GluN2A and GluN2B NMDA Receptor Subunits Differentially Modulate Striatal Output Pathways and Contribute to Levodopa-Induced Abnormal Involuntary Movements in Dyskinetic Rats

Abstract

Dual probe microdialysis was used to investigate whether GluN2A and GluN2B NMDA receptor subunits regulate striatal output pathways under dyskinetic conditions. The preferential GluN2A antagonist NVP-AAM077 perfused in the dopamine-depleted striatum of 6-hydroxydopamine hemilesioned dyskinetic rats reduced GABA and glutamate levels in globus pallidus whereas the selective GluN2B antagonist Ro 25-6981 elevated glutamate without affecting pallidal GABA. Moreover, intrastriatal NVP-AAM077 did not affect GABA but elevated glutamate levels in substantia nigra reticulata whereas Ro 25-6981 elevated GABA and reduced nigral glutamate. To investigate whether GluN2A and GluN2B NMDA receptor subunits are involved in motor pathways underlying dyskinesia expression, systemic NVP-AAM077 and Ro 25-6981 were tested for their ability to attenuate levodopainduced abnormal involuntary movements. NVP-AAM077 failed to prevent dyskinesia while Ro 25-6981 mildly attenuated it. We conclude that in the dyskinetic striatum, striatal GluN2A subunits tonically stimulate the striato-pallidal pathway whereas striatal GluN2B subunits tonically inhibit striato-nigral projections. Moreover, GluN2A subunits are not involved in dyskinesia expression whereas GluN2B subunits minimally contribute to it. KEYWORDS: GABA, microdialysis, NMDA receptor subunits, NVP-AAM077, 6-OHDA, Ro 25-6981 A lterations in glutamate (GLU) neurotransmission and, in particular, abnormal function of striatal NMDA receptors, play a key role in driving symptoms of Parkinson's disease (PD) and long-term motor complications (e.g., dyskinesia) associated with L-DOPA therapy.1−3 The focus on the pathogenic role of NMDA receptors (and the therapeutic potential of NMDA receptor antagonists) has further grown after the discovery of their structural and functional heterogeneity. NMDA receptors are heteromers usually containing two NR1 and two NR2 subunits. NR2 subunits, classified into four (A-D) types, 4−6 govern NMDA channel gating and confer different physiopharmacological properties to the receptor-channel complex. 7,8 NMDA receptors containing the GluN2A and GluN2B subunits are highly expressed in the basal ganglia, 9,10 and several studies have reported plastic changes in striatal NR2 subunit expression levels, phosphorylation state and trafficking in response to dopamine (DA) depletion and chronic L-DOPA therapy (reviewed in ref 3).These changes have been pathogenically linked to PD since ifenprodil, the first identified GluN2B selective antagonist, and its analogues such as (R)-(R*,S*)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidinepropanol (Ro 25-6981) attenuated motor impairment in different models of parkinsonism 11−15 By using dual or triple probe microdialysis in awake rats, 16 we have attempted to investigate a possible correlation between the antiparkinsonian/antidyskinetic profiles of GluN2A and GluN2B selective antagonists with their ability to modulate GABA release from globus pallidus (GP) or substantia nigra reticulata (SNr), taken as ...

The Role of GluN2A and GluN2B Subunits on the Effects of NMDA Receptor Antagonists in Modeling Schizophrenia and Treating Refractory Depression

“…The lack of effect of Ro 25-6981 could be because of an insufficient dosage or it is also possible that a transient surge in either 5-HT or glutamate in the mPFC could have been missed because of dilution effects in the 20-min dialysate sample. Alternatively, the effects of Ro 25-6981 may be area specific because it has been reported that this compound increases dialysate glutamate in other brain areas such as the globus pallidus (Mabrouk et al, 2013). Furthermore, it is also known that stereotypies produced by MK-801 do not result from changes in prefrontal cortex activity .…”

“…At the end of each epoch, the predominant behavior was rated as immobility, climbing, and swimming by an experimenter blind to the treatment. As these drugs allegedly possess a fast antidepressant action and display similar pharmacokinetic profiles in microdialysis studies (Mabrouk et al, 2013), their administration was carried out 20 min before the test session.…”

Dopaminergic modulation of striatal networks in health and Parkinson's disease

“…Using the BAC-TRAP approach [63], Heiman et al [64] have shown how remarkably complex these changes in dSPN gene expression are. Although it has been widely assumed that sensitized D1R signaling was necessary for these adaptations with chronic L-DOPA treatment, work by Alcacer et al [65] has questioned this proposition, pointing to the probable importance of NMDAR signaling through Ras [66-68]. …”

The Kinase Fyn As a Novel Intermediate in l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…Moreover, PSD-95, which has been recently shown to mediate LID [8], promotes the phosphorylation of NMDARs by Fyn [14]. The NR2B subunit is critical in the regulation of the glutamate NMDAR and therefore in the development of LID [15,16]. Indeed, a clinical trial with the NR2B antagonist CP-101,606 has been proven to reduce LID despite its side effects [17].…”