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Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi-parkinsonian rats

Smith, Gaynor A; Breger, Ludivine S LU ; Lane, Emma L LU and Dunnett, Stephen B (2012) In Neuropharmacology 63(5). p.28-818
Abstract

Foetal cell transplantation in patients with Parkinson's disease can induce motor complications independent of L-DOPA administration, known as graft-induced dyskinesia. In the 6-OHDA lesioned rat model of Parkinson's disease, post-transplantation abnormal movements can develop in response to an amphetamine challenge, a behaviour which is used to model graft-induced dyskinesia. Although L-DOPA-induced dyskinesia has been well characterised pharmacologically, we lack knowledge on the modulation of post-transplantation amphetamine-induced dyskinesia which may shed light on the mechanisms underlying graft-induced dyskinesia. We assessed a series of drugs effective at reducing L-DOPA-induced dyskinesia against post-transplantation... (More)

Foetal cell transplantation in patients with Parkinson's disease can induce motor complications independent of L-DOPA administration, known as graft-induced dyskinesia. In the 6-OHDA lesioned rat model of Parkinson's disease, post-transplantation abnormal movements can develop in response to an amphetamine challenge, a behaviour which is used to model graft-induced dyskinesia. Although L-DOPA-induced dyskinesia has been well characterised pharmacologically, we lack knowledge on the modulation of post-transplantation amphetamine-induced dyskinesia which may shed light on the mechanisms underlying graft-induced dyskinesia. We assessed a series of drugs effective at reducing L-DOPA-induced dyskinesia against post-transplantation amphetamine-induced dyskinesia. Agents include: dopaminergic antagonists (D₁: CP94253; D₂: SCH-22390; D₃: nafadotride), serotonergic agonists (5-HT(1A): 8-OH-DPAT; 5-HT(1B): CP94253), opioid antagonist (μ: naloxone), cannabinoid agonist (CB₁: WIN55, 212-2), adrenergic antagonist (α₁ and α₂: yohimbine) and glutamatergic antagonists (NMDA: amantadine and MK-801; mGluR5: MTEP; AMPA: IEM1460). Abnormal involuntary movements in response to amphetamine were decreased by SCH-22390, raclopride, CP94253 and 8-OH-DPAT, yet were unaltered by naloxone, WIN55, 212-2, yohimbine, amantadine, MTEP and IEM1460. Unusually, MK-801 increased the appearance of amphetamine-induced dyskinesia. The results suggest that dopaminergic, serotoninergic and glutamatergic systems are likely to have a fundamental role in the development of graft-induced dyskinesias, which are mechanistically distinct from L-DOPA-induced behvaviours. Importantly, the expression of D₁ and D₂ receptors was unrelated to the severity of AIMs.

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keywords
Animals, Anti-Dyskinesia Agents, Cell Transplantation, Disease Models, Animal, Dopamine Antagonists, Dopamine Uptake Inhibitors, Dose-Response Relationship, Drug, Dyskinesia, Drug-Induced, Dyskinesias, Excitatory Amino Acid Antagonists, Female, Mesencephalon, Methamphetamine, Neostriatum, Nerve Tissue Proteins, Neurons, Parkinson Disease, Random Allocation, Rats, Rats, Sprague-Dawley, Receptors, Neurotransmitter, Serotonin Receptor Agonists, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
in
Neuropharmacology
volume
63
issue
5
pages
11 pages
publisher
Elsevier
external identifiers
  • Scopus:84864425280
ISSN
1873-7064
DOI
10.1016/j.neuropharm.2012.06.011
language
English
LU publication?
no
id
84fe45fe-d152-4288-98d3-1704911628f0
date added to LUP
2016-10-04 13:20:53
date last changed
2016-10-13 05:14:40
@misc{84fe45fe-d152-4288-98d3-1704911628f0,
  abstract     = {<p>Foetal cell transplantation in patients with Parkinson's disease can induce motor complications independent of L-DOPA administration, known as graft-induced dyskinesia. In the 6-OHDA lesioned rat model of Parkinson's disease, post-transplantation abnormal movements can develop in response to an amphetamine challenge, a behaviour which is used to model graft-induced dyskinesia. Although L-DOPA-induced dyskinesia has been well characterised pharmacologically, we lack knowledge on the modulation of post-transplantation amphetamine-induced dyskinesia which may shed light on the mechanisms underlying graft-induced dyskinesia. We assessed a series of drugs effective at reducing L-DOPA-induced dyskinesia against post-transplantation amphetamine-induced dyskinesia. Agents include: dopaminergic antagonists (D₁: CP94253; D₂: SCH-22390; D₃: nafadotride), serotonergic agonists (5-HT(1A): 8-OH-DPAT; 5-HT(1B): CP94253), opioid antagonist (μ: naloxone), cannabinoid agonist (CB₁: WIN55, 212-2), adrenergic antagonist (α₁ and α₂: yohimbine) and glutamatergic antagonists (NMDA: amantadine and MK-801; mGluR5: MTEP; AMPA: IEM1460). Abnormal involuntary movements in response to amphetamine were decreased by SCH-22390, raclopride, CP94253 and 8-OH-DPAT, yet were unaltered by naloxone, WIN55, 212-2, yohimbine, amantadine, MTEP and IEM1460. Unusually, MK-801 increased the appearance of amphetamine-induced dyskinesia. The results suggest that dopaminergic, serotoninergic and glutamatergic systems are likely to have a fundamental role in the development of graft-induced dyskinesias, which are mechanistically distinct from L-DOPA-induced behvaviours. Importantly, the expression of D₁ and D₂ receptors was unrelated to the severity of AIMs.</p>},
  author       = {Smith, Gaynor A and Breger, Ludivine S and Lane, Emma L and Dunnett, Stephen B},
  issn         = {1873-7064},
  keyword      = {Animals,Anti-Dyskinesia Agents,Cell Transplantation,Disease Models, Animal,Dopamine Antagonists,Dopamine Uptake Inhibitors,Dose-Response Relationship, Drug,Dyskinesia, Drug-Induced,Dyskinesias,Excitatory Amino Acid Antagonists,Female,Mesencephalon,Methamphetamine,Neostriatum,Nerve Tissue Proteins,Neurons,Parkinson Disease,Random Allocation,Rats,Rats, Sprague-Dawley,Receptors, Neurotransmitter,Serotonin Receptor Agonists,Comparative Study,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {5},
  pages        = {28--818},
  publisher    = {ARRAY(0x9d5dd38)},
  series       = {Neuropharmacology},
  title        = {Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi-parkinsonian rats},
  url          = {http://dx.doi.org/10.1016/j.neuropharm.2012.06.011},
  volume       = {63},
  year         = {2012},
}