Evidence for a role of the 5-HT1B receptor and its adaptor protein, p11, in l-DOPA treatment of an animal model of Parkinsonism

  1. Xiaoqun Zhang*,
  2. Per E. Andren†,
  3. Paul Greengard‡,§, and
  4. Per Svenningsson*,‡,§
  1. ‡Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY10021;
  2. *Section of Translational Neuropharmacology, Department of Physiology and Pharmacology, Karolinska Institute, 17177 Stockholm, Sweden; and
  3. †Laboratory for Biological and Medical Mass Spectrometry, Uppsala University, 75123 Uppsala, Sweden

  1. Contributed by Paul Greengard, December 16, 2007 (received for review December 3, 2007)

Abstract

Parkinson's disease (PD) is characterized by a progressive degeneration of substantia nigra dopaminergic neurons projecting to the striatum. Restoration of dopamine transmission by l-DOPA relieves symptoms of PD but causes prominent side effects. There is a strong serotonin innervation of the striatum by serotonergic neurons that remains relatively preserved in PD. The study of this innervation has been largely neglected. Here, we demonstrate that chronic l-DOPA administration to 6-OHDA-lesioned rodents increases, via D1 receptors, the levels of the 5-HT1B receptor and its adaptor protein, p11, in dopamine-denervated striatonigral neurons. Using unilaterally 6-OHDA-lesioned p11 WT and KO mice, it was found that administration of a selective 5-HT1B receptor agonist, CP94253, inhibited l-DOPA-induced rotational behavior and abnormal involuntary movements in a p11-dependent manner. These data reveal an l-DOPA-induced negative-feedback mechanism, whereby the serotonin system may influence the symptomatology of Parkinsonism.

Footnotes

  • §To whom correspondence may be addressed. E-mail: greengard{at}rockefeller.edu or per.svenningsson{at}ki.se

  • Author contributions: P.G. and P.S. designed research; X.Z. and P.S. performed research; P.E.A. contributed new reagents/analytic tools; X.Z., P.G., and P.S. analyzed data; and X.Z., P.G., and P.S. wrote the paper.

  • The authors declare no conflict of interest.

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  1. Published online before print February 6, 2008, doi: 10.1073/pnas.0711839105 PNAS February 12, 2008 vol. 105 no. 6 2163-2168
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