Denervation and repeated l-DOPA induce a coordinate expression of the transcription factor NGFI-B in striatal projection pathways in hemi-parkinsonian rats

Abstract

Repeated intermittent administration of l-DOPA in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway results in a progressive increase of contraversive circling behavior. In this study, we have investigated the effects of denervation and repeated l-DOPA administration on the expression of the nuclear receptor nerve growth factor inducible-B (NGFI-B) in striatal output pathways of unilaterally 6-OHDA-lesioned rats. The denervation process induced an increase of NGFI-B and enkephalin (ENK) mRNA levels and the increase of NGFI-B took place predominantly in ENK-containing cells. The percentage of cells colocalizing NGFI-B and dynorphin (DYN) was significantly reduced. Repeated l-DOPA treatment increased the striatal level of DYN mRNA but it further reduced the percentage of NGFI-B/DYN double-labeled cells. On the intact side, repeated l-DOPA treatment increased NGFI-B expression in both striatal subpopulations. Additional acute studies were performed in normal rats to determine the role of the denervation process in the coordinate expression of NGFI-B in striatal subpopulations. A combination of selective D1 and D2 agonists induced an important increase of striatal NGFI-B expression selectively in DYN-containing neurons. These results demonstrate that the denervation process causes a differential regulation of NGFI-B in the two striatal output pathways which is further exacerbated by l-DOPA treatment. These molecular changes in response to dopamine depletion and dopamine replacement therapy may contribute to the long-term effects of l-DOPA and to the development of behavioral sensitization.

Keywords

• Parkinson’s disease
• Transcription factor
• Nuclear receptor
• Direct pathway
• Indirect pathway
• Enkephalin