D1-receptor-related priming is attenuated by antisense-meditated 'knockdown' of fosB expression

S. J. Crocker, M. Morelli, N. Wigle, Yusaku Nakabeppu, G. S. Robertson

Research output: Contribution to journalArticle

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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 elicit more vigorous circling. The molecular basis for this behavioural phenomenon, termed priming, is unknown. D1-receptor-related priming has been associated with a profound elevation of immediate-early gene (IEG) expression in the denervated striatum. Since immediate-early genes encode known transcriptional regulating factors, this observation has led to the suggestion that IEG induction may play a role in the gene signaling pathways which mediate priming. In the present study, we addressed the role of induction of the IEG fosB in dopamine agonist-induced priming by examining whether inhibition of the synthesis of FosB proteins (FosB and ΔFosB) by intrastriatal delivery of an antisense oligonucleotide to fosB reduced apomorphine-induced priming. Intrastriatal delivery of an antisense, but not a random, oligonucleotide to fosB 18 and 6 h before apomorphine reduced the ability of this mixed D1/D2-like receptor agonist to prime circling induced by the specific D1-like receptor agonist SKF38393. Immunohistochemical analysis revealed 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 Fos2-16-like immunoreactivities were unaffected by either the antisense or random oligonucleotides, indicating that the antisense oligonucleotide attenuated apomorphine-induced priming by selectively blocking the synthesis of FosB proteins. Taken together, these findings suggest that fosB induction in the denervated striatum plays a role in mediating D1-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 D1-receptor-mediated increases in fosB expression may be involved in those intracellular events responsible for the generation of these debilitating side effects.

Original languageEnglish
Pages (from-to)69-77
Number of pages9
JournalMolecular Brain Research
Volume53
Issue number1-2
DOIs
Publication statusPublished - Jan 1 1998

Fingerprint

Apomorphine
Immediate-Early Genes
Antisense Oligonucleotides
Dopamine Agonists
Oligonucleotides
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
Oxidopamine
Parkinson Disease
Dopamine
Proteins
Gene Expression
Injections
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

D1-receptor-related priming is attenuated by antisense-meditated 'knockdown' of fosB expression. / Crocker, S. J.; Morelli, M.; Wigle, N.; Nakabeppu, Yusaku; Robertson, G. S.

In: Molecular Brain Research, Vol. 53, No. 1-2, 01.01.1998, p. 69-77.

Research output: Contribution to journalArticle

Crocker, S. J. ; Morelli, M. ; Wigle, N. ; Nakabeppu, Yusaku ; Robertson, G. S. / D1-receptor-related priming is attenuated by antisense-meditated 'knockdown' of fosB expression. In: Molecular Brain Research. 1998 ; Vol. 53, No. 1-2. pp. 69-77.
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