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

Neuroscience and Biobehavioral Reviews, Vol. 21, No. 4, pp. 447-453, 1997 Copyright © 1997 Published by Elsevier Science Ltd Printed in Great Britain. All rights reserved 0149-7634/97 $32.00 + .00

PII: S0149-7634(96)00038-3

Modulation of Levodopa-induced Motor Response Complications by NMDA Antagonists in Parkinson' s Disease P I E R R E J. B L A N C H E T , S T E L L A M. P A P A , L E O V E R H A G E N M E T M A N , M. M A R A L M O U R A D I A N A N D T H O M A S N. C H A S E *

Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, Bldg 1O, Rm 5 C103, 10 Center Drive MSC 1406, Bethesda, MD 20892-1406, USA BLANCHET, P.J., S.M. PAPA, L.V. METMAN, M.M. MOURADIAN,T.N. CHASE. Modulation of levodopa-inducedmotor response complications by NMDA antagonists in Parkinson's disease. NEUROSCI BIOBEHAV REV 21(4) 447-453, 1997.--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 D 1- and Dz-dependent responses and the progressive shortening in the duration of response induced by long-term exposure to levodopa in 6-hydroxydopamine-h;sionedrats. Preliminary results further suggest that NMDA receptor blockade can counteract levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesionednon-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 stfiatopallidal complex. Taken together, our observations suggest that abnormal glutamate transmission or dysregulationof NMDA receptor-mediated mechanisms contribute to levodopa-inducedmotor 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-relatedmotor response complications in Parkinson's disease. © 1997 Elsevier Science Ltd. NMDA

glutamate dopamine

1. I~I'RODUCTION

using excitatory amino acids have become the focus of great interest in PD research ever since the role of the subthalamic nucleus (STN) as an excitatory driving force within the basal ganglia circuitry was suggested (1,39,50,71). This paved the way for the demonstration that parkinsonism could be reversed by counteracting the excessive STN activity through toxic ablation (6), high-frequency stimulation (45) or pharmacological antagonism of S T N efferents within the internal pallidal segment (17,18). In addition, glutamate can influence stfiatal efferent function through complex interactions with medium-spiny neurons and cholinergic interneurons (24). Recently, we explored the possibility of modulating levodopa-induced motor response complications in animal models of PD and patients with PD using a variety of glutamate receptor antagonists specific for the N-methylD-aspartate (NMDA) receptor. The evidence provided suggests that upregulated N M D A receptor-mediated mechanisms and/or overactive glutamatergic pathways contribute to the pathophysiological mechanisms underlying these complications.

THE experience of ParkirLson's disease (PD) patients taking levodopa is initially rewarding and sustained during the 3 - 5 years of treatment. Unfortunately in most cases, the long-term response to levodopa is increasingly compromised by motor response complications that can become quite disabling (4,44). "[he duration of response to each dose of levodopa first declines gradually, a phenomenon referred to as the 'wem'ing-off' effect or 'end-of-dose deterioration'. With time, these fluctuations often become more random and unpred~Lctable with sudden shifts between mobile and immobile states, known as the 'on-off" effect, and associated with various abnormal involuntary movements collectively called 'dyskinesias'. The younger (62) and most severely disabled subjects (7,11) appear particularly at risk of developing dyskinesias with levodopa replacement. The manipulation of currently available dopaminergic drugs is often a limited and impractical strategy against these complications (48), thus stimulating the search for novel strategies targeting nondopaminergic systems. Amongst these, the motor pathways

*ExperimentalTherapeutics Branch, National Institute of Neurological Disorders and Stroke, Bldg 10, Rm 5C103, 10 Center Drive MSC 1406, Bethesda, MD 20892-1406, USA. 447

