute to the motor response complications that ultimately affect most parkinsonian patients. Current evidence suggests that alterations in signaling systems linking dopaminergic and glutamatergic receptors within these GABAergic efferent neurons induce NMDA receptor modification. Functionally, the resultant long-term change in glutamatergic synaptic efficacy leads to alterations in spiny neuron output, favoring the appearance of motor complications. Although dopaminomimetic replacement strategies that provide more continuous DA receptor stimulation should alleviate these disabling complications, more innovative approaches to the interdiction of pathologic changes in signal transduction components or glutamate receptor sensitivity could ultimately prove safer and more effective for the treatment of all stages of PD.

Preproenkephalin mRNA expression in the caudate-putamen of MPTP monkeys after chronic treatment with the D2 agonist U91356A in continuous or intermittent mode of administration: comparison with L-DOPA therapy.

The effect of chronic treatment with the D2 dopamine agonist U91356A or L-DOPA therapy on the regulation of preproenkephalin (PPE) mRNA was investigated in the caudate-putamen of previously drug-naive cynomolgus monkeys Macaca fascicularis rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In MPTP monkeys, pulsatile treatment with either L-DOPA or U91356A relieved parkinsonian symptoms but caused progressive sensitization to treatment and, as expected, induced choreic dyskinesias. In contrast, U91356A given in a continuous mode led to partial behavioral tolerance without appearance of dyskinesias. Using in situ hybridization histochemistry, lesioning was shown to produce elevation of PPE mRNA levels in the lateral and medial parts of the putamen and in the lateral part of the caudate nucleus compared to control animals at the three rostrocaudal regions analyzed. In general, no change of PPE mRNA levels were observed in the medial caudate after MPTP lesioning with or without L-DOPA or U91356A treatments in the three rostrocaudal regions measured except for an increase in the caudal part of L-DOPA-treated MPTP monkeys. In the putamen and lateral caudate nucleus, elevated PPE mRNA expression by MPTP generally was not corrected (or only partially corrected) by chronic L-DOPA treatment except for the rostral medial putamen where correction to control values was observed. In general, pulsatile administration of U91356A partially corrected the lesion-induced elevation of PPE mRNA levels in the putamen and lateral caudate nucleus whereas the correction was more pronounced and widespread when MPTP monkeys received the continuous administration of this drug. These results indicate that the mode of administration of a D2 dopamine receptor agonist, such as U91356A, although at a roughly equivalent dosage influences the extent of inhibition of the expression of PPE in the denervated striatum of monkeys. In addition, the general lack of correction of the MPTP-induced increase of PPE mRNA in the striatum of L-DOPA-treated monkeys compared to the decreases observed with the D2 agonist treatments suggest that the D1 agonist component of L-DOPA therapy opposes the D2 agonist activity. Hence, D1 receptor agonist activity would stimulate PPE mRNA expression whereas D2 receptor agonists inhibit the expression of this peptide. Increases in PPE expression in the striatum may be implicated in the induction of dyskinesias since both groups of treated MPTP monkeys displaying dyskinesias had elevated striatal PPE mRNA levels whereas the MPTP monkeys with the lowest striatal PPE mRNA levels developed tolerance without dyskinesias.

Lack of efficacy of a nicotine transdermal treatment on motor and cognitive deficits in Parkinson's disease

UNLABELLED Studies assessing the efficacy of nicotine in Parkinsons disease (PD) have generated contradictory results. The controversy seems to stem from uncontrolled factors including the lack of objective measures, the practice effect in a test-retest design, and the absence of plasmatic dosage. This study aimed at further controlling these factors using transdermal nicotine in PD. METHODS Twenty-two nonsmoking PD patients received a transdermal nicotine treatment over 25 days in increasing titrated doses. Motor and cognitive assessments were carried out on days 11 and 25 (low-dose and high-dose assessments, respectively) and after a 14-day washout period. RESULTS Patients tolerated nicotine poorly. Thirteen (59%) withdrew, mostly because of acute side effects. In the remaining nine patients, nicotine neither improved nor worsened motor or cognitive functioning in comparison with 10 age, gender and education matched controls. CONCLUSIONS Transdermal nicotine is not effective in treating motor and cognitive deficits in PD. The results obtained with our objective measures confirm a recent double-blind, placebo-controlled study that used clinical measures. It is possible that nicotine lacks specificity in targeting critical nicotinic receptors that might be involved in PD pathophysiology. The low tolerability may be related to such a lack of specificity of nicotine, which would directly stimulate the autonomic nervous system.

