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Impact of the lesion procedure on the profiles of motor impairment and molecular responsiveness to L-DOPA in the 6-hydroxydopamine mouse model of Parkinson's disease.

Francardo, Veronica LU ; Recchia, Alessandra; Popovic, Nataljia; Andersson, Daniel; Nissbrandt, Hans and Cenci Nilsson, Angela LU (2011) In Neurobiology of Disease 42. p.327-340
Abstract
6-Hydroxydopamine (6-OHDA) lesions are being used in the mouse for basic research on Parkinson's disease and L-DOPA-induced dyskinesia. We set out to compare unilateral lesion models produced by intrastriatal or intramesencephalic injections of a fixed 6-OHDA concentration (3.2μg/μl) in C57BL/6 mice. In the first experiment, toxin injections were performed either at two striatal coordinates (1 or 2μl per site, termed "striatum(2×1μl)" and "striatum(2×2μl)" models), in the medial forebrain bundle (MFB), or in the substantia nigra pars compacta (SN) (1μl per site). All the four lesion models produced significant forelimb use asymmetry, but spontaneous turning asymmetry only occurred in the MFB and striatum(2×2μl) models. After the behavioral... (More)
6-Hydroxydopamine (6-OHDA) lesions are being used in the mouse for basic research on Parkinson's disease and L-DOPA-induced dyskinesia. We set out to compare unilateral lesion models produced by intrastriatal or intramesencephalic injections of a fixed 6-OHDA concentration (3.2μg/μl) in C57BL/6 mice. In the first experiment, toxin injections were performed either at two striatal coordinates (1 or 2μl per site, termed "striatum(2×1μl)" and "striatum(2×2μl)" models), in the medial forebrain bundle (MFB), or in the substantia nigra pars compacta (SN) (1μl per site). All the four lesion models produced significant forelimb use asymmetry, but spontaneous turning asymmetry only occurred in the MFB and striatum(2×2μl) models. After the behavioral studies, the induction of phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) by acute L-DOPA (30mg/kg) was used as a marker of post-synaptic supersensitivity. Striatal pERK1/2 expression was sparse in the SN and striatum(2×1μl) groups, but pronounced in the striatum(2×2μl) and MFB-lesioned mice. In further experiments, mice with MFB and striatal(2×2μl) lesions were used to compare behavioral and molecular responses to chronic L-DOPA treatment (12days at 3 and 6mg/kg/day). Maximally severe abnormal involuntary movements (AIMs) occurred in all MFB-lesioned mice, whereas only 35% of the mice with striatal lesions developed dyskinesia. Striatal tissue levels of dopamine were significantly lower in the dyskinetic animals (both MFB and striatum(2×2μl) groups) in comparison with the non-dyskinetic ones. Noradrenaline levels were significantly reduced only in MFB lesioned animals and did not differ among the dyskinetic and non-dyskinetic cases with striatal lesions. In all groups, the L-DOPA-induced AIM scores correlated closely with the number of cells immunoreactive for tyrosine hydroxylase or FosB/∆FosB in the striatum. In conclusion, among the four lesion procedures examined here, only the MFB and striatum(2×2μl) models yielded a degree of dopamine denervation sufficient to produce spontaneous postural asymmetry and molecular supersensitivity to L-DOPA. Both lesion models are suitable to reproduce L-DOPA-induced dyskinesia, although only MFB lesions yield a pronounced and widespread expression of post-synaptic supersensitivity markers in the striatum. (Less)
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Contribution to journal
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published
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Neurobiology of Disease
volume
42
pages
327 - 340
publisher
Elsevier
external identifiers
  • wos:000290081700013
  • pmid:21310234
  • scopus:79954630030
ISSN
0969-9961
DOI
10.1016/j.nbd.2011.01.024
language
English
LU publication?
yes
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f3967052-71fe-461a-8283-b17d6280d51f (old id 1831976)
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http://www.ncbi.nlm.nih.gov/pubmed/21310234?dopt=Abstract
date added to LUP
2011-03-01 14:26:15
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2017-08-20 03:10:58
@article{f3967052-71fe-461a-8283-b17d6280d51f,
  abstract     = {6-Hydroxydopamine (6-OHDA) lesions are being used in the mouse for basic research on Parkinson's disease and L-DOPA-induced dyskinesia. We set out to compare unilateral lesion models produced by intrastriatal or intramesencephalic injections of a fixed 6-OHDA concentration (3.2μg/μl) in C57BL/6 mice. In the first experiment, toxin injections were performed either at two striatal coordinates (1 or 2μl per site, termed "striatum(2×1μl)" and "striatum(2×2μl)" models), in the medial forebrain bundle (MFB), or in the substantia nigra pars compacta (SN) (1μl per site). All the four lesion models produced significant forelimb use asymmetry, but spontaneous turning asymmetry only occurred in the MFB and striatum(2×2μl) models. After the behavioral studies, the induction of phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) by acute L-DOPA (30mg/kg) was used as a marker of post-synaptic supersensitivity. Striatal pERK1/2 expression was sparse in the SN and striatum(2×1μl) groups, but pronounced in the striatum(2×2μl) and MFB-lesioned mice. In further experiments, mice with MFB and striatal(2×2μl) lesions were used to compare behavioral and molecular responses to chronic L-DOPA treatment (12days at 3 and 6mg/kg/day). Maximally severe abnormal involuntary movements (AIMs) occurred in all MFB-lesioned mice, whereas only 35% of the mice with striatal lesions developed dyskinesia. Striatal tissue levels of dopamine were significantly lower in the dyskinetic animals (both MFB and striatum(2×2μl) groups) in comparison with the non-dyskinetic ones. Noradrenaline levels were significantly reduced only in MFB lesioned animals and did not differ among the dyskinetic and non-dyskinetic cases with striatal lesions. In all groups, the L-DOPA-induced AIM scores correlated closely with the number of cells immunoreactive for tyrosine hydroxylase or FosB/∆FosB in the striatum. In conclusion, among the four lesion procedures examined here, only the MFB and striatum(2×2μl) models yielded a degree of dopamine denervation sufficient to produce spontaneous postural asymmetry and molecular supersensitivity to L-DOPA. Both lesion models are suitable to reproduce L-DOPA-induced dyskinesia, although only MFB lesions yield a pronounced and widespread expression of post-synaptic supersensitivity markers in the striatum.},
  author       = {Francardo, Veronica and Recchia, Alessandra and Popovic, Nataljia and Andersson, Daniel and Nissbrandt, Hans and Cenci Nilsson, Angela},
  issn         = {0969-9961},
  language     = {eng},
  pages        = {327--340},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {Impact of the lesion procedure on the profiles of motor impairment and molecular responsiveness to L-DOPA in the 6-hydroxydopamine mouse model of Parkinson's disease.},
  url          = {http://dx.doi.org/10.1016/j.nbd.2011.01.024},
  volume       = {42},
  year         = {2011},
}