448

BLANCHET ET AL. 2. 'WEARING-OFF' AND 'ON-OFF' FLUCTUATIONS

Several lines of evidence suggest that the development of the 'wearing-off' effect is in part related to the severity of the dopaminergic nigrostriatal degeneration. A shortening in levodopa response duration has been correlated to the extent of the nigrostriatal degeneration in rats exposed to the neurotoxin 6-hydroxydopamine (6-OHDA) (59). Likewise in PD patients, the striatal storage capacity of dopamine measured with L-[18F]fluorodopa positron emission tomography is more impaired in fluctuating subjects compared to those with a stable response to levodopa (43) and, consequently, patients become increasingly dependent on the immediate circulating levodopa levels to maintain a response. In this context, an optimal, steady-state intravenous levodopa infusion quickly and markedly improves motor variability in fluctuating patients (35,56) and, not unexpectedly, the rate of reappearance of parkinsonian disability following the abrupt cessation of a levodopa infusion is faster in more advanced cases (28). However, recent clinical evidence now suggests that not only presynaptic but also postsynaptic dopaminergic mechanisms contribute to 'wearing-off' and 'on-off' fluctuations. In fact, the stable clinical response brought about by a constant levodopa intravenous infusion (56) or subcutaneous apomorphine infusion (30) is less complete in patients with 'on-off' compared to 'wearing-off' and the duration of response of PD patients to apomorphine, a direct-acting postsynaptic D I/Dz agonist, is shorter in fluctuating compared to stable responders (15,66). In 6-OHDA-lesioned rats, shortening in the duration of response to levodopa can be rapidly produced following chronic levodopa treatment despite constant dopamine cell loss (59). Similarly in drug-naive, 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primates, an apparent

120

100 o

=~ 80

60

Levodopa Day 1

Levodopa Day 22

Levodopa + MK-801 Day 23

FIG. 1. Rotational response of 6-OHDA-lesioned rats to a dose of levodopa/ benserazide (25 mg kg-1/6.25 mg kg -1, i.p.) measured on the 1st and 22nd days of chronic, twice daily injections with levodopa/benserazide (same dose), On day 23, the rotational resl~onse was assessed following the administration of MK-801 (0.1 mg kg-l, i.p.) immediately before levodopa was given. MK-801 acutely reversed the shortening in duration of the response to levodopa seen with chronic treatment. The duration of response provided reflects the efficacy half-time, or the time interval when turning first exceeds half maximal rate to the point when turning falls below half maximal rate. **p < 0.01 compared with day 1; tp < 0.01 compared with day 22; n = 13; ANOVA followed by Duncan's post-hoe test (27)

