Internal globus pallidus discharge is nearly suppressed during levodopa-induced dyskinesias.

The functional status of the globus pallidus internal segment (GPi) plays a key role in mediating the effects of antiparkinsonian drugs. During long-term levodopa therapy, patients develop abnormal movements, dyskinesias, the pathophysiological basis of which is poorly understood. We recorded single cells in the GPi of parkinsonian monkeys continuously through the "off" and "on" states, and 10 to 15 minutes later during "on with or without dyskinesias," depending on two doses of levodopa. The transition from the "off" to the "on" state was characterized by a decrease (most cells), no change, or an increase in firing rate of individual cells. During dyskinesias, firing rates declined profoundly in almost all cells, with decrements as low as 97% in individual cells. These changes occurred only when dyskinesias were present. The difference in GPi activity between "on" and "on with dyskinesias" suggests that normal motor function in Parkinson's disease critically depends on fine tuning of the basal ganglia output. Dyskinesias result from an imbalanced low GPi discharge, a circumstance that may be susceptible to development of new therapeutic approaches.

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 Parkinson's disease.

Levodopa-induced dyskinesias improved by a glutamate antagonist in Parkinsonian monkeys.

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor have been reported to potentiate the antiparkinsonian action of levodopa and reverse levodopa-induced motor fluctuations in animal models of Parkinson's disease. To evaluate the effect of NMDA receptor blockade on dyskinesias complicating the response to long-term levodopa therapy, we studied the selective antagonist LY235959 in six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. Drugs were administered subcutaneously, LY235959 at doses of 0.5, 1.0, 3.0, and 5.0 mg/kg and levodopa/benserazide at doses that produced moderate dyskinesias while almost totally reversing parkinsonian signs. Compared with vehicle control injections, LY235959 (3.0 mg/kg) abolished oral dyskinesias and diminished choreic dyskinesias by 68% (p < 0.01). Lower doses had smaller effects, although still significant, on oral dyskinesias (55% reduction at 1.0 mg/kg, p < 0.05). The highest LY235959 dose (5.0 mg/kg) prolonged oral dyskinesia suppression, but tended to increase dystonia severity. LY235959 had no effect on motor function when given alone and did not reduce the antiparkinsonian response to levodopa. These findings suggest that NMDA receptor blockade may ameliorate the dyskinetic complications of long-term levodopa therapy, without diminishing the beneficial effects on parkinsonian signs.

Reversal of levodopa-induced motor fluctuations in experimental parkinsonism by NMDA receptor blockade.

Dopaminoceptive system alterations in the basal ganglia have been implicated in the pathogenesis of wearing-off fluctuations that complicate levodopa therapy of Parkinson's disease. To evaluate the contribution of glutamatergic mechanisms to the associated changes in striatal efferent pathway function, we examined the ability of N-methyl-D-aspartate (NMDA) receptor blockade to modify the motor response changes produced by chronic levodopa administration to hemiparkinsonian rats. Unilaterally 6-hydroxydopamine lesioned rats, given levodopa/benserazide (25/6.25 mg/kg) twice daily for 3 weeks, developed a progressive shortening in the duration of their motor response to levodopa similar to that occurring in parkinsonian patients with wearing-off phenomenon. The acute systemic administration of MK-801 (0.1 mg/kg) to these animals completely reversed the decrease in turning duration (P < 0.01). Intrastriatal injection of the NMDA antagonist was even more effective in prolonging the levodopa response (P < 0.01), while intranigrally injected MK-801 produced no statistically significant change in the duration of levodopa-induced rotation. Rotational intensity was unaffected by all routes of MK-801 administration. These results suggest that drugs capable of blocking NMDA receptors, especially in striatum, may help ameliorate motor fluctuations in patients with advanced Parkinson's disease.

MK-801 reverses effects of chronic levodopa on D1 and D2 dopamine agonist-induced rotational behavior.

