Changes in the prodynorphin gene and DARPP-32 state in 6-OHDA-lesioned rats following long-term treatment with l-dopa.
Recent evidence revealed a crucial role of direct striatal pathway pathophysiological over-activation in the pathogenesis of l-dopa-induced dyskinesias (LID). In order to explore the potential mechanism(s) involved in the over-activation of direct striatal pathways, this study was designed to examine changes in prodynorphin (PDyn) gene expression as well as phosphorylation of dopamine and 32 kDa cAMP-regulated phosphoprotein (DARPP-32) in rats with LID using in situ hybridization and immunoblotting. Our data demonstrated significantly increased levels of PDyn mRNA and phospho-Thr-34 DARPP-32 and significantly decreased phospho-Thr-75 DARPP-32 in LID rats compared with control and l-dopa treated groups. Following treatment of the non-competitive NMDA receptor antagonist dizocilpine (MK-801), the LID-induced changes in PDyn mRNA, phospho-Thr-34 DARPP-32 and phospho-Thr-75 DARPP-32 were largely reversed. Collectively, these findings suggested that changes of the DARPP-32 phosphorylation state may be important for over-activation of the direct pathway.
Guan
Qiang
Q
Department of Neurology, Tongji Hospital, Tongji University, Shanghai 200065, China. guanqianglu@126.com
Zhan
Qing
Q
He
Yusheng
Y
Tan
Laixun
L
D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects* / Q000235:genetics; D004298:Dopamine / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics*; D004334:Drug Administration Schedule; D004409:Dyskinesia, Drug-Induced / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004745:Enkephalins / Q000235:genetics*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009498:Neurotoxins; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013912:Threonine / Q000378:metabolism; D013995:Time
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004745:Enkephalins; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; C497930:Ppp1r1b protein, rat; D011498:Protein Precursors; D012333:RNA, Messenger; D013912:Threonine; D007980:Levodopa; D016627:Oxidopamine; C033660:preproenkephalin; D004298:Dopamine