Alteration of glutamate receptors in the striatum of dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys following dopamine agonist treatment

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Abstract

The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal lesion and dopaminomimetic treatment on parameters of glutamatergic activity within the basal ganglia of monkeys were studied in relation with the development of dyskinesias. Drug-naive controls, saline-treated MPTP monkeys, as well as MPTP monkeys treated with either a long-acting D2 agonist (cabergoline) or a D1 agonist (SKF-82958) given by intermittent injections or continuous infusion, were included in this study. 3H-l-glutamate, 3H-α-amino-3-hydroxy-5-methylisoxasole-4-propionate (AMPA), 3H-glycine, 3H-CGP39653 (an N-methyl-d-aspartate, NMDA, antagonist selective for NR1/NR2A assembly) and 3H-Ro 25-6981 (an NMDA antagonist selective for NR1/NR2B assembly), specific binding to glutamate receptors, the expression of the NR1 subunit of NMDA receptors and glutamate, glutamine and glycine concentrations were studied by autoradiography, in situ hybridization and high-performance liquid chromatography (HPLC), respectively. Pulsatile SKF-82958 and cabergoline treatment relieved parkinsonian symptoms, whereas animals continuously treated with SKF-82958 remained akinetic. Pulsatile SKF-82958 induced dyskinesias in two of the three animals tested, whereas cabergoline did not. MPTP induced no significant changes of striatal specific binding of the radioligands used, NR1 mRNA expression and amino acid concentrations. In the putamen, pulsatile SKF-82958 treatment was associated with decreased content of glycine and glutamate, whereas only glycine was decreased in cabergoline-treated monkeys. Cabergoline and continuous administration of SKF-82958 led to lower levels of NR1 mRNA in the caudate in comparison to pulsatile SKF-82958 administration. The development of dyskinesias following a D1 agonist treatment was associated with an upregulation of 3H-glutamate [+49%], 3H-AMPA [+38%], 3H-CGP39653 [+111%], 3H-glycine [+26%, nonsignificant] and 3H-Ro 25-6981 [+33%] specific binding in the striatum in comparison to nondyskinetic MPTP monkeys. Our data suggest that supersensitivity to glutamatergic input in the striatum might play a role in the pathogenesis of dopaminomimetic-induced dyskinesias and further support the therapeutic potential of glutamate antagonists in Parkinson's disease.

Introduction

Dopaminomimetics are the main pharmacological tool used to treat patients suffering from Parkinson's disease (PD) in order to improve their quality of life (Olanow and Koller, 1998). However, an important proportion of parkinsonian patients eventually develops dyskinesias as a long-term limitation of dopaminomimetic therapy (Nutt, 1990). In order to devise an antiparkinsonian pharmacotherapy displaying a lower potential to induce dyskinesias, a better understanding of the neurochemical substrate of dopaminomimetic-induced dyskinesias (DID) is needed.

Nigrostriatal dopaminergic depletion is the main biochemical characteristic of PD and probably plays an important role in the development of DID Langston et al., 2000, Nutt, 1990. The nigrostriatal projections make synaptic contacts with the dendrites of medium spiny output neurons, the main representative of the neuronal population of the striatum Kotter, 1994, Parent et al., 1995. In PD, dopaminomimetic pharmacotherapy generally produces a pulsatile stimulation of dopamine receptors, which probably contrasts with the normal physiological tonic dopamine receptor stimulation Chase et al., 1998, Verhagen Metman et al., 2000. This nonphysiological stimulation is thought to induce pathological changes at the level of the striatal medium spiny output neurons that are critical for the development of DID Calon et al., 2000, Chase et al., 1998, Verhagen Metman et al., 2000.