The effect of dizocilpine (MK-801) on dopaminergic agonist-induced rotational behavior was investigated in rats with 6-hydroxydopamine lesions of the nigrostriatal pathway after chronic administration of levodopa. The rotational response to the D2 agonist quinpirole was markedly increased in levodopa-treated animals compared with rats chronically administered saline. The increase in responsiveness to quinpirole was reversed by co-administered MK-801. Conversely, the rotational response to the D1 agonist SKF 38393 was reduced following chronic treatment with levodopa. The decrease in response to SKF 38393 was also reversed by MK-801. Chronic treatment with levodopa failed to alter the rotational responses to two other D1 preferring agonists SKF 81297 and SKF 82968, but responses to both agonists were increased by the co-administration of MK-801. These data support the hypothesis the MK-801 may reverse the differential changes in D1 and D2 agonist-induced motor responses which result from chronic treatment with levodopa.

NMDA receptor blockade reverses motor response alterations induced by levodopa.

Motor fluctuations that ultimately complicate the response of most parkinsonian patients to levodopa therapy might represent a form of behavioral or neuronal plasticity. Since various forms of neuronal plasticity appear to be mediated by glutamate transmission through the N-methyl-D-aspartate (NMDA) receptor, the effect of NMDA receptor blockade on the development of alterations in the motor response to chronic levodopa was evaluated in hemiparkinsonian rats. Repeated levodopa administration decreased rotational behavior induced by a D1 dopamine receptor agonist, increased D2 agonist-induced rotation and progressively reduced the duration of the motor response to levodopa itself. Acute pretreatment with the noncompetitive NMDA antagonist MK-801 completely reversed all these changes. These findings suggest that NMDA receptor-mediated mechanisms contribute to the behavioral plasticity associated with chronic levodopa treatment and that NMDA antagonists might be effective in reversing the motor response complications of the long-term levodopa therapy.

Motor fluctuations in levodopa treated parkinsonian rats: relation to lesion extent and treatment duration.

The pathogenesis of the motor fluctuations that complicate levodopa treatment of most parkinsonian patients remains uncertain. To evaluate the contribution of the degree of dopamine neuron loss and the duration of levodopa exposure, rats whose nigrostriatal system had been previously lesioned unilaterally by 6-hydroxydopamine received twice daily levodopa (25 mg/kg) injections for three weeks. The magnitude of the rotational response to levodopa more than doubled during the first week of treatment (P < 0.01), but remained essentially constant thereafter. Rats with over 95 percent loss of dopaminergic neurons evidenced a progressive shortening in the duration of levodopa's motor effects (P < 0.01) as well as a failure of nearly 8 percent of levodopa injections to elicit any response after the first week of treatment. In contrast, response changes resembling those associated with end of dose deterioration and on-off fluctuations in parkinsonian patients did not occur in the less severely lesioned rats. These results suggest that the extent of a dopamine neuron loss must exceed a relatively high threshold before intermittent levodopa treatment produces changes favoring the rapid appearance of motor fluctuations of the wearing-off and on-off types.

Excitatory amino acid receptor antagonists modify regional cerebral metabolic responses to levodopa in 6-hydroxydopamine-lesioned rats.

Excitatory amino acid receptor antagonists have been proposed as novel therapeutic agents to be used with levopoda in the treatment of Parkinson's disease. We examined the neural substrates for the interaction between levodopa and antagonists of either the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or N-methyl-D-aspartate type of excitatory amino acid receptor using 2-deoxyglucose autoradiography. Thus, we compared the effects of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (10 mg/kg, i.v.) and the N-methyl-D-aspartate antagonist MK-801 (0.1 mg/kg, i.v.) on cerebral metabolic responses to levodopa (25 mg/kg, i.v., with 12.5 mg/kg benserazide) in rats with a unilateral nigrostriatal pathway lesion. Levodopa increased glucose utilization ipsilateral to the lesion in substantia nigra pars reticula (up to 104%), entopeduncular nucleus (up 90%) and subthalamic nucleus (up 30%), indicating that levodopa alters striatal output through the striatonigral, striatoentopeduncular and striatopallidal pathways. Levodopa also decreased metabolic rate in lateral habenula (down 39%), a target of projections from entopeduncular nucleus, implying a reduction in basal ganglia output. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline and MK-801 by themselves did not affect glucose utilization in any of these regions. Pretreatment with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline reduced the effect of levodopa in substantia nigra pars reticulata but not in entopeduncular nucleus or subthalamic nucleus, while MK-801 attenuated the effect of levodopa in all three of these structures; neither 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline nor MK-801 altered the effect of levodopa in lateral habenula. When given at the same doses to a separate group of lesioned animals, neither 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline nor MK-801 affected rotational behavior elicited by levodopa. These findings indicate that alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl-D-aspartate receptor antagonists differentially modify dopamine receptor-mediated striatal output. alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor blockade may preferentially attenuate the effect of dopamine receptor activation on the striatonigral pathway, while N-methyl-D-aspartate blockade appears to reduce the actions of dopamine on the striatonigral, striatoentopeduncular and striatopallidal pathways.(ABSTRACT TRUNCATED AT 400 WORDS)

