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In vivo evidence for a differential contribution of striatal and nigral D1 and D2 receptors to l-DOPA induced dyskinesia and the accompanying surge of nigral amino acid levels

Mela, Flora; Marti, Matteo; Bido, Simone; Cenci Nilsson, Angela LU and Morari, Michele (2012) In Neurobiology of Disease 45(1). p.573-582
Abstract
Evidence for an involvement of striatal D1 receptors in levodopa-induced dyskinesia has been presented whereas the contribution of striatal D2 receptors remains controversial. In addition, whether D1 and D2 receptors located in the substantia nigra reticulata shape the response to levodopa remains unknown. We therefore used dual probe microdialysis to unravel the impact of striatal and nigral D1 or 02 receptor blockade on abnormal involuntary movements (AIMS) and striatal output pathways in unilaterally 6-hydroxydopamine lesioned dyskinetic rats. Regional perfusion of D1/D5 (SCH23390) and D2/D3 (raclopride) receptor antagonists was combined with systemic administration of levodopa. Levodopa-induced AIMS coincided with a prolonged surge of... (More)
Evidence for an involvement of striatal D1 receptors in levodopa-induced dyskinesia has been presented whereas the contribution of striatal D2 receptors remains controversial. In addition, whether D1 and D2 receptors located in the substantia nigra reticulata shape the response to levodopa remains unknown. We therefore used dual probe microdialysis to unravel the impact of striatal and nigral D1 or 02 receptor blockade on abnormal involuntary movements (AIMS) and striatal output pathways in unilaterally 6-hydroxydopamine lesioned dyskinetic rats. Regional perfusion of D1/D5 (SCH23390) and D2/D3 (raclopride) receptor antagonists was combined with systemic administration of levodopa. Levodopa-induced AIMS coincided with a prolonged surge of GABA and glutamate levels in the substantia nigra reticulata. Intrastriatal SCH23390 attenuated the levodopa-induced AIM scores (similar to 50%) and prevented the accompanying neurochemical response whereas raclopride was ineffective. When perfused in the substantia nigra, both antagonists attenuated AIM expression (similar to 21-40%). However, only intranigral SCH23390 attenuated levodopa-induced nigral GABA efflux, whereas raclopride reduced basal GABA levels without affecting the response to levodopa. In addition, intranigral raclopride elevated amino acid release in the striatum and revealed a (mild) facilitatory effect of levodopa on striatal glutamate. We conclude that both striatal and nigral D1 receptors play an important role in dyskinesia possibly via modulation of the striato-nigral direct pathway. In addition, the stimulation of nigral D2 receptors contributes to dyskinesia while modulating glutamate and GABA efflux both locally and in the striatum. (C) 2011 Elsevier Inc. All rights reserved. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
keywords
Dyskinesia, D1 receptor, D2 receptor, GABA, Glutamate, L-DOPA, Raclopride, SCH23390, Striatum, Substantia nigra reticulata
in
Neurobiology of Disease
volume
45
issue
1
pages
573 - 582
publisher
Elsevier
external identifiers
  • wos:000297883500063
  • scopus:81955164758
ISSN
0969-9961
DOI
10.1016/j.nbd.2011.09.015
language
English
LU publication?
yes
id
39175ef2-12b3-4cc5-95c0-6fde5286db57 (old id 2278885)
date added to LUP
2012-01-11 13:21:11
date last changed
2017-09-10 03:01:37
@article{39175ef2-12b3-4cc5-95c0-6fde5286db57,
  abstract     = {Evidence for an involvement of striatal D1 receptors in levodopa-induced dyskinesia has been presented whereas the contribution of striatal D2 receptors remains controversial. In addition, whether D1 and D2 receptors located in the substantia nigra reticulata shape the response to levodopa remains unknown. We therefore used dual probe microdialysis to unravel the impact of striatal and nigral D1 or 02 receptor blockade on abnormal involuntary movements (AIMS) and striatal output pathways in unilaterally 6-hydroxydopamine lesioned dyskinetic rats. Regional perfusion of D1/D5 (SCH23390) and D2/D3 (raclopride) receptor antagonists was combined with systemic administration of levodopa. Levodopa-induced AIMS coincided with a prolonged surge of GABA and glutamate levels in the substantia nigra reticulata. Intrastriatal SCH23390 attenuated the levodopa-induced AIM scores (similar to 50%) and prevented the accompanying neurochemical response whereas raclopride was ineffective. When perfused in the substantia nigra, both antagonists attenuated AIM expression (similar to 21-40%). However, only intranigral SCH23390 attenuated levodopa-induced nigral GABA efflux, whereas raclopride reduced basal GABA levels without affecting the response to levodopa. In addition, intranigral raclopride elevated amino acid release in the striatum and revealed a (mild) facilitatory effect of levodopa on striatal glutamate. We conclude that both striatal and nigral D1 receptors play an important role in dyskinesia possibly via modulation of the striato-nigral direct pathway. In addition, the stimulation of nigral D2 receptors contributes to dyskinesia while modulating glutamate and GABA efflux both locally and in the striatum. (C) 2011 Elsevier Inc. All rights reserved.},
  author       = {Mela, Flora and Marti, Matteo and Bido, Simone and Cenci Nilsson, Angela and Morari, Michele},
  issn         = {0969-9961},
  keyword      = {Dyskinesia,D1 receptor,D2 receptor,GABA,Glutamate,L-DOPA,Raclopride,SCH23390,Striatum,Substantia nigra reticulata},
  language     = {eng},
  number       = {1},
  pages        = {573--582},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {In vivo evidence for a differential contribution of striatal and nigral D1 and D2 receptors to l-DOPA induced dyskinesia and the accompanying surge of nigral amino acid levels},
  url          = {http://dx.doi.org/10.1016/j.nbd.2011.09.015},
  volume       = {45},
  year         = {2012},
}