Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function

Nat Med. 2003 Jun;9(6):762-7. doi: 10.1038/nm875. Epub 2003 May 12.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / metabolism
  • Acrylamides / pharmacology
  • Animals
  • Antiparkinson Agents / therapeutic use
  • Antiparkinson Agents / toxicity*
  • Dopamine Agents / metabolism
  • Dopamine Agents / toxicity
  • Dopamine Antagonists / pharmacology
  • Dyskinesia, Drug-Induced*
  • Female
  • Haplorhini
  • Humans
  • Isoquinolines / pharmacology
  • Levodopa / therapeutic use
  • Levodopa / toxicity*
  • MPTP Poisoning / drug therapy
  • MPTP Poisoning / metabolism
  • Molecular Structure
  • Motor Activity / drug effects
  • Naphthalenes / pharmacology
  • Neostriatum / cytology
  • Neostriatum / drug effects
  • Neostriatum / metabolism
  • Piperazines / pharmacology
  • Pyrrolidines / pharmacology
  • Rats
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D3

Substances

  • ((E)-N-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)butyl)-3-phenylacrylamide
  • Acrylamides
  • Antiparkinson Agents
  • DRD3 protein, human
  • Dopamine Agents
  • Dopamine Antagonists
  • Drd3 protein, rat
  • Isoquinolines
  • Naphthalenes
  • Piperazines
  • Pyrrolidines
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • BP 897
  • Levodopa
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • nafadotride