Characterisation of striatal NMDA receptors involved in the generation of parkinsonian symptoms: Intrastriatal microinjection studies in the 6‐OHDA‐lesioned rat

Abstract

Treatments for Parkinson's disease based on replacement of lost dopamine have several problems. Following loss of dopamine, enhanced N-methyl-D-aspartate (NMDA) receptor-mediated transmission in the striatum is thought to be part of the cascade of events leading to the generation of parkinsonian symptoms. We determined the localisation and pharmacological characteristics of NMDA receptors that play a role in generating parkinsonian symptoms within the striatum. Rats were lesioned unilaterally with 6-hydroxydopamine (6-OHDA), and cannulae implanted bilaterally to allow injection of a range of NMDA receptor antagonists at different striatal sites. When injected rostrally into the dopamine-depleted striatum, the glycine site partial agonist, (+)-HA-966 (44-400 nmol) caused a dose-dependent contraversive rotational response consistent with an antiparkinsonian action. (+)-HA-966 (400 nmol) had no effect when infused into more caudal regions of the dopamine-depleted striatum, or following injection into any striatal region on the dopamine-intact side. To determine the pharmacological profile of NMDA receptors involved in inducing parkinsonism in 6-OHDA-lesioned rats, a range of NMDA receptor antagonists was infused directly into the rostral striatum. Ifenprodil (100 nmol) and 7-chlorokynurenate (37 nmol), but not MK-801 (15 nmol) or D-APV (25 nmol) elicited a dramatic rotational response when injected into the dopamine-depleted striatum. This pharmacological profile is not consistent with an effect mediated via blocking NR2B-containing NMDA receptors. The effect of intrastriatal injection of ifenprodil was increased in animals previously treated with levodopa (L-dopa) methyl ester. This was seen as an increase in on-time and in peak rotational response. We propose that stimulation of NR2B-containing NMDA receptors in the rostral striatum underlies the generation of parkinsonian symptoms. These studies are in line with previous findings suggesting that administration of NR2B-selective NMDA receptor antagonists may be therapeutically beneficial for parkinsonian patients, when given de novo and following L-dopa treatment.

Dopamine D1-Dependent Trafficking of StriatalN-Methyl-d-aspartate Glutamate Receptors Requires Fyn Protein Tyrosine Kinase but Not DARPP-32

“…In Parkinson's disease, the primary disturbance is a loss of dopaminergic innervation, but this loss elicits secondary alterations in glutamate receptors, especially those of the N-methyl-D-aspartate (NMDA) class (Chase and Oh, 2000). Altered striatal NMDA receptor functions make important contributions, both to symptoms of the disease and to the response to treatment with dopaminergic drugs (Calabresi et al, 2000a;Nash and Brotchie, 2002;Oh and Chase, 2002).…”

Effect of rasagiline on the molecular composition of the excitatory postsynaptic density

“…In striatal neurons, hyperfunction of NMDA receptors is suggested to contribute to parkinsonian symptoms and to treatment-induced motor complications, including L-DOPA-induced dyskinesia in Parkinson's disease (Nash and Brotchie, 2002; Verhagen Metman, 2002). In particular, subcellular redistribution of NR2A and NR2B subunits of NMDA receptor, leading to an increased NR2A/NR2B ratio at synaptic sites, is a key element in the complex modifications of glutamatergic synapses which occur both in experimental parkinsonism and in L-DOPA induced dyskinesia (Gardoni et al, 2006;Picconi et al, 2004).…”

An Overview of Target Specific Neuro-Protective and Neuro-Restorative Strategies

“…Selective NMDA receptor antagonists, such as ifenprodil and CP-101,606, have been developed in an attempt to avoid the side effects of non-selective blockers. Ifenprodil, has anti-Parkinsonian actions in rat and, and nonhuman primates (Nash and Brotchie, 2002). CP-101,606 reduced Parkinsonian symptoms, in both haloperidol-treated rats, and MPTP-lesioned nonhuman primates (Steece, 2000).…”