Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function.
In monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), expression of the dopamine D3 receptor was decreased. However, levodopa-induced dyskinesia (LID), similar to the debilitating and pharmacoresistant involuntary movements elicited after long-term treatment with levodopa in patients with Parkinson disease (PD), was associated with overexpression of this receptor. Administration of a D3 receptor-selective partial agonist strongly attenuated levodopa-induced dyskinesia, but left unaffected the therapeutic effect of levodopa. In contrast, attenuation of dyskinesia by D3 receptor antagonists was accompanied by the reappearance of PD-like symptoms. These results indicated that the D3 receptor participated in both dyskinesia and the therapeutic action of levodopa, and that partial agonists may normalize D3 receptor function and correct side effects of levodopa therapy in patients with PD.
Bézard
Erwan
E
Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen, 33076 Bordeaux, France. erwan.bezard@umr5543.u-bordeaux2.fr
Ferry
Sandrine
S
Mach
Ulrich
U
Stark
Holger
H
Leriche
Ludovic
L
Boraud
Thomas
T
Gross
Christian
C
Sokoloff
Pierre
P
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use / Q000633:toxicity*; D015259:Dopamine Agents / Q000378:metabolism / Q000633:toxicity; D018492:Dopamine Antagonists / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced; D005260:Female; D000882:Haplorhini; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007980:Levodopa / Q000627:therapeutic use / Q000633:toxicity*; D020267:MPTP Poisoning / Q000188:drug therapy / Q000378:metabolism; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D050637:Receptors, Dopamine D3
C476326:((E)-N-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)butyl)-3-phenylacrylamide; D000178:Acrylamides; D000978:Antiparkinson Agents; C493593:DRD3 protein, human; D015259:Dopamine Agents; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D007546:Isoquinolines; D009281:Naphthalenes; D010879:Piperazines; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C120565:BP 897; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C097285:nafadotride