'wearing-off' effect to each dose of the synthetic dopaminomimetic full DI agonist SKF 82958 was observed, the duration of action declining by nearly 40% following 1 week of treatment (9); the shortened response to SKF 82958 was reversed by prior dosing, 4 h earlier, with the D2 family receptor agonist quinpirole which was no longer effective when the animals were challenged with their next scheduled dose of SKF 82958. These data suggest that plastic changes in central dopaminoceptive systems occur following chronic exposure to dopaminergic drugs. Such alterations could underlie levodopa response fluctuations in PD. Pharmacological observations made in 6-OHDAlesioned rats have suggested that NMDA receptor activation is involved in the 'wearing-off' effect following chronic exposure to levodopa. Indeed in that model, acute NMDA receptor blockade with MK-801 is able to reverse the shortened duration of action of levodopa without affecting the magnitude of the resulting motor response (26) (Fig. 1). Potentiation of the levodopa effects with NMDA receptor blockade has also been reported in monoamine-depleted rats (37,40,47), 6-OHDA-lesioned rats (46,55) and MPTPlesioned monkeys (46,73,79). Just how NMDA receptor activation is linked to the altered motor response to levodopa remains conjectural, but rearrangements in dopamine D I and D2 receptor-mediated mechanisms could be at play. The answer to this question has been sought in several experiments using the 6-OHDA-lesioned rat model, but conclusions have varied depending on the NMDA receptor antagonist used and on previous exposure to levodopa. Acute NMDA receptor blockade with the non-competitive antagonist MK-801 (12) leaves the responsiveness of levodopa-naive 6-OHDA-lesioned rats to a D1 agonist intact. D I receptor responsiveness is also maintained in normal rats chronically exposed to MK-801 (23), but potentiated responses have been reported in reserpinised mice with reversible monoaminergic depletion (72). This pharmacological interaction is different in 6-OHDAlesioned rats with prior chronic exposure to levodopa that results in desensitization of D1 receptor-dependent responses, an effect reversed with NMDA receptor blockade (13,27). Thus, NMDA transmission appears to have a negative impact on D Fdependent responses in dopaminedenervated rodents under conditions of chronic levodopa treatment. The existence of opposing effects between striatal NMDA and D1 receptors on the phosphorylation of DARRP-32 could explain why NMDA receptor blockade enhances D1 receptor function (34). NMDA receptor blockade may also remove the effects of acetylcholine on the collateral inhibition of D1 receptor-bearing striatonigral neurons by reducing basal acetylcholine release (24). In contrast, the influence of MK-801 on D2 receptordependent responses is generally negative in normal rats (23), reserpinised mice (72), and in 6-OHDA-lesioned rats previously exposed to levodopa or not (12,54,55). However, the reduction in D2 receptor responses is apparently not seen with every NMDA antagonist in reserpinised mice (72), and the competitive NMDA antagonist CPP can reportedly potentiate the locomotor effects of the D2 agonist lisuride in 6-OHDA-lesioned rats (78). More importantly, MK-801 has the potential to overcome quite effectively the supersensitive D2 receptor-mediated responses observed following chronic intermittent levodopa treatment (13,27). Thus, NMDA transmission appears to enhance D2 receptor

NMDA ANTAGONISTS IN PARKINSON'S DISEASE

449

TABLE 1 EFFECTS OF DIFFERENT GLUTAMATE ANTAGONISTS ON THE MOTOR RESPONSE OF LEVODOPA-TREATED PARKINSON'S DISEASE PATIENTS Drug

N o patients*

Akinesia

Dyskinesia

Reference

Amantadine

12

Unchanged (1 patient)

(31)

Amantadine Amantadine Amantadine

23 42 47

Increased chorea (1 patient) -Unchanged

(29) (69) (74)

Arnantadine

20F

Increased chorea (1 patient)

(70)

Amantadine sulfate Memantine

4 14F

-Unchanged (5 patients)

(16) (63)

Memantine Budipine Ifenprodil Lamotrigine

2 16 20 (9NF) 5F

--Unchanged (11 patients) Variable increase (3 patients)

(64) (36) (52) (80)

Dextromethorphan Dextromethorphan Dextromethorphan Dextromethorphan + Quinidine Dextrorphan

6NF 9 21NT 20F

Improvement in magnitude of response to a suboptimal dose of levodopa (1 patient); duration of response reduced by 60% (1 patient) Transient improvement Improvement in magnitude of response Transient increase in magnitude of levodopa response when amantadine added (one third of patients) Transient improvement in magnitude and duration of response Mean improvement in magnitude of response only (?) 10/14 completed trial; improvement in magnitude of response (5 patients) and off periods (6 patients); off periods worse (1 patient) Improvement in magnitude of response (1 patient) Improvement in magnitude of response Unchanged Improvement in wearing-off in 3 patients, transient in 1 more Mild improvement in magnitude of response Modest improvement in magnitude of response Unchanged 6/20 completed trial; reduction in daily off time and motor fluctuations Unchanged

---Improved in subset of patients

(14) (68) (53) (77)

Improved

(10)

