Serotonergic modulation of receptor occupancy in rats treated with l-DOPA after unilateral 6-OHDA lesioning

Adjmal Nahimi, Mette Høltzermann, Anne M. Landau, Mette Simonsen, Steen Jakobsen, Aage Kristian Olsen Alstrup, Kim Vang, Arne Møller, Gregers Wegener, Albert Gjedde, Doris J. Doudet

Research output: Contribution to journalArticle

Abstract

Recent studies suggest that l-3,4 dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID), a severe complication of conventional l-DOPA therapy of Parkinson's disease, may be caused by dopamine (DA) release originating in serotonergic neurons. To evaluate the in vivo effect of a 5-HT 1A agonist [(±)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide, 8-OHDPAT] on the l-DOPA-induced increase in extracellular DA and decrease in [ 11C]raclopride binding in an animal model of advanced Parkinson's disease and LID, we measured extracellular DA in response to l-DOPA or a combination of l-DOPA and the 5-HT 1A agonist, 8-OHDPAT, with microdialysis, and determined [ 11C]raclopride binding to DA receptors, with micro-positron emission tomography, as the surrogate marker of DA release. Rats with unilateral 6-hydroxydopamine lesions had micro-positron emission tomography scans with [ 11C]raclopride at baseline and after two pharmacological challenges with l-DOPA + benserazide with or without 8-OHDPAT co-treatment. Identical challenge regimens were used with the subsequent microdialysis concomitant with ratings of LID severity. The baseline increase of [ 11C]raclopride-binding potential (BP ND) in lesioned striatum was eliminated by the l-DOPA challenge, while the concurrent administration of 8-OHDPAT prevented this l-DOPA-induced displacement of [ 11C]raclopride significantly in lesioned ventral striatum and near significantly in the dorsal striatum. With microdialysis, the l-DOPA challenge raised the extracellular DA in parallel with the emergence of strong LID. Co-treatment with 8-OHDPAT significantly attenuated the release of extracellular DA and LID. The 8-OHDPAT co-treatment reversed the l-DOPA-induced decrease of [ 11C]raclopride binding and increase of extracellular DA and reduced the severity of LID. The reversal of the effect of l-DOPA on [ 11C]raclopride binding, extracellular DA and LID by 5-HT agonist administration is consistent with the notion that part of the DA increase associated with LID originates in serotonergic neurons.

Original languageEnglish (US)
Pages (from-to)806-817
Number of pages12
JournalJournal of Neurochemistry
Volume120
Issue number5
DOIs
StatePublished - Mar 1 2012

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Keywords

  • 5-HT receptor agonist
  • 6-hydroxydopamine
  • Parkinson's disease
  • l -DOPA induced dyskinesia
  • micro-positron emission tomography and microdialysis

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Nahimi, A., Høltzermann, M., Landau, A. M., Simonsen, M., Jakobsen, S., Alstrup, A. K. O., Vang, K., Møller, A., Wegener, G., Gjedde, A., & Doudet, D. J. (2012). Serotonergic modulation of receptor occupancy in rats treated with l-DOPA after unilateral 6-OHDA lesioning. Journal of Neurochemistry, 120(5), 806-817. https://doi.org/10.1111/j.1471-4159.2011.07598.x