title: Chronic alterations in dopaminergic neurotransmission produce a persistent elevation of deltaFosB-like protein(s) in both the rodent and primate striatum.
abstract: Using an antibody that recognizes the products of all known members of the fos family of immediate early genes, it was demonstrated that destruction of the nigrostriatal pathway by 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle produces a prolonged (>3 months) elevation of Fos-like immunoreactivity in the striatum. Using retrograde tract tracing techniques, we have previously shown that this increase in Fos-like immunoreactivity is located predominantly in striatal neurons that project to the globus pallidus. In the present study, Western blots were performed on nuclear extracts from the intact and denervated striatum of 6-OHDA-lesioned rats to determine the nature of Fos-immunoreactive protein(s) responsible for this increase. Approximately 6 weeks after the 6-OHDA lesion, expression of two Fos-related antigens with apparent molecular masses of 43 and 45 kDa was enhanced in the denervated striatum. Chronic haloperidol administration also selectively elevated expression of these Fos-related antigens, suggesting that their induction after dopaminergic denervation is mediated by reduced activation of D2-like dopamine receptors. Western blot immunostaining using an antibody which recognizes the N-terminus of FosB indicated that the 43 and 45 kDa Fos-related antigens induced by dopaminergic denervation and chronic haloperidol administration may be related to a truncated form of FosB known as deltaFosB. Consistent with this proposal, retrograde tracing experiments confirmed that deltaFosB-like immunoreactivity in the deafferented striatum was located predominantly in striatopallidal neurons. Gel shift experiments demonstrated that elevated AP-1 binding activity in denervated striata contained FosB-like protein(s), suggesting that enhanced deltaFosB levels may mediate some of the effects of prolonged dopamine depletion on AP-1-regulated genes in striatopallidal neurons. In contrast, chronic administration of the D1-like receptor agonist CY 208243 to 6-OHDA-lesioned rats dramatically enhanced deltaFosB-like immunoreactivity in striatal neurons projecting to the substantia nigra. Western blot immunostaining revealed that deltaFosB and, to a lesser extent, FosB are elevated by chronic D1-like agonist administration. Both the quantitative reverse transcriptase-polymerase chain reaction and the ribonuclease protection assay demonstrated that deltafosB mRNA levels were substantially enhanced in the denervated striatum by chronic D1-like agonist administration. Lastly, we examined the effects of chronic administration ofD1-like and D2-like dopamine receptor agonists on striatal deltaFosB expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson's disease. In monkeys rendered Parkinsonian by MPTP, there was a modest increase in deltaFosB-like protein(s), while the development of dyskinesia produced by chronic D1-like agonist administration was accompanied by large increases in DeltaFosB-like protein(s). In contrast, administration of the long-acting D2-like agonist cabergoline, which alleviated Parkinsonian symptoms without producing dyskinesia reduced deltaFosB levels to near normal. Taken together, these results demonstrate that chronic alterations in dopaminergic neurotransmission produce a persistent elevation of deltaFosB-like protein(s) in both the rodent and primate striatum.
authors.affiliation: Department of Pharmacology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: J P
authors.initials: JP
authors.lastname: Doucet
authors.forename: Y
authors.initials: Y
authors.lastname: Nakabeppu
authors.forename: P J
authors.initials: PJ
authors.lastname: Bedard
authors.forename: B T
authors.initials: BT
authors.lastname: Hope
authors.forename: E J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: B J
authors.initials: BJ
authors.lastname: Jasmin
authors.forename: J S
authors.initials: JS
authors.lastname: Chen
authors.forename: M J
authors.initials: MJ
authors.lastname: Iadarola
authors.forename: M
authors.initials: M
authors.lastname: St-Jean
authors.forename: N
authors.initials: N
authors.lastname: Wigle
authors.forename: P
authors.initials: P
authors.lastname: Blanchet
authors.forename: R
authors.initials: R
authors.lastname: Grondin
authors.forename: G S
authors.initials: GS
authors.lastname: Robertson
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000096:biosynthesis* / Q000235:genetics; D001483:Base Sequence; D001552:Benzazepines / Q000494:pharmacology; D015153:Blotting, Western; D000077465:Cabergoline; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003714:Denervation; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000633:toxicity*; D065127:Dopamine D2 Receptor Antagonists; D004873:Ergolines / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D016762:Genes, fos; D006220:Haloperidol / Q000633:toxicity; D007211:Indoles / Q000494:pharmacology; D020267:MPTP Poisoning; D008252:Macaca fascicularis; D008297:Male; D008970:Molecular Weight; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D016627:Oxidopamine / Q000633:toxicity*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism; D010617:Phenanthridines / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000819:agonists; D013045:Species Specificity; D013997:Time Factors; D014157:Transcription Factors
chemical_list: D001426:Bacterial Proteins; D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D004873:Ergolines; C483820:Fosb protein, rat; D007211:Indoles; D009419:Nerve Tissue Proteins; D010617:Phenanthridines; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D014157:Transcription Factors; C054531:CY 208-243; C071262:SK&F 82958; D016627:Oxidopamine; D006220:Haloperidol; D000077465:Cabergoline