AMPA receptor antagonist LY293558 reverses preproenkephalin mRNA overexpression in the striatum of 6-OHDA-lesioned-rats treated with L-dopa.
Striatal neurons that contain GABA and enkephalin and project to the external segment of the pallidum are thought to be overactive in Parkinson's disease. Furthermore, it has been shown that the appearance of L-dopa-induced dyskinesias is correlated to an increase of preproenkephalin (PPE) mRNA expression and that some antagonists of glutamate receptors can prevent and reverse L-dopa-induced dyskinesias in parkinsonian rats. The aim of this study was therefore to analyse the effect of a systemic treatment with glutamate receptor antagonists, alone or in combination with L-dopa, on the PPE mRNA level in rats with a 6-hydroxydopamine-induced unilateral lesion of the nigrostriatal pathway. In vehicle-treated animals, PPE mRNA levels were markedly increased in the striatum on the lesioned side. Sub-chronic L-dopa treatment, with bi-daily injections for 22 days, induced a further increase in PPE mRNA expression in the denervated striatum. Administration of the AMPA receptor antagonist, LY293558, partially reversed the lesion-induced and L-dopa-induced increases in PPE mRNA expression. However, although the administration of the NMDA receptor antagonist MK801 showed a tendency to decrease this L-dopa induced overexpression, it did not reach significance. This study provides evidence that glutamatergic antagonists, and particularly AMPA antagonists, tend to reverse PPE neurochemical changes at the striatal level induced by L-dopa in hemiparkinsonian rats.
Périer
Céline
C
INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 47 Boulevard de l'Hôpital, 75013 Paris, France.
Marin
Concepció
C
Bonastre
Mercè
M
Tolosa
Eduardo
E
Hirsch
Etienne C
EC
D000818:Animals; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D004745:Enkephalins / Q000235:genetics*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology*; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009419:Nerve Tissue Proteins; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*
D050483:Dopamine Plasma Membrane Transport Proteins; D004745:Enkephalins; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013777:Tetrazoles; D007980:Levodopa; D016291:Dizocilpine Maleate; C082309:tezampanel; D016627:Oxidopamine; C033660:preproenkephalin; D004298:Dopamine