D-1-RECEPTOR-RELATED PRIMING IS ATTENUATED BY ANTISENSE-MEDITATED KNOCKDOWN OF FOSB EXPRESSION

Citation
Sj. Crocker et al., D-1-RECEPTOR-RELATED PRIMING IS ATTENUATED BY ANTISENSE-MEDITATED KNOCKDOWN OF FOSB EXPRESSION, Molecular brain research, 53(1-2), 1998, pp. 69-77
Citations number
34
Categorie Soggetti
Neurosciences
Journal title
ISSN journal
0169328X
Volume
53
Issue
1-2
Year of publication
1998
Pages
69 - 77
Database
ISI
SICI code
0169-328X(1998)53:1-2<69:DPIABA>2.0.ZU;2-G
Abstract
Administration of dopamine receptor agonists to rats with unilateral 6 -hydroxydopamine lesions of the nigrostriatal pathway produce changes in the denervated striatum that enable a subsequent injection to elici t more vigorous circling. The molecular basis for this behavioural phe nomenon, termed priming, is unknown. D-1-receptor-related priming has been associated with a profound elevation of immediate-early gene (IEG ) expression in the denervated striatum. Since immediate-early genes e ncode known transcriptional regulating factors, this observation has l ed to the suggestion that IEG induction may play a role in the gene si gnaling pathways which mediate priming. In the present study, we addre ssed the role of induction of the IEG fosB in dopamine agonist-induced priming by examining whether inhibition of the synthesis of FosB prot eins (FosB and Delta FosB) by intrastriatal delivery of an antisense o ligonucleotide to fosB reduced apomorphine-induced priming. Intrastria tal delivery of an antisense, but not a random, oligonucleotide to fos B 18 and 6 h before apomorphine reduced the ability of this mixed D-1/ D-2-like receptor agonist to prime circling induced by the specific D- 1-like receptor agonist SKF38393. Immunohistochemical analysis reveale d that only the antisense oligonucleotide blocked apomorphine-induced increases in FosB-like immunoreactivity in the denervated striatum. In contrast, apomorphine-induced increases in JunB-, NGFI-A- and Fos(2-1 6)-like immunoreactivities were unaffected by either the antisense or random oligonucleotides, indicating that the antisense oligonucleotide attenuated apomorphine-induced priming by selectively blocking the sy nthesis of FosB proteins. Taken together, these findings suggest that fosB induction in the denervated striatum plays a role in mediating D- 1-receptor-related priming. Dopamine replacement therapy for Parkinson 's disease is often complicated by the development of dyskinetic side effects. Results from the present study suggest that D-1-receptor-medi ated increases in fosB expression may be involved in those intracellul ar events responsible for the generation of these debilitating side ef fects. (C) 1998 Elsevier Science B.V.