Brain-derived neurotrophic factor controls dopamine D3 receptor expression: therapeutic implications in Parkinson's disease.
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.
Guillin
Olivier
O
Unité de Neurobiologie et Pharmacologie Moléculaire, INSERM U 573, Centre Paul Broca, 2 ter rue d'Alésia, 75014, Paris, France. olivierguillin@yahoo.fr
Griffon
Nathalie
N
Bezard
Erwan
E
Leriche
Ludovic
L
Diaz
Jorge
J
Gross
Christian
C
Sokoloff
Pierre
P
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D018491:Dopamine Agonists / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D050637:Receptors, Dopamine D3
D019208:Brain-Derived Neurotrophic Factor; C493593:DRD3 protein, human; D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3