Changes in the regional and compartmental distribution of FosB- and JunB-like immunoreactivity induced in the dopamine-denervated rat striatum by acute or chronic L-DOPA treatment

doi:10.1016/S0306-4522(99)00294-8

Neuroscience

Volume 94, Issue 2, September 1999, Pages 515-527

https://doi.org/10.1016/S0306-4522(99)00294-8 Get rights and content

Abstract

This study was carried out in order to examine the effects of acute or chronic L-DOPA treatment on striatally expressed FosB- and JunB-like proteins in a rat model of Parkinson's disease. Rats with a unilateral, near-total 6-hydroxydopamine lesion of the ascending mesostriatal projection received either an acute challenge or a one-week treatment with 10 mg/kg/day methyl L-DOPA (combined with 15 mg/mg benserazide), and were killed at either 3 h or two days post-injection. Both acute and chronic L-DOPA treatment caused a pronounced, persistent increase in the number of FosB-like immunoreactive cells in the dopamine-denervated striata (five- and seven-fold increase, respectively, above the levels found in lesioned but non-drug-treated controls), but the two treatment groups differed markedly with respect to both the average amount of staining per cell, which was two-fold larger in the chronic L-DOPA cases, and the anatomical distribution of the labeled cells. After an acute injection of L-DOPA, FosB-positive cells were distributed rather uniformly across all striatal subregions, whereas chronic L-DOPA treatment induced discrete clusters of strongly FosB-like immunoreactive cells within medial and central striatal subregions, as well as in a large, yet sharply defined portion of the lateral caudate–putamen. Strongly labeled cell clusters that appeared in the medial and central caudate–putamen were preferentially located within calbindin-poor, μ-opioid receptor-rich striosomes, whereas the lateral area displaying FosB activation encompassed both striosomal and matrix domains. In both the medial and the lateral striatum a near-total overlap was found between strongly FosB-like immunoreactive cell groups and areas showing pronounced dynorphin expression. NADPH-diaphorase-positive striatal interneurons did not express FosB-like immunoreactivity after a 6-hydroxydopamine lesion alone, a negligible proportion of them did after an acute L-DOPA challenge, but about 8% of these interneurons were FosB positive following chronic L-DOPA treament. Like FosB, JunB was induced in the DA-denervated striatum by both acute and chronic L-DOPA treatment, and exhibited similar distribution patterns. However, JunB did not exhibit prolonged expression kinetics, and was somewhat down-regulated in the chronically compared with the acutely L-DOPA-treated rats.

The present results show that L-DOPA administration produces a long-lasting increase in the levels of FosB-, but not JunB-like immunoreactivity in the dopamine-denervated striatum. More importantly, these data show that striatal induction of FosB- and JunB-like proteins by chronic L-DOPA treatment exhibits both regional and compartmental specificity.

Section snippets

Subjects

Female Sprague–Dawley rats (BK Universal, Stockholm, Sweden; 200–225 g body weight at the beginning of the experiments) were housed under a 12 h light/dark cycle with free access to food and water. All rats included in the present study sustained unilateral injections of 6-OHDA in the ascending DA fibre bundle six to eight weeks prior to initiation of the L-DOPA (or saline) treatment. The experimental procedures used were in accordance with the rules laid down by the Swedish authorities. All

Effects of 6-hydroxydopamine lesions, acute or chronic L-DOPA treatment on striatal FosB-like immunoreactivity

On the side of the striatum contralateral to the 6-OHDA lesion, FosB-like-immunoreactive cells were sparse, and confined to the NAc and medial portion of the CPu (Fig. 1A). L-DOPA administration did not have any effect on either the pattern or the overall levels of FosB-like immunoreactivity in the intact striatum. Therefore, only the side of the striatum ipsilateral to the 6-OHDA lesion was considered for quantitative analyses and statistical comparisons. The 6-OHDA lesion alone produced an

Discussion

In the present study we have compared the patterns of FosB-JunB expression produced in the DA-denervated striatum by acute or chronic L-DOPA treatment, and performed a thorough quantitative analysis of striatal FosB-like immunoreactivity. Both acute and chronic treatment with L-DOPA caused a pronounced, persistent increase in the number of FosB-like positive cells (five- and seven-fold increase, respectively, above the levels found in 6-OHDA-lesioned, non-drug-treated controls), but the two

Conclusions

Working on a rat model of Parkinson's disease, we have shown that both DA denervation and DA replacement by L-DOPA induce the expression of JunB and FosB-related proteins in striatal neurons, but that the regional and compartmental distribution of these proteins is markedly different under each condition. Since distinct functions have been associated with different striatal subregions and compartments, these data suggest that striatal FosB-JunB expression has different functional implications

Acknowledgments

We warmly thank Mehrdad Shamloo, Elisabetta Vaudano, Luciano Conti and Massimo DeFraja, for helpful discussion and support concerning the Western blot technique, and Deniz Kirik for his support concerning computer-guided stereology. The excellent technical assistance of Gertrude Stridsberg, Ulla Jarl and Alicja Flash is gratefully acknowledged. This work was supported by grants from the Tore Nilson's Foundation for Medical Research, Åke Wiberg's Foundation, Greta and Johan Kock's Foundations,

References (52)

