Systemic administration of NMDA and AMPA receptor antagonists reverses the neurochemical changes induced by nigrostriatal denervation in basal ganglia.
In Parkinson's disease, nigrostriatal denervation leads to an overactivity of the subthalamic nucleus and its target areas, which is responsible of the clinical manifestations of the disease. Because the subthalamic nucleus uses glutamate as neurotransmitter and is innervated by glutamatergic fibers, pharmacological blockade of glutamate transmission might be expected to restore the cascade of neurochemical changes induced by a dopaminergic denervation within the basal ganglia. To test this hypothesis, two types of glutamate antagonists, the NMDA receptor antagonist MK-801 and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist LY293558, were administered systemically, either alone or in combination with L-DOPA, in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway. The effect of treatment was assessed neurochemically by analyzing at the cellular level the functional activity of basal ganglia output structures and the subthalamic nucleus using the expression levels of the mRNAs coding for glutamic acid decarboxylase and cytochrome oxidase, respectively, as molecular markers of neuronal activity. The present study shows that treatment with glutamate antagonists, and particularly with AMPA antagonists, alone or in combination with L-DOPA, reverses the overactivity of the subthalamic nucleus and its target areas induced by nigrostriatal denervation. These results furnish the neurochemical basis for the potential use of glutamate antagonists as therapeutic agents in Parkinson's disease.
Vila
M
M
INSERM U. 289, Hôpital de la Salpêtrière, Paris, France.
Marin
C
C
Ruberg
M
M
Jimenez
A
A
Raisman-Vozari
R
R
Agid
Y
Y
Tolosa
E
E
Hirsch
E C
EC
D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D003714:Denervation; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000235:genetics; D007546:Isoquinolines / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology*; D016627:Oxidopamine / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D012333:RNA, Messenger; D018091:Receptors, AMPA; D013777:Tetrazoles; D007980:Levodopa; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C082309:tezampanel; D016627:Oxidopamine; D003576:Electron Transport Complex IV; D005968:Glutamate Decarboxylase; D004298:Dopamine