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

https://doi.org/10.1016/S0149-7634(96)00038-3Get rights and content

Abstract

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.

References (80)

  • S. Kaur et al.

    Antiparkinsonian action of dextromethorphan in the reserpine-treated mouse

    European Journal of Pharmacology

    (1995)
  • M.D. Kelland et al.

    Apomorphine-induced changes in striatal and pallidal neuronal activity are modified by NMDA and muscarinic receptor blockade

    Life Sciences

    (1992)
  • R. Kötter

    Postsynaptic integration of glutamatergic and dopaminergic signals in the striatum

    Progress in Neurobiology

    (1994)
  • D.J. Laurie et al.

    Ligand affinities at recombinant N-methyl-d-aspartate receptors depend on subunit composition

    European Journal of Pharmacology [Molecular Pharmacology Section]

    (1994)
  • P. Limousin et al.

    Effect on parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation

    Lancet

    (1995)
  • G. Micheletti et al.

    Chronic administration of NMDA antagonists induces D2 receptor synthesis in rat striatum

    Molecular Brain Research

    (1992)
  • I.J. Mitchell et al.

    Neural mechanisms underlying parkinsonian symptoms based upon regional uptake of 2-deoxyglucose in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

    Neuroscience

    (1989)
  • D.T. Monaghan et al.

    l-[3H]Glutamate binds to kainate-, NMDA- and AMPA-sensitive binding sites: an autoradiographic analysis

    Brain Research

    (1985)
  • M. Morelli et al.

    MK-801 potentiates dopaminergic D1 but reduces D2 responses in the 6-hydroxydopamine model of Parkinson's disease

    European Journal of Pharmacology

    (1990)
  • S.M. Papa et al.

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

    Brain Research

    (1994)
  • Z.-H. Qin et al.

    D2 dopamine receptor messenger RNA is altered to a greater extent by blockade of glutamate receptors than by blockade of dopamine receptors

    Neuroscience

    (1994)
  • R.G. Robertson et al.

    Dyskinesia in the primate following injection of an excitatory amino acid antagonist into the medial segment of the globus pallidus

    Brain Research

    (1989)
  • Y. Smith et al.

    Neurons of the subthalamic nucleus in primates display glutamate but not GABA immunoreactivity

    Brain Research

    (1988)
  • M.S. Starr et al.

    Facilitation of dopamine D1 receptor-but not dopamine D1D2 receptor-dependent locomotion by glutamate antagonists in the reserpine-treated mouse

    European Journal of Pharmacology

    (1993)
  • H. Wachtel et al.

    NBQX (6-nitro-sulfamoyl-benzo-quinoxaline-dione) and CPP (3-carboxy-piperazin-propyl phosphonic acid) potentiate dopamine agonist induced rotations in substantia nigra lesioned rats

    Neuroscience Letters

    (1992)
  • U. Wüllner et al.

    The competitive NMDA antagonist CGP40.116 enhances L-DOPA response in MPTP-treated marmosets

    Neuropharmacology

    (1992)
  • A. Barbeau et al.

    Adverse clinical side effects of levodopa therapy

  • P.J. Bédard et al.

    Role of selective D1 and D2 agonists in inducing dyskinesia in drug-naive MPTP monkeys

  • H. Bergman et al.

    Reversal of experimental parkinsonism by lesions of the subthalamic nucleus

    Science

    (1990)
  • K.J. Bergmann et al.

    Parkinson's disease and long-term levodopa therapy

  • P.J. Blanchet et al.

    Continuous administration decreases and pulsatile administration increases behavioral sensitivity to a novel dopamine D-2 agonist (U-91356A) in MPTP monkeys

    Journal of Pharmacology and Experimental Therapeutics

    (1995)
  • P.J. Blanchet et al.

    Dyskinesia and wearing-off following dopamine D1 receptor agonist treatment in drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates

    Movement Disorders

    (1996)
  • P.J. Blanchet et al.

