Local NMDA Antagonism Prevents Inversion of Dopamine Responses in Striatal Medium Spiny Neurons in the Parkinsonian Macaque Öffentlichkeit
Burke Jr., Kenneth John (2012)
Published
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
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Figure
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Figure
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Figure
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Figure
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Figure
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Figure
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Figure
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Table
1................................................................................................................................28
Table
2................................................................................................................................29
Discussion......................................................................................................................................
30
References......................................................................................................................................
34
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