Brain-derived neurotrophic factor controls dopamine D3 receptor expression: therapeutic implications in Parkinson's disease

Eur J Pharmacol. 2003 Nov 7;480(1-3):89-95. doi: 10.1016/j.ejphar.2003.08.096.

Abstract

Brain-derived neurotrophic factor (BDNF) belongs to a family of proteins related to nerve growth factor, which are responsible for neuron proliferation, survival and differentiation. A more diverse role for BDNF as a neuronal extracellular transmitter has, nevertheless, been proposed. Here we show that BDNF synthesized by dopamine neurons is responsible for the appearance of the dopamine D3 receptor during development and maintains its expression in adults. Moreover, BDNF triggers behavioral sensitization to levodopa in hemiparkinsonian rats. In monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which develop levodopa-induced dyskinesia, we show an overexpression of this receptor. Administration of a dopamine D3 receptor-selective partial agonist strongly attenuated levodopa-induced dyskinesia, while leaving unaffected the therapeutic effect of levodopa. These results suggest that the dopamine D3 receptor participates in both dyskinesia and the therapeutic action of levodopa and that partial agonists may normalize dopamine D3 receptor function and correct side-effects of levodopa therapy in PD patients.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / physiology*
  • Brain-Derived Neurotrophic Factor / therapeutic use
  • Dopamine Agonists / pharmacology
  • Dopamine Agonists / therapeutic use
  • Gene Expression Regulation / drug effects
  • Humans
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / biosynthesis*
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D3

Substances

  • Brain-Derived Neurotrophic Factor
  • DRD3 protein, human
  • Dopamine Agonists
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3