title: The anti-dyskinetic effect of dopamine receptor blockade is enhanced in parkinsonian rats following dopamine neuron transplantation.
abstract: Graft-induced dyskinesia (GID) is a serious complication induced by dopamine (DA) cell transplantation in parkinsonian patients. We have recently shown that DA D2 receptor blockade produces striking blockade of dyskinesia induced by amphetamine in grafted 6-OHDA-lesioned rats, a model of GID. This study was designed to investigate whether blockade of DA D1 receptors could produce similar outcome, and to see whether the effect of these treatments in grafted rats was specific for dyskinesia induced by amphetamine, or could also influence L-DOPA-induced dyskinesia (LID). L-DOPA-primed rats received transplants of fetal DA neurons into the DA-denervated striatum. Beginning at 20weeks after transplantation rats were subjected to pharmacological treatments with either L-DOPA (6mg/kg) or amphetamine (1.5mg/kg) alone, or in combination with the D1 receptor antagonist SCH23390, the D2 receptor antagonist eticlopride, and the 5-HT1A agonist/D2 receptor antagonist buspirone. Grafted rats developed severe GID, while LID was reduced. Both eticlopride and SCH23390 produced near-complete suppression of GID already at very low doses (0.015 and 0.1mg/kg, respectively). Buspirone induced similar suppression at a dose as low as 0.3mg/kg, which is far lower than the dose known to affect LID in non-grafted dyskinetic rats. In agreement with our previous results, the effect of buspirone was independent from 5-HT1A receptor activation, as it was not counteracted by the selective 5-HT1A antagonist WAY100635, but likely due to D2 receptor blockade. Most interestingly, the same doses of eticlopride, SCH23390 and buspirone were found to suppress LID in grafted but not in control dyskinetic rats. Taken together, these data demonstrate that the DA cell grafts strikingly exacerbate the effect of DA D1 and D2 receptor blockade against both GID and LID, and suggest that the anti-GID effect of buspirone seen in patients may also be due to blockade of DA D2 receptors.
authors.affiliation: Wallenberg Neuroscience Center, Division of Neurobiology, Lund University, 221 84 Lund, Sweden.
authors.forename: Eunju
authors.initials: E
authors.lastname: Shin
authors.affiliation: Department of Biomedical Sciences, Cagliari University, Cittadella Universitaria, SS 554km 4.500, 09042 Monserrato, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Lisci
authors.affiliation: Department of Biomedical Sciences, Cagliari University, Cittadella Universitaria, SS 554km 4.500, 09042 Monserrato, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Tronci
authors.affiliation: Department of Biomedical Sciences, Cagliari University, Cittadella Universitaria, SS 554km 4.500, 09042 Monserrato, Italy.
authors.forename: Camino
authors.initials: C
authors.lastname: Fidalgo
authors.affiliation: Department of Biomedical Sciences, Cagliari University, Cittadella Universitaria, SS 554km 4.500, 09042 Monserrato, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Stancampiano
authors.affiliation: Wallenberg Neuroscience Center, Division of Neurobiology, Lund University, 221 84 Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Björklund
authors.affiliation: Department of Biomedical Sciences, Cagliari University, Cittadella Universitaria, SS 554km 4.500, 09042 Monserrato, Italy. Electronic address: manolocarta@unica.it.
authors.forename: Manolo
authors.initials: M
authors.lastname: Carta
mesh_terms: D000661:Amphetamine / Q000633:toxicity; D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000627:therapeutic use*; D000978:Antiparkinson Agents / Q000633:toxicity; D001552:Benzazepines / Q000627:therapeutic use; D002065:Buspirone / Q000627:therapeutic use; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000627:therapeutic use; D018492:Dopamine Antagonists / Q000627:therapeutic use; D065127:Dopamine D2 Receptor Antagonists; D059290:Dopaminergic Neurons / Q000637:transplantation*; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D005260:Female; D007211:Indoles / Q000494:pharmacology; D007980:Levodopa / Q000633:toxicity; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology; D020734:Parkinsonian Disorders / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors*; D017448:Receptors, Dopamine D2 / Q000819:agonists; D012457:Salicylamides / Q000627:therapeutic use; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use
chemical_list: D018726:Anti-Dyskinesia Agents; D000978:Antiparkinson Agents; D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C534628:SCH 23390; D012457:Salicylamides; D017366:Serotonin Receptor Agonists; C046649:ropinirole; D007980:Levodopa; D000661:Amphetamine; C045989:eticlopride; D002065:Buspirone
keywords: Buspirone; Cell transplantation; Dopamine D(1) receptor; Dopamine D(2) receptor; Eticlopride; Graft-induced dyskinesia; L-DOPA-induced dyskinesia; Parkinson's disease; SCH23390