AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys.
OBJECTIVE
To evaluate the contribution of amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) glutamate receptors to the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias.


BACKGROUND
Motor fluctuations and dyskinesias reflect, in part, altered function of glutamate receptors of the NMDA subtype. The possible role of AMPA receptors, however, has not yet been examined.


METHODS
The authors compared the ability of an AMPA agonist (CX516) and a noncompetitive AMPA antagonist (LY300164) to alter parkinsonian symptoms and levodopa-induced dyskinesia in MPTP-lesioned monkeys. Eight levodopa-treated parkinsonian monkeys received rising doses of each drug, first in monotherapy and then in combination with low-, medium-, and high-dose levodopa.


RESULTS
CX516 alone, as well as when combined with low-dose levodopa, did not affect motor activity but induced dyskinesia. Moreover, following injection of the higher doses of levodopa, it increased levodopa-induced dyskinesia by up to 52% (p < 0.05). LY300164 potentiated the motor activating effects of low-dose levodopa, increasing motor activity by as much as 86% (p < 0.05), and that of medium-dose levodopa as much as 54% (p < 0.05). At the same time, LY300164 decreased levodopa-induced dyskinesia by up to 40% (p < 0.05).


CONCLUSIONS
AMPA receptor upregulation may contribute to the expression of levodopa-induced dyskinesia. Conceivably, noncompetitive AMPA receptor antagonists could be useful, alone or in combination with NMDA antagonists, in the treatment of PD, by enhancing the antiparkinsonian effects of levodopa without increasing and possibly even decreasing levodopa-induced dyskinesia.
Konitsiotis
S
S
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892-1406, USA.
Blanchet
P J
PJ
Verhagen
L
L
Lamers
E
E
Chase
T N
TN
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology* / Q000627:therapeutic use; D004149:Dioxoles / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D007980:Levodopa / Q000008:administration & dosage; D008252:Macaca fascicularis; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy*; D010880:Piperidines / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000819:agonists* / Q000037:antagonists & inhibitors*; D012720:Severity of Illness Index
C097396:1-(quinoxalin-6-ylcarbonyl)piperidine; D004149:Dioxoles; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D018091:Receptors, AMPA; D001569:Benzodiazepines; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C085266:talampanel