Idiopathic myoclonus in the oromandibular region during sleep: a possible source of confusion in sleep bruxism diagnosis.

As part of a larger study, polysomnographic and audiovisual data were recorded over 2 nights in 41 subjects with a clinical diagnosis of sleep bruxism (SB). Electromyographic (EMG) events related to SB were scored according to standard criteria (Lavigne et al. J Dent Res 1996;75:546–552). Post hoc analysis revealed that rapid shock‐like contractions with the characteristics of myoclonus in the jaw muscles were observed in four subjects. EMG bursts characterized as myoclonus were significantly shorter in duration than bursts classified as SB. None of the subjects had any history of myoclonus while awake. Myoclonic episodes were more frequent in sleep stages 1 and 2 than in REM. Half of the episodes contained one or two contractions whereas the other half had three or more repetitive contractions. SB and myoclonus coexisted in one subject. To rule out sleep epilepsy, full electroencephalogram montage was done in three subjects and no epileptic spikes were noted. Our results suggest that approximately 10% of subjects clinically diagnosed as SB could present oromandibular myoclonus during sleep.

Modulation of levodopa-induced motor response complications by NMDA antagonists in Parkinson's disease.

The complex dopamine-glutamate interactions within the basal ganglia are disrupted by chronic nigrostriatal denervation and standard replacement therapy with levodopa. Acute N-methyl-D-aspartate (NMDA) receptor blockade is able to overcome the changes in dopamine D1- and D2-dependent responses and the progressive shortening in the duration of response induced by long-term exposure to levodopa in 6-hydroxydopamine-lesioned rats. Preliminary results further suggest that NMDA receptor blockade can counteract levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned non-human primates and parkinsonian patients without substantially altering the motor benefit derived from levodopa. These results appear to be in accordance with our 2-deoxyglucose studies in 6-hydroxydopamine-lesioned rats showing that NMDA receptor blockade can attenuate many of the changes in synaptic activity induced by levodopa, particularly in the striatopallidal complex. Taken together, our observations suggest that abnormal glutamate transmission or dysregulation of NMDA receptor-mediated mechanisms contribute to levodopa-induced motor response complications. Additional preclinical and clinical experiments need to be completed with well tolerated glutamate antagonists to determine the full potential of glutamate receptor blockade as a long-term strategy against levodopa-related motor response complications in Parkinsons disease.

Movement chunking during sequence learning is a dopamine-dependant process: a study conducted in Parkinson's disease

Chunking of single movements into integrated sequences has been described during motor learning, and we have recently demonstrated that this process involves a dopamine-dependant mechanism in animal (Levesque et al. in Exp Brain Res 182:499–508, 2007; Tremblay et al. in Behav Brain Res 198:231–239, 2009). However, there is no such evidence in human. The aim of the present study was to assess this question in Parkinson’s disease (PD), a neurological condition known for its dopamine depletion in the striatum. Eleven PD patients were tested under their usual levodopa medication (ON state), and following a 12-h levodopa withdrawal (OFF state). Patients were compared with 12 healthy participants on a motor learning sequencing task, requiring pressing fourteen buttons in the correct order, which was determined by visual stimuli presented on a computer screen. Learning was assessed from three blocks of 20 trials administered successively. Chunks of movements were intrinsically created by each participant during this learning period. Then, the sequence was shuffled according to the participant’s own chunks, generating two new sequences, with either preserved or broken chunks. Those new motor sequences had to be performed separately in a fourth and fifth blocks of 20 trials. Results showed that execution time improved in every group during the learning period (from blocks 1 to 3). However, while motor chunking occurred in healthy controls and ON-PD patients, it did not in OFF-PD patients. In the shuffling conditions, a significant difference was seen between the preserved and the broken chunks conditions for both healthy participants and ON-PD patients, but not for OFF-PD patients. These results suggest that movement chunking during motor sequence learning is a dopamine-dependent process in human.