Opposite effects of NMDA and AMPA receptor blockade on catalepsy induced by dopamine receptor antagonists.

Excitatory amino acid antagonists have been proposed as novel therapeutic agents for Parkinson's disease due to their ability to reverse akinesia in animal models of this disorder. To further evaluate this therapeutic potential, we examined the effects of a N-methyl-D-aspartate (NMDA) and an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist on catalepsy produced by dopamine D1 or D2 receptor antagonists in rats. Male Sprague-Dawley rats were injected with dizocilpine (MK-801 0.025, 0.05 or 0.1 mg/kg i.p.), 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX 12.5 mg/kg i.p.) or saline prior to administration of either raclopride (2.5 mg/kg i.p.) or SCH 23390 (0.5 mg/kg i.p.). Catalepsy was evaluated with both grid and bar tests every 20 min for 2.7 h. MK-801 (0.1 mg/kg) reversed the catalepsy produced by either raclopride or SCH 23390 but did not stimulate locomotion when given alone at this dose. At 0.05 mg/kg, MK-801 markedly decreased SCH 23390-induced catalepsy, but did not affect the catalepsy produced by raclopride. In contrast, NBQX increased raclopride-induced catalepsy, but had no effect on catalepsy elicited by SCH 23390. These findings suggest that blockade of NMDA receptors, but not non-NMDA receptors, may reverse the catalepsy produced by dopamine receptor antagonists.

Cortical activity preceding self-initiated and externally triggered voluntary movement.

The cortical electromyogram (EMG) activity, preceding voluntary movements, was recorded in 12 normal subjects in two different situations: first, when movements were self-induced by the subjects by their own will; and second, in response to threshold electrical stimulation of the index finger, a brief flash of a light-emitting diode (LED), and a click. Four types of movements were studied: (a) fast extension of the right wrist, (b) fast supination of the left wrist, (c) either movement depending on the subject's own decision or on which index finger was stimulated, and (d) fast sequential right and left wrist extension. In all subjects, self-initiated movements were preceded by a typical Bereitschaftspotential (BP) starting 1,290 +/- 208 ms before the EMG discharge. When the same movements were triggered by an external clue, there was no BP. The BP was present, although with a shorter duration, when subjects were asked to wait for a brief period after index finger stimulation, before extending the right wrist. From these results, we conclude that the BP is closely associated with the timing of internally generated movements, and that different cortical areas are probably involved in the generation of self-induced and externally referenced movements in humans.

Orthostatic tremor: an essential tremor variant?

Three patients with a clear-cut history of essential tremor of the upper limbs presented with the clinical features reported by Heilman as orthostatic tremor. Electromyographic findings included 6-8 Hz postural tremor in all four limbs. Highly synchronized 16 Hz rhythmic discharges were found in the legs upon standing. This peculiar pattern of discharge was also observed in the upper limbs and spinal muscles. High frequency rhythmic bursts, either alternating or co-contracting were present in specific postures not necessarily related to standing. An additional group of 12 patients with postural tremor of the legs was studied; seven of these showed modification in the frequency and synchronization of the muscle discharges upon standing. Although none of them had the full-blown clinical syndrome of orthostatic tremor, they complained of mild unsteadiness upon standing, together with a vague sensation of stiffness in the lower limbs. The present findings induce us to think that there might be a link between essential tremor and the so-called orthostatic tremor. Orthostatic tremor might be an essential-tremor-related entity that may be caused by a derangement in the central mechanism in charge of the organization of certain motor activities, not necessarily controlling the standing position.