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
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.