Denervation and repeated L-DOPA induce a coordinate expression of the transcription factor NGFI-B in striatal projection pathways in hemi-parkinsonian rats.
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 D(1) and D(2) 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.
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D003714:Denervation / Q000379:methods; D004745:Enkephalins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007980:Levodopa / Q000008:administration & dosage*; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D004268:DNA-Binding Proteins; D004745:Enkephalins; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D007980:Levodopa