title: Serotonergic modulation of receptor occupancy in rats treated with L-DOPA after unilateral 6-OHDA lesioning.
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 [(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.
authors: Center of Functionally Integrative Neuroscience, Aarhus University Hospitals, Aarhus University, Denmark. adjmal@pet.auh.dk
authors: Adjmal
authors: A
authors: Nahimi
authors: Mette
authors: M
authors: Høltzermann
authors: Anne M
authors: AM
authors: Landau
authors: Mette
authors: M
authors: Simonsen
authors: Steen
authors: S
authors: Jakobsen
authors: Aage Kristian Olsen
authors: AK
authors: Alstrup
authors: Kim
authors: K
authors: Vang
authors: Arne
authors: A
authors: Møller
authors: Gregers
authors: G
authors: Wegener
authors: Albert
authors: A
authors: Gjedde
authors: Doris J
authors: DJ
authors: Doudet
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D001345:Autoradiography; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics; D004409:Dyskinesia, Drug-Induced / Q000000981:diagnostic imaging / Q000188:drug therapy; D005260:Female; D007839:Functional Laterality; D007980:Levodopa / Q000009:adverse effects*; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D020891:Raclopride / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D059326:Serotonergic Neurons / Q000187:drug effects*; D017366:Serotonin Receptor Agonists
chemical_list: D000978:Antiparkinson Agents; D002247:Carbon Isotopes; D018765:Dopamine Uptake Inhibitors; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D020891:Raclopride; D007980:Levodopa; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D016627:Oxidopamine; D003042:Cocaine; D004298:Dopamine