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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Adjmal Nahimi
  • Mette Høltzermann
  • Anne M. Landau
  • Mette Kildevæld Simonsen
  • Steen Jakobsen
  • Aage Kristian Olsen Alstrup
  • Kim Vang
  • Peter Arne Møller
  • Gregers Wegener
  • Gjedde, Albert
  • Doris Doudet
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 [(11) C]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 [(11) C]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 [(11) C]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 [(11) C]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 [(11) C]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 [(11) C]raclopride binding and increase of extracellular DA and reduced the severity of LID. The reversal of the effect of L-DOPA on [(11) C]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
JournalJournal of Neurochemistry
Issue number5
Pages (from-to)806-17
Number of pages12
Publication statusPublished - Mar 2012

    Research areas

  • 8-Hydroxy-2-(di-n-propylamino)tetralin, Analysis of Variance, Animals, Antiparkinson Agents, Autoradiography, Carbon Isotopes, Cocaine, Disease Models, Animal, Dopamine, Dopamine Uptake Inhibitors, Dyskinesia, Drug-Induced, Female, Functional Laterality, Levodopa, Microdialysis, Motor Activity, Oxidopamine, Parkinson Disease, Positron-Emission Tomography, Protein Binding, Raclopride, Rats, Rats, Sprague-Dawley, Receptors, Dopamine, Receptors, Serotonin, Serotonergic Neurons, Serotonin Receptor Agonists

ID: 44913741