Postural sway and effect of levodopa in early Parkinson's disease

OBJECTIVE To characterize postural stability control and levodopa responsiveness in early Parkinsons disease (PD). METHODS Postural sway was studied during quiet stance in ten patients within six years of PD onset, both before (OFF) and after (ON) regular oral levodopa dosing. Postural sway was recorded using a force platform during 30 sec with eyes open, and six dependent variables were examined. RESULTS Mild baseline subclinical changes in postural sway were recorded in our patients. Clear benefit was observed in five out of six characteristics (mean sway, transversal sway, sagittal sway, sway intensity, and sway area) in the ON condition. CONCLUSION Postural control mechanisms are affected early in PD and modulated by dopamine.

Impact of Parkinson's disease and dopaminergic medication on proprioceptive processing

Increasing evidence suggests that the pathophysiology of movement disorders in Parkinsons disease (PD) includes deficits in sensory processing and integration. However, the exact nature of these deficits and the ability of dopamine medication to correct them have not been thoroughly examined in previous studies. For instance, it remains unclear whether PD patients have globally impaired sensorimotor integration functions or selective deficiencies in processing proprioception. We evaluated the specific deficits of PD patients in sensorimotor integration and proprioceptive processing by testing their ability to perform three-dimensional (3D) reaching movements in four conditions in which the sensory signals defining target and hand positions (visual and/or proprioceptive) varied. Ten healthy subjects and 11 PD patients, ON dopamine medication and in the OFF state, were tested. PD patients in the OFF state showed a greater mean level of 3D errors relative to controls when the only available sensory information about target and hand position came from proprioception, but this difference did not reach significance. This indicates that deficient proprioception is not an early key feature of PD. Interestingly, the inaccuracies of a number of PD subjects further increased in the ON medicated state relative to healthy controls when reaching to proprioceptively-defined targets, and this between group difference was statistically significant. However, dopamine medication did not consistently degrade the reaching accuracy of PD patients, with both negative and positive effects on accuracy of reaching to proprioceptive-defined targets. Together, these findings indicate that dopamine replacement therapy not only did not normalize sensorimotor performance to the level of controls, but also induced deficits in the processing of proprioceptive information in some of the PD patients tested. Furthermore, the diversity of effects of medication on accuracy of reaching to proprioceptively-defined targets supports the idea that dysfunction of dopaminergic circuits within the basal ganglia is not primarily responsible for the proprioceptive processing deficits of PD patients.

Prevalence of spontaneous oral dyskinesia in the elderly: A reappraisal

The prevalence and status of spontaneous oral dyskinesia (SOD), clinically defined as the presence of oral stereotypies of no apparent cause, remain controversial in the elderly. The reported high prevalence of SOD in institutionalized demented cases, the apparent similarity between SOD and tardive dyskinesia (TD), and the role of aging in both conditions, are used as arguments to minimise the prevalence of TD and causal role of antipsychotics. We observed 1,018 (69.3% women) noninstitutionalized, frail elderly subjects attending day care centers to document the prevalence and phenomenology of SOD. A total of 38 subjects, including 29 women, were suspected of having SOD, for a prevalence rate of 3.7% (95% confidence interval, 2.6–4.9%), 4.1% for women and 2.9% for men. A survey covering medical and dental issues was filled out by 508 volunteers. Subjects with suspected SOD reported more frequent ill‐fitting dental devices (P = 0.002; odds ratio [OR] = 3.5), oral pain (P = 0.01; OR = 3.0), and a lower rate of perception of good oral health (P = 0.04; OR = 0.4) compared to nondyskinetics. Individuals with suspected SOD typically presented with mild stereotyped masticatory or labial movements compared to the more complex phenomenology of probable TD cases. Thus, SOD is comparatively infrequent in the elderly. The relation between its distinct orodental health profile and stereotyped manifestations warrants further attention.