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

Authors

  • Adjmal Nahimi,

    1. Center of Functionally Integrative Neuroscience, Aarhus University Hospitals, Aarhus University, Denmark
    2. Department of Nuclear Medicine and PET Centre, Aarhus University Hospitals, Aarhus University, Denmark
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  • Mette Høltzermann,

    1. Department of Nuclear Medicine and PET Centre, Aarhus University Hospitals, Aarhus University, Denmark
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  • Anne M. Landau,

    1. Center of Functionally Integrative Neuroscience, Aarhus University Hospitals, Aarhus University, Denmark
    2. Department of Nuclear Medicine and PET Centre, Aarhus University Hospitals, Aarhus University, Denmark
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  • Mette Simonsen,

    1. Center of Functionally Integrative Neuroscience, Aarhus University Hospitals, Aarhus University, Denmark
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  • Steen Jakobsen,

    1. Department of Nuclear Medicine and PET Centre, Aarhus University Hospitals, Aarhus University, Denmark
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  • Aage Kristian Olsen Alstrup,

    1. Center of Functionally Integrative Neuroscience, Aarhus University Hospitals, Aarhus University, Denmark
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  • Kim Vang,

    1. Center of Functionally Integrative Neuroscience, Aarhus University Hospitals, Aarhus University, Denmark
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  • Arne Møller,

    1. Center of Functionally Integrative Neuroscience, Aarhus University Hospitals, Aarhus University, Denmark
    2. Department of Nuclear Medicine and PET Centre, Aarhus University Hospitals, Aarhus University, Denmark
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  • Gregers Wegener,

    1. Centre for Psychiatric Research, Aarhus University Hospitals, Aarhus University, Denmark
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  • Albert Gjedde,

    1. Department of Neuroscience and Pharmacology, University of Copenhagen, Denmark
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  • Doris J. Doudet

    1. Center of Functionally Integrative Neuroscience, Aarhus University Hospitals, Aarhus University, Denmark
    2. Department of Nuclear Medicine and PET Centre, Aarhus University Hospitals, Aarhus University, Denmark
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Address correspondence and reprint requests to Adjmal Nahimi, MD, PhD student, Department of Nuclear Medicine and PET Centre, Center of Functionally Integrative Neuroscience, Aarhus University Hospitals, Aarhus University, Norrebrogade 44, Building 10G, 6th Floor, 8000 Aarhus C, Denmark. E-mails: adjmal@pet.auh.dk; adjmalnahimi@gmail.com

Abstract

J. Neurochem (2012) 120, 806–817.

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-HT1A 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-HT1A 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 (BPND) 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.

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