2F

*F: response fluctuators on levedopa; NF: non-fluctuators

function. Overall, NMDA receptor blockade may optimise NMDA receptor sensitivity and its impact on postsynaptic DI and D2 receptor-dependent responses to counteract motor complications in PD patients. The pharmacological effects of NMDA antagonist treatment on dopamine-dependent behaviours have been studied in acute paradigms and long-term effects remain to be clarified. Unfortunately, few NMDA receptor antagonists have been tested thus far in PD (Table 1). The aminoadamantanes amantadine and memantine have been studied most extensively. Overall, this class of drugs provides mild and variable potentiation of the antiparkinsonian effects to levodopa that tends to wane over time. The clinical results with budipine (antimuscarinic and non-competitive NMDA antagonist), ifenprodil (non-competitive NMDA antagonist at the polyamine modulatory site) and lamotrigine (glutamate release inhibitor) have not been replicated and drug levels have not been measured. Dextromethorphan (DM), a dextrorotatory morphinan without affinity for opioid receptors acting as a non-competitive NMDA receptor antagonist, has produced variable and inconsistent results in the dose range tested. We evaluated the effects of DM (oral dose range 60-120 mg day -~) against levodoparelated motor complications in a pilot add-on study of 20 patients, who also took quinidine (100mg orally twice dally) to inhibit the hepatic O-demethylation of DM (77). Fourteen patients could not complete the trial due to adverse effects and/or decreased levodopa efficacy. Six patients tolerating DM then entered a double-blind, placebo-controlled, cross-over study that included two arms of 2 weeks each separated by a wash-out of 1 week. In this subgroup of patients, the Unified Parkinson's Disease Rating Scale (UPDRS section IV) scores showed a mean

dally increase in the duration of the antiparkinsonian response (total 'ON' time) with less motor fluctuations when DM was added to the antiparkinsonian treatment kept constant throughout the study, compared to placebo. This benefit could not be replicated following a different paradigm testing dextrorphan (10), a non-competitive NMDA antagonist more potent than its O-methyl ester derivative DM (21). Two patients with advanced PD and moderately severe motor fluctuations including peak-dose dyskinesias were given intravenous infusions of dextrorphan (DX) hydrochloride for 6 h dally in rising doses, whilst all other antiparkinsonian medications were withheld. DX alone showed no antiparkinsonian activity and when the best tolerated dose was combined with a single intravenous effective dose of levodopa, no definite synergy was observed either. However, the use of a single dose of levodopa in combination with the NMDA antagonist is not ideal for studying the synergistic effects between NMDA receptor antagonists and levodopa reported by others (46,73,79). Experimental flaws contribute to the difficulty in demonstrating a synergy between NMDA receptor antagonists and levodopa. Most study designs sought changes in the magnitude of response to levodopa rather than changes in the duration of action, and the use of optimal doses of oral levodopa likely produced a ceiling effect interfering with the demonstration of synergy. In addition, the therapeutic index of NMDA receptor antagonists often precludes sufficient doses. Thus, the role of NMDA receptor activation in motor response fluctuations to levodopa and the synergistic role of NMDA antagonists suggested in rodent experiments will certainly require safer and more selective drugs to be confirmed clinically.

