Local NMDA Antagonism Prevents Inversion of Dopamine Responses in Striatal Medium Spiny Neurons in the Parkinsonian Macaque Open Access

Abstract

Dopaminergic innervation of medium spiny neurons (MSN) of the striatum is essential
for normal motor behavior. However, in patients with idiopathic Parkinson's disease (PD), long-
term levodopa replacement therapy is associated with debilitating motor complications such as
involuntary choreiform movements (levodopa-induced dyskinesias, LID). In non-human primate
models of advanced parkinsonism with chronic levodopa therapy, striatal MSNs are profoundly
hyperactive and often exhibit reversal of levodopa-induced firing rate changes ("inversions") that
is highly correlated with the onset of LID. It was hypothesized that baseline hyperactivity
mediated by hyperglutamatergic tone may lead to these abnormal inversions and are ultimately
the cause of LID. To address this hypothesis, local microinjections of the subunit non-selective
competitive NMDA receptor antagonist LY235959 were performed at the site of extracellular
recordings in the striatum in two awake, behaving rhesus monkeys with MPTP-induced
advanced parkinsonism with LID using an injectrode apparatus, followed by subcutaneous
systemic levodopa administration. We found that local microinjection of the vehicle (artificial
cerebral spinal fluid, aCSF) alone had no effect on firing rates and did not alter the pathological
heterogeneity of MSN responses to systemic levodopa, whereas reduction of baseline activity via
local microinjections of the competitive NMDA antagonist at a 9 mM concentration completely
abolished the abnormal inversion responses of MSNs to systemic levodopa. This finding has
profound implications for the elucidation of the pathophysiological mechanisms underlying LID,
as well as the development of pharmacological agents designed to alleviate dyskinetic side
effects of chronic levodopa replacement therapy in idiopathic PD.

Table of Contents

Introduction...................................................................................................................................... 1

Parkinson's Disease: Clinical Symptoms and Treatment.................................................... 1

Levodopa-Induced Dyskinesia............................................................................................. 2

MPTP-Induced Parkinsonism.............................................................................................. 3

Basal Ganglia Circuitry....................................................................................................... 4

Striatal Neurophysiology in Health and Disease................................................................. 5

Hypotheses....................................................................................................................................... 9

Primary Hypothesis............................................................................................................. 9

Secondary Hypotheses......................................................................................................... 9

Methods..........................................................................................................................................10

Subjects.............................................................................................................................. 10

Experimental Equipment and Setup................................................................................... 11

Experimental Design.......................................................................................................... 12

Data Analysis..................................................................................................................... 14

Results............................................................................................................................................ 16

Local Microinjection of aCSF Does Not Change Firing Frequency of MSNs.................. 16

Local Microinjection of LY236969 at 9mM Concentration
Reduces Firing Frequencies of MSNs.................................................................... 16

Local Microinjection of aCSF Yields a Variety of Striatal
MSN Responses to Systemic Levodopa.................................................................. 17

Firing Frequency Reductions via Local Microinjection of Competitive NMDA
Antagonist LY235959 Prevents Bidirectional Responses of Striatal MSNs.......... 18

Figures and Tables......................................................................................................................... 19

Figure 1.............................................................................................................................. 19

Figure 2.............................................................................................................................. 20

Figure 3.............................................................................................................................. 21

Figure 4.............................................................................................................................. 22

Figure 5.............................................................................................................................. 23

Figure 6.............................................................................................................................. 24

Figure 7.............................................................................................................................. 25

Figure 8.............................................................................................................................. 26

Figure 9.............................................................................................................................. 27

Table 1................................................................................................................................28

Table 2................................................................................................................................29

Discussion...................................................................................................................................... 30

References...................................................................................................................................... 34

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	BS
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience
Keyword	Parkinson's dyskinesia dopamine disease l-dopa MPTP electrophysiology levodopa LID striatum physiology NMDA medium MSN inversion spiny
Committee Chair / Thesis Advisor	Papa, Stella, Emory University
Committee Members	Traynelis, Stephen, Emory University Crutcher, Michael D, Emory University Jaeger, Dieter, Emory University

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