    Acute pharmacologic blockade of dyskinesias in Parkinson's disease

    Movement Disorders

    (1996)
  • J. Blin et al.

    Does levodopa aggravate Parkinson's disease?

    Neurology

    (1988)
  • R.C. Boldry et al.

    Influence of previous exposure to levodopa on the interaction between dizocilpine and dopamine D1 and D2 agonists in rats with 6-hydroxydopamine-induced lesions

    Journal of Pharmacology and Experimental Therapeutics

    (1993)
  • D. Bravi et al.

    Wearing-off fluctuations in Parkinson's disease: contribution of postsynaptic mechanisms

    Annals of Neurology

    (1994)
  • M. Brenner et al.

    Amantadine sulphate in treating Parkinson's disease: clinical effects, psychometric tests and serum concentrations

    Journal of Neurology

    (1989)
  • J.M. Brotchie et al.

    Alleviation of parkinsonism by antagonism of excitatory amino acid transmission in the medial segment of the globus pallidus in rat and primate

    Movement Disorders

    (1991)
  • A.L. Buller et al.

    The molecular basis of NMDA receptor subtypes: Native receptor diversity is predicted by subunit composition

    Journal of Neuroscience

    (1994)
  • C. Cepeda et al.

    Neuromodulatory actions of dopamine in the neostriatum are dependent upon the excitatory amino acid receptor sybtypes activated

  • Cited by (82)

    • Principles and Practice of Movement Disorders

      2021, Principles and Practice of Movement Disorders
    • Anti-NMDA Receptor Encephalitis: Clinical Features and Basic Mechanisms

      2018, Advances in Pharmacology
      Citation Excerpt :

      In addition, NMDA knockdown in mice leads to hypoventilation, the cause of death in many patients with anti-NMDARE (Forrest et al., 1994). Finally, NMDAR modulation is linked to control of dyskinesias, an aspect that could be associated with the prominent dyskinesia in anti-NMDARE (Blanchet, Papa, Metman, Mouradian, & Chase, 1997). Thus, studies identifying NMDARs as the autoantigen in this disorder are consistent with the expected features of dysfunctional NMDARs.

    • Chronic treatment with MPEP, an mGlu5 receptor antagonist, normalizes basal ganglia glutamate neurotransmission in L-DOPA-treated parkinsonian monkeys

      2013, Neuropharmacology
      Citation Excerpt :

      Hence, this evidence strongly suggests that NMDA receptors containing NR2B subunits are involved in the pathophysiology of LID and might contribute to their development. Although less receptor specific, dextrorphan, dextromethorphan and amantadine, known to block NMDA receptors, also show antidyskinetic activity in humans (Blanchet et al., 1996, 1997; Luginger et al., 2000; Metman et al., 1999; Rajput et al., 1998; Ruzicka et al., 2000; Snow et al., 2000; Verhagen Metman et al., 1998a). The role of AMPA receptors in LID is also supported by reports of improved LID with blockade of AMPA receptors in the MPTP monkey model (Bibbiani et al., 2005; Konitsiotis et al., 2000).

    • Intermittent Dopaminergic Stimulation causes Behavioral Sensitization in the Addicted Brain and Parkinsonism

      2009, International Review of Neurobiology
      Citation Excerpt :

      Moreover, l-DOPA alters gene expression-related neuronal phenotype for striatal glutamatergic transmission (Chase and Oh, 2000; Oh and Chase, 2002), both affecting NMDA (Oh et al., 1999) and non-NMDA (Marin et al., 2000) glutamate receptor subunits. This mechanism has been implicated in motor sensitization leading to dyskinesia as demonstrated by blocking NMDA (Blanchet et al., 1997) or AMPA (Konitsiotis et al., 2000) glutamate receptors to reduce l-DOPA-induced dyskinesia. These findings extended the role of glutamate antagonists from preventing the pathogenesis of PD to the treatment of drug-induced motor complications (Fornai et al., 1996, 1997; Zuddas et al., 1992).

    View all citing articles on Scopus

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

    View full text