title: The decrease of dopamine D₂/D₃ receptor densities in the putamen and nucleus caudatus goes parallel with maintained levels of CB₁ cannabinoid receptors in Parkinson's disease: a preliminary autoradiographic study with the selective dopamine D₂/D₃ antagonist [³H]raclopride and the novel CB₁ inverse agonist [¹²⁵I]SD7015.
abstract: Cannabinoid type-1 receptors (CB₁Rs) modulate synaptic neurotransmission by participating in retrograde signaling in the adult brain. Increasing evidence suggests that cannabinoids through CB₁Rs play an important role in the regulation of motor activities in the striatum. In the present study, we used human brain samples to examine the relationship between CB₁R and dopamine receptor density in case of Parkinson's disease (PD). Post mortem putamen, nucleus caudatus and medial frontal gyrus samples obtained from PD patients were used for CB₁R and dopamine D₂/D₃ receptor autoradiography. [¹²⁵I]SD7015, a novel selective CB₁R inverse agonist, developed by a number of the present co-authors, and [³H]raclopride, a dopamine D₂/D₃ antagonist, were used as radioligands. Our results demonstrate unchanged CB₁R density in the putamen and nucleus caudatus of deceased PD patients, treated with levodopa (L-DOPA). At the same time dopamine D₂/D₃ receptors displayed significantly decreased density levels in case of PD putamen (control: 47.97 ± 10.00 fmol/g, PD: 3.73 ± 0.07 fmol/g (mean ± SEM), p<0.05) and nucleus caudatus (control: 30.26 ± 2.48 fmol/g, PD: 12.84 ± 5.49 fmol/g, p<0.0005) samples. In contrast to the putamen and the nucleus caudatus, in the medial frontal gyrus neither receptor densities were affected. Our data suggest the presence of an unaltered CB₁R population even in late stages of levodopa treated PD. This further supports the presence of an intact CB₁R population which, in line with the conclusion of earlier publications, may be utilized as a pharmacological target in the treatment of PD. Furthermore we found discrepancy between a maintained CB₁R population and a decreased dopamine D₂/D₃ receptor population in PD striatum. The precise explanation of this conundrum requires further studies with simultaneous examination of the central cannabinoid and dopaminergic systems in PD using higher sample size.
authors.affiliation: Department of Neurology, University of Debrecen, H-4012 Debrecen, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Farkas
authors.forename: Katalin
authors.initials: K
authors.lastname: Nagy
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Jia
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
authors.forename: Miklós
authors.initials: M
authors.lastname: Palkovits
authors.forename: Sean R
authors.initials: SR
authors.lastname: Donohou
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Domokos
authors.initials: D
authors.lastname: Máthé
authors.forename: László
authors.initials: L
authors.lastname: Csiba
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
mesh_terms: D000368:Aged; D001345:Autoradiography / Q000379:methods; D016022:Case-Control Studies; D002421:Caudate Nucleus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008297:Male; D010300:Parkinson Disease / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D011699:Putamen / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000493:pharmacokinetics; D020891:Raclopride / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D013893:Thiram / Q000493:pharmacokinetics
chemical_list: C572934:4-cyano-1-(2-iodophenyl)-5-(4-methoxyphenyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide; D018492:Dopamine Antagonists; D007457:Iodine Radioisotopes; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013893:Thiram; D020891:Raclopride