450

BLANCHET ET AL. 3. LEVODOPA-INDUCEDDYSKINESIAS

It is generally accepted that both pre-and postsynaptic alterations in the dopaminergic nigrostriatal system contribute to the induction of levodopa-induced dyskinesias. Levodopa produces dyskinesias only in dopaminedenervated subjects, and the threshold for levodopa-induced dyskinesias declines with advancing disease. A disrupted balance in striatal efferent function favoring D1 receptor transmission has been implicated (58,75), but this view remains controversial. Studies in 6-OHDA-lesioned rats have suggested the development of subsensitive D1 receptor-mediated responses and supersensitive D2 receptormediated responses following chronic treatment with levodopa (13,25,27), and the same alterations could possibly occur in PD. Once present, levodopa-induced dyskinesias can be reproduced by acute challenge with most selective, postsynaptic dopamine D2 agonists, even when given for the first time to MPTP-lesioned non-human primates (5) or PD patients (33) Some experiments have suggested that NMDA receptor activation is involved in the altered pharmacological responses displayed by dopamine D1 and D2 receptor subtypes after chronic exposure to levodopa since NMDA receptor blockade can reverse the subsensitivity to a D1 agonist and the supersensitivity to a D2 agonist in 6-OHDA-lesioned rats (13,27). Pharmacological desensitisation of striatal D2 receptors has been associated with a lower risk to develop dyskinesias in MPTP-lesioned primates (8). The possibility of overcoming the abnormal D~ and D2 receptor responsiveness following chronic levodopa treatment with NMDA receptor blockade is of strategic importance and could well benefit PD patients with levodopa-induced dyskinesias. Very few studies have examined the effects of NMDA receptor blockade in MPTP-lesioned non-human primates displaying levodopa-induced dyskinesias. The administration of the NMDA antagonist MK-801 (0.03 mg kg -1 s.c.) antagonised both the dyskinetic and antiparkinsonian responses to levodopa in cynomolgus monkeys (32), whilst a three-fold higher dose given to squirrel monkeys antagonised the antiparkinsonian response to levodopa, and converted predominantly choreic dyskinesias into prominent dystonia (67). Dose-dependent and species-dependent factors might have contributed to these results. Recently, our group tested the competitive NMDA antagonist LY 235959 in combination with a single, dyskinetic dose of levodopa in six MPTP-lesioned cynomolgus and rhesus monkeys with levodopa-induced dyskinesias involving oral and limb musculature of a mixed choreic/dystonic character (60). Whilst various doses of LY 235959 (0.5, 1, 3, 5 mg kg-1 s.c.) acutely failed to alter the antiparkinsonian response to levodopa, suppression of oral dyskinesias for 1 h and 70% attenuation in choreic movements were observed with a dose of 3 mg kg -1. Dystonic movements were unaffected. This effect proved to be dose-dependent and to follow an inverted U-shaped dose-response curve since low doses were ineffective and the highest dose actually worsened dystonia in two of the three animals manifesting this complication. No anaesthetic effect was observed. To our knowledge, this is the first observation of a differential antichoreic effect provided by an NMDA antagonist in an animal model of PD. Thus far, the clinical potential of NMDA receptor

antagonists against levodopa-induced dyskinesias in PD patients has not been examined thoroughly and reports have been difficult to interpret (Table 1). However, encouraging results have been obtained with DM (77) and DX (10). Following oral DM treatment for 2 weeks, a mean reduction in the daily duration and intensity of dyskinesias was observed on the Unified Parkinson's Disease Rating Scale (UPDRS section IV) in a subset of six patients maintained on the same antiparkinsonian drug regimen, compared to placebo (vide supra). Moreover, the intravenous infusion of a well tolerated dose of DX over 6 h in two patients acutely decreased the peak-dose dyskinesia scores (by 86% in one patient and 50% in the other) induced by a single, previously determined, intravenous effective dose of levodopa, compared to levodopa alone. DX alone showed no antiparkinsonian or dyskinetic effect and did not consistently alter the antiparkinsonian response to levodopa. It is noteworthy that in these last two patients and in the MPTP-lesioned non-human primates treated with LY 235959, an antichoreic effect and resulting improvement in therapeutic index were obtained following acute NMDA receptor blockade without causing any clinically significant alteration in the antiparkinsonian response to levodopa. This suggests that the dyskinetic and antiparkinsonian responses provided by levodopa can be mediated by different mechanisms (57). These mechanisms and glutamatedopamine interactions would certainly be more adequately studied with drugs possessing better specificity and selectivity for NMDA receptor subtypes present in the basal ganglia. Systemically applied NMDA receptor blockade cannot provide a definite and comprehensive understanding of the sites and mechanisms underlying this acute antidyskinetic effect, but speculative comments can be proposed. In the basal ganglia, the striatum is probably a major site for pharmacological interactions between NMDA antagonists and dopamine as suggested by the greater striatal [3H]MK-801 binding (putamen > caudate) compared to other basal ganglia nuclei (3), the convergence of glutamatergic and dopaminergic inputs on individual medium spiny neurons (20,41) and the potentiation of D~ agonist-induced c-fos expression in the dorsolateral striatum with NMDA receptor blockade (55). Although the density of NMDA sites in the striatum is relatively low (2,3,51), local variations in subunit composition (19,42) and altered sensitivity of the receptors under certain pathological and pharmacological conditions might increase the degree and extent of the pharmacological responses to different NMDA antagonists (17). In fact, a selective increase in NMDA-sensitive binding in the rostral striatum in some PD cases has been reported (76), potentially enhancing the net contribution of NMDA receptor activation to glutamate effects locally. The interactions between glutamate and dopamine are complex and dependent upon the subtype of glutamatergic receptors present. Dopamine markedly potentiates NMDA-evoked responses in the striatum in vitro, whilst it attenuates nonNMDA responses (20). Thus, NMDA receptor antagonists could well reduce the overactive excitatory influences in the striatum and/or block supersensitive NMDA receptors resulting from excessive, exogenous levodopa concentrations in the brain. In addition, NMDA receptor blockade with MK-801 is reportedly able to cause a rapid and profound decrease in striatal D2 receptor mRNA in