Besides dopaminergic influence, the striatal medium spiny output neurons receive massive glutamatergic inputs from the cerebral cortex and are the site of a close interaction between dopamine and glutamate receptors Calabresi et al., 2000, Cepeda et al., 1993, Kotter, 1994. In this view, recent evidence suggests a link between alterations of glutamate receptor function in the striatum and the pathogenesis of motor complication associated with dopaminomimetic therapy, including DID. At a molecular level, alterations of the sensitivity of striatal glutamatergic receptors, especially those of the N-methyl-d-aspartate (NMDA) subtype, are observed in 6-hydroxydopamine (OHDA)-treated rats, which have developed motor complications following levodopa treatment (Verhagen Metman et al., 2000). This was mainly evidenced by changes in the phosphorylation state of NMDA receptor subunits Dunah et al., 2000, Oh et al., 1998, Oh et al., 1999. Moreover, systemic administration of NMDA antagonists in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys tends to improve the therapeutic window of levodopa Blanchet et al., 1999, Papa and Chase, 1996. Improvement of DID with NMDA antagonists was also reported in human parkinsonian patients Blanchet et al., 1996c, Blanchet et al., 1997, Snow et al., 2000, Verhagen Metman et al., 1998, Verhagen Metman et al., 1999.

These experimental observations suggest that further studies on the relationship between glutamatergic neurotransmission in the basal ganglia and the development of DID are warranted. In order to do so, the authors have studied the effect of treatments with either SKF-82958 (a short-acting D1 agonist) or cabergoline (a long-acting D2 agonist) in MPTP-treated monkeys on glutamate receptors and on glutamate, glutamine and glycine concentrations in the basal ganglia. Glutamate receptors were studied using 3H-l-glutamate, 3H-α-amino-3-hydroxy-5-methylisoxasole-4-propionate (AMPA), 3H-glycine (a NMDA receptor coagonist), 3H-CGP39653 (an NMDA antagonist selective for NR1/NR2A assembly) and 3H-Ro 25-6981 (an NMDA antagonist selective for NR1/NR2B assembly) autoradiography, and NR1 subunit messenger ribonucleic acid (mRNA) expression was analyzed by in situ hybridization. The aim of the protocol was to identify alterations of glutamatergic activity that might be related to MPTP-induced nigrostriatal denervation and to the development of DID.

Section snippets

Animals and treatments

Fifteen drug-naive, female, ovariectomized cynomolgus monkeys (Macaca fascicularis) weighting between 2.5 and 4.0 kg were used in this study. Three animals were used as normal healthy controls, whereas 12 monkeys received, at weekly intervals, standard subcutaneous doses of MPTP (2–3 mg/dose) until an enduring and satisfactory parkinsonian syndrome developed using the Laval University Disability Scale for MPTP monkeys (Gomez-Mancilla et al., 1993). After the last dose of MPTP, all monkeys were

Behavior

Intermittent administration of SKF-82958 injections induced a good relief of parkinsonian symptoms, whereas continuous infusion of SKF-82958 did not produce any perceptible improvement of motor symptoms. This absence of notable response was interpreted as D1 dopamine receptor desensitization (Blanchet et al., 1996b). However, two of the three animals treated with pulsatile injections of SKF-82958 developed persistent dyskinesias. On the other hand, cabergoline brought a good recovery of

Effect of MPTP-induced denervation

According to a previous report on these animals, MPTP administration induced a severe dopamine depletion (90–99%, depending on the caudate–putamen subregion) as well as an extensive dopamine transporter decrease (−92% versus control) in the striatum (Goulet et al., 1999). Dopamine transporter expression was also shown to be dramatically reduced (−86% versus control) in the substantia nigra pars compacta (Goulet et al., 1999). Although these changes in striatal dopaminergic activity were robust,

Conclusion

Two main conclusions may be drawn from the present data as follows. (1) The severe MPTP-induced denervation of the nigrostriatal pathway was not associated with alteration of 3H-l-glutamate, 3H-AMPA, 3H-glycine, 3H-Ro 25-6981 and 3H-CGP39653 specific binding to glutamate receptors in the striatum. Moreover, MPTP had no effect the expression of NR1 subunit of NMDA receptor as well as on glutamate, glutamine and glycine concentrations in the striatum. (2) The development of dyskinesias following

Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research (CIHR; P.J. Bedard and T.D.P.). F.C. holds a health professional studentship from Novartis in association with the CIHR and from the Fonds de la Recherche en Santé du Québec. The authors thank F. Hoffman-La Roche (Switzerland) for the generous gift of 3H-Ro 25-6981 and Ro 04-5595.

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