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 2012
Externally publishedYes

Fingerprint

Dihydroxyphenylalanine
Oxidopamine
Raclopride
Rats
Dyskinesias
Modulation
8-Hydroxy-2-(di-n-propylamino)tetralin
Dopamine
Serotonin Receptor Agonists
Microdialysis
Serotonergic Neurons
Positron emission tomography
Positron-Emission Tomography
Neurons
Parkinson Disease
Serotonin
Benserazide
Dopamine Receptors
Animals
Animal Models

Keywords

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

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., ... 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

Serotonergic modulation of receptor occupancy in rats treated with l-DOPA after unilateral 6-OHDA lesioning. / Nahimi, Adjmal; Høltzermann, Mette; Landau, Anne M.; Simonsen, Mette; Jakobsen, Steen; Alstrup, Aage Kristian Olsen; Vang, Kim; Møller, Arne; Wegener, Gregers; Gjedde, Albert; Doudet, Doris J.

In: Journal of Neurochemistry, Vol. 120, No. 5, 03.2012, p. 806-817.

Research output: Contribution to journalArticle

Nahimi, A, Høltzermann, M, Landau, AM, Simonsen, M, Jakobsen, S, Alstrup, AKO, Vang, K, Møller, A, Wegener, G, Gjedde, A & Doudet, DJ 2012, 'Serotonergic modulation of receptor occupancy in rats treated with l-DOPA after unilateral 6-OHDA lesioning', Journal of Neurochemistry, vol. 120, no. 5, pp. 806-817. https://doi.org/10.1111/j.1471-4159.2011.07598.x
Nahimi, Adjmal ; Høltzermann, Mette ; Landau, Anne M. ; Simonsen, Mette ; Jakobsen, Steen ; Alstrup, Aage Kristian Olsen ; Vang, Kim ; Møller, Arne ; Wegener, Gregers ; Gjedde, Albert ; Doudet, Doris J. / Serotonergic modulation of receptor occupancy in rats treated with l-DOPA after unilateral 6-OHDA lesioning. In: Journal of Neurochemistry. 2012 ; Vol. 120, No. 5. pp. 806-817.
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