Denervation and repeated l-DOPA induce complex regulatory changes in neurochemical phenotypes of striatal neurons: Implication of a dopamine D1-dependent mechanism

Abstract

Motor complications induced through repeated L-DOPA treatment in patients with Parkinson's disease are thought to be the consequence of molecular adaptations that occur in response to repeated dopamine receptors stimulation. Here, we studied the molecular changes taking place in the denervated striatum of unilaterally 6-OHDA-lesioned rats repeatedly treated with L-DOPA alone or combined to the D1 receptor antagonist SCH23390. We looked at the territorial patterns of expression of neurotensin (NT), dynorphin (DYN), enkephalin (ENK) and Nur77 (also known as NGFI-B) mRNA expression in the striatum and contrasted these with markers of glutamatergic transport and dopaminergic receptor functions. The denervation process induced NT and Nur77 mRNA expression in ENK-positive cells. Subsequent repeated L-DOPA treatment led to a sensitization of L-DOPA-induced rotational response and produced a second surge of NT induction, this time limited to DYN-positive cells and preferentially restricted to the lateral striatum. In this specific territory, the number of Nur77-positive cells was decreased, in response to L-DOPA, when compared to the medial part of the lesioned striatum. L-DOPA treatment increased dopamine D3 receptor and glutamate transporter 1 (GLT1) mRNA expression in the lesioned striatum and that, specifically in an area overlapping one of Nur77 decrease and of NT/DYN induction. The concomitant administration of SCH23390 with repeated L-DOPA treatment blocked the development of behavioral sensitization and the appearance of all L-DOPA-induced molecular reorganizations reported above. Our results showed that repeated L-DOPA treatment produces, in a denervated striatum, a complex pattern of genes regulation in both the direct and the indirect striatal output pathways. This phenomenon is located preferentially in a striatal area receiving converging inputs from the thalamus and sensorimotor cortex and is dependent upon D1 receptor stimulation.