NMDA ANTAGONISTS IN PARKINSON'S DISEASE

451

normal rats (61), but increases in striatal D2 receptor m R N A expression and receptor density have been obtained after more prolonged treatment with MK-801 (49). These results raise the important issue of the temporal profile o f the impact of N M D A receptor blockade on the effects of levodopa in the basal ganglia. Our studies of the cerebral metabolic responses to levodopa and MK-801 in 6-OHDA-lesioned rats, using the [14C]2-deoxyglucose me~ahod, revealed indirect evidence of the potential of N M D A receptor blockade to affect synaptic activity in the striatopaUidal complex. In that model, the drug combination of MK-801 and levodopa produced a widespread attenuation o f the increase in regional glucose utilization produced by levodopa alone in the output stations of the basal ganglia (substantia nigra pars reticulata and entopeduncular nucleus) and the subthalamic nucleus (26). In comparison, the tx-an~ino-3-hydroxy-5-methylisoxazole4-propionic acid ( A M P A ) receptor antagonist 2,3-dihydroxy-6-nitro-7- sulfamoy 1-benzo(F)quinoxaline (NBQX) showed a weaker and more restricted attenuation of the levodopa-induced increase in glucose utilization in the substantia nigra pars reticulata only, suggesting that A M P A receptor blockade may not provide adequate control over levodopa-related motor response complications in PD patients. The attenuation in glucose utilization response to levodopa in the subthalamic nucleus with MK-801 may

reflect decreased activity along the paUidosubthalamic pathway (originating from neurons in the lateral segment of the globus pallidus). N M D A receptor blockade with MK-801 is known to reduce the apomorphine-induced excitation of certain pallidal neurons in normal, anaesthetised rats (38). Consequently, neurons in the subthalamic nucleus may be disinhibited, thereby opposing dyskinesias (22). Thus, systemically administered N M D A antagonists may promote a complex reorganisation in striatopallidal function with the potential to alter levodopa-induced motor response complications. However, the potential of excessive N M D A receptor blockade to disrupt motor function and favor dystonia (60,67) should be borne in mind. Dystonia can also be produced after local application of the broad spectrum excitatory amino acid antagonist kynurenic acid in the ventral part of the lateral pallidal segment (65). Thus, our preliminary pharmacological studies in animal models of PD and PD patients provide examples of the acute effects of N M D A receptor blockade on levodopa-induced motor response complications, and raise the suspicion that overactive excitatory influences in the basal ganglia may contribute to their development. Evidently, N M D A antagonists offering optimal selectivity and good therapeutic index need to be tested chronically before they can be proposed as a useful approach against levodopa-induced motor response complications in PD.

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