TY - JOUR

T1 - Serotonergic modulation of receptor occupancy in rats treated with L-DOPA after unilateral 6-OHDA lesioning

AU - Nahimi, Adjmal

AU - Høltzermann, Mette

AU - Landau, Anne M.

AU - Simonsen, Mette Kildevæld

AU - Jakobsen, Steen

AU - Alstrup, Aage Kristian Olsen

AU - Vang, Kim

AU - Møller, Peter Arne

AU - Wegener, Gregers

AU - Gjedde, Albert

AU - Doudet, Doris

N1 - © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

PY - 2012/3

Y1 - 2012/3

N2 - 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.

AB - 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.

KW - 8-Hydroxy-2-(di-n-propylamino)tetralin

KW - Analysis of Variance

KW - Animals

KW - Antiparkinson Agents

KW - Autoradiography

KW - Carbon Isotopes

KW - Cocaine

KW - Disease Models, Animal

KW - Dopamine

KW - Dopamine Uptake Inhibitors

KW - Dyskinesia, Drug-Induced

KW - Female

KW - Functional Laterality

KW - Levodopa

KW - Microdialysis

KW - Motor Activity

KW - Oxidopamine

KW - Parkinson Disease

KW - Positron-Emission Tomography

KW - Protein Binding

KW - Raclopride

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptors, Dopamine

KW - Receptors, Serotonin

KW - Serotonergic Neurons

KW - Serotonin Receptor Agonists

U2 - 10.1111/j.1471-4159.2011.07598.x

DO - 10.1111/j.1471-4159.2011.07598.x

M3 - Journal article

C2 - 22117574

VL - 120

SP - 806

EP - 817

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 5

ER -