D.M. Bronstein et al.
Role of a 35 kDa fos-related antigen (FRA) in the long-term induction of striatal dynorphin expression in the 6-hydroxydopamine lesioned rat
Molec. Brain Res.
(1994)
R.J. Carey
Chronic L-DOPA treatment in the unilateral 6-OHDA rat: evidence for behavioral sensitization and biochemical tolerance
Brain Res.
(1991)
D.G. Cole et al.
Levodopa induction of Fos immunoreactivity in rat brain following partial and complete lesions of the substantia nigra
Expl Neurol.
(1993)
J.P. Donoghue et al.
Neostriatal projections from individual cortical fields conform to histochemically distinct striatal compartments in the rat
Brain Res.
(1986)
C.R. Gerfen
The neostriatal mosaic: multiple levels of compartmental organization
Trends Neurosci.
(1992)
A.M. Graybiel
Building action repertoires: memory and learning functions of the basal ganglia
Curr. Opin. Neurobiol.
(1995)
Y. Kawaguchi et al.
Striatal interneurons: chemical, physiological and morphological characterization
Trends Neurosci.
(1995)
A.J. McGeorge et al.
The organization of the projection from the cerebral cortex to the striatum in the rat
Neuroscience
(1989)
R. Moratalla et al.
Network-level changes in the expression of inducible Fos-Jun proteins in the striatum during chronic cocaine treatment and withdrawal
Neuron
(1996)
Y. Nakabeppu et al.
A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity
Cell
(1991)

K.R. Pennypacker et al.

Apomorphine induction of AP-1 DNA binding in the rat striatum after dopamine depletion

Molec. Brain Res.

(1992)

I. Pérez-Otaño et al.

MPTP-Parkinsonism is accompanied by persistent expression of D-FosB-like proteins in dopaminergic pathways

Molec. Brain Res.

(1998)

H.A. Robertson et al.

D-1-dopamine receptor agonists selectively activate striatal c-fos independent of rotational behavior

Brain Res.

(1989)

U. Ungerstedt et al.

Quantitative recording of rotational behavior in rats after 6-hydroxydopamine lesions of the nigrostriatal system

Brain Res.

(1970)

D. Vallone et al.

Behavioral sensitization in 6-hydroxydopamine-lesioned rats is related to compositional changes of the AP-1 transcription factor: evidence for the induction of FosB- and JunD-related proteins

Molec. Brain Res.

(1997)

S.R. Vincent et al.

Histochemical mapping of nitric oxide synthase in the rat brain

Neuroscience

(1992)

Andersson M., Hibertson A. and Cenci M. A. (1999) Striatal fosB expression is causally linked with L-DOPA-induced...

S. Berretta et al.

Dopamine and glutamate agonists stimulate neuron-specific expression of Fos-like proteins in the striatum

J. Neurophysiol.

(1992)

Björklund A. and Lindvall O. (1986) Catecholaminergic brain stem regulatory systems. In Handbook of Physiology, Section...

S.J. Boyson et al.

Quantitative autoradiographic localization of the D1 and D2 subtypes of dopamine receptors in rat brain

J. Neurosci.

(1986)

Brotchie J. M., Henry B., Hille C. J. and Crossman A. R. (1998) Opioid peptide precursor expression in animal models of...

M.A. Cenci et al.

Transection of corticostriatal afferents reduces amphetamine- and apomorphine-induced striatal Fos expression and turning behavior in unilaterally 6-hydroxydopamine-lesioned rats

Eur. J. Neurosci.

(1993)

M.A. Cenci et al.

L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA

Eur. J. Neurosci.

(1998)

M.A. Cenci-Nilsson et al.

L-DOPA-induced expression of FosB-related proteins in the dopamine-denervated rat striatum: compartmental and cellular phenotypes, correlations with dyskinesia

Soc. Neurosci. Abstr.

(1998)

J. Chen et al.

Chronic Fos-related antigens: stable variants of DFosB induced in brain by chronic treatments

J. Neurosci.

(1997)

J. Chen et al.

Regulation of ΔFosB and FosB-like proteins by electroconvulsive seizure and cocaine treatments

Molec. Pharmac.

(1995)

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Changes in the regional and compartmental distribution of FosB- and JunB-like immunoreactivity induced in the dopamine-denervated rat striatum by acute or chronic L-DOPA treatment

Abstract

Section snippets

Subjects

Effects of 6-hydroxydopamine lesions, acute or chronic L-DOPA treatment on striatal FosB-like immunoreactivity

Discussion

Conclusions

Acknowledgments

Molec. Brain Res.

Brain Res.

Expl Neurol.

Brain Res.

Trends Neurosci.

Curr. Opin. Neurobiol.

Trends Neurosci.

Neuroscience

Neuron

Cell

Molec. Brain Res.

Molec. Brain Res.

Brain Res.

Brain Res.

Molec. Brain Res.

Neuroscience

Dopamine and glutamate agonists stimulate neuron-specific expression of Fos-like proteins in the striatum

J. Neurophysiol.

Quantitative autoradiographic localization of the D1 and D2 subtypes of dopamine receptors in rat brain

J. Neurosci.

Transection of corticostriatal afferents reduces amphetamine- and apomorphine-induced striatal Fos expression and turning behavior in unilaterally 6-hydroxydopamine-lesioned rats

Eur. J. Neurosci.

L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA

Eur. J. Neurosci.

L-DOPA-induced expression of FosB-related proteins in the dopamine-denervated rat striatum: compartmental and cellular phenotypes, correlations with dyskinesia

Soc. Neurosci. Abstr.

Chronic Fos-related antigens: stable variants of DFosB induced in brain by chronic treatments

J. Neurosci.

Regulation of ΔFosB and FosB-like proteins by electroconvulsive seizure and cocaine treatments

Molec. Pharmac.