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Selective Regulation of 5-HT1B Serotonin Receptor Expression in the Striatum by Dopamine Depletion and Repeated L-DOPA Treatment: Relationship to L-DOPA-Induced Dyskinesias

  • Fernando E. Padovan-Neto
  • Santanna Patterson
  • Nivea M. F. Voelkner
  • Feras Altwal
  • Joel A. Beverley
  • Anthony R. West
  • Heinz SteinerEmail author
Article

Abstract

Dopamine and serotonin in the basal ganglia interact in a bidirectional manner. On the one hand, serotonin (5-HT) receptors regulate the effects of dopamine agonists on several levels, ranging from molecular signaling to behavior. These interactions include 5-HT receptor-mediated facilitation of dopamine receptor-induced gene regulation in striatal output pathways, which involves the 5-HT1B receptor and others. Conversely, there is evidence that dopamine action by psychostimulants regulates 5-HT1B receptor expression in the striatum. To further investigate the effects of dopamine and agonists on 5-HT receptors, we assessed the expression of 5-HT1B and other serotonin receptor subtypes in the striatum after unilateral dopamine depletion by 6-OHDA and subsequent treatment with L-DOPA (5 mg/kg; 4 weeks). Neither dopamine depletion nor L-DOPA treatment produced significant changes in 5-HT2C, 5-HT4, or 5-HT6 receptor expression in the striatum. In contrast, the 6-OHDA lesion caused a (modest) increase in 5-HT1B mRNA levels throughout the striatum. Moreover, repeated L-DOPA treatment markedly further elevated 5-HT1B expression in the dopamine-depleted striatum, an effect that was most robust in the sensorimotor striatum. A minor L-DOPA-induced increase in 5-HT1B expression was also seen in the intact striatum. These changes in 5-HT1B expression mimicked changes in the expression of neuropeptide markers (dynorphin, enkephalin mRNA) in striatal projection neurons. After repeated L-DOPA treatment, the severity of L-DOPA-induced dyskinesias and turning behavior was positively correlated with the increase in 5-HT1B expression in the associative, but not sensorimotor, striatum ipsilateral to the lesion, suggesting that associative striatal 5-HT1B receptors may play a role in L-DOPA-induced behavioral abnormalities.

Keywords

Dopamine Serotonin Gene expression L-DOPA Striatum Parkinson’s disease 

Notes

Funding Information

This work was supported in part by the National Institutes of Health Grants (DA011261 and DA046794 to H.S.; NS088554 to A.R.W.) and Rosalind Franklin University of Medicine and Science.

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Authors and Affiliations

  1. 1.Department of Neuroscience, The Chicago Medical SchoolRosalind Franklin University of Medicine and ScienceNorth ChicagoUSA
  2. 2.Department of Psychology, Faculty of Philosophy, Sciences and Letters of Ribeirão PretoUniversity of São PauloRibeirão Preto, 14040-901Brazil
  3. 3.Department of Cellular and Molecular Pharmacology, The Chicago Medical SchoolRosalind Franklin University of Medicine and ScienceNorth ChicagoUSA
  4. 4.School of Graduate and Postdoctoral StudiesRosalind Franklin University of Medicine and ScienceNorth ChicagoUSA

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