Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi-parkinsonian rats.
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.
Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, Wales, UK. gsmith@mcLean.harvard.edu
Gaynor A
GA
Smith
Ludivine S
LS
Breger
Emma L
EL
Lane
Stephen B
SB
Dunnett
D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D017690:Cell Transplantation / Q000009:adverse effects*; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020820:Dyskinesias / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008694:Methamphetamine / Q000008:administration & dosage / Q000633:toxicity; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D010300:Parkinson Disease / Q000628:therapy*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017981:Receptors, Neurotransmitter / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use
D018726:Anti-Dyskinesia Agents; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D017981:Receptors, Neurotransmitter; D017366:Serotonin Receptor Agonists; D008694:Methamphetamine