AMPA receptor antagonist LY293558 reverses preproenkephalin mRNA overexpression in the striatum of 6-OHDA-lesioned-rats treated with l-dopa.

Abstract 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. [ABSTRACT FROM AUTHOR]