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: Szabolcs Farkas, Katalin Nagy, Zhisheng Jia, Tibor Harkany, Miklós Palkovits, Sean R Donohou, Victor W Pike, Christer Halldin, Domokos Máthé, László Csiba, Balázs Gulyás
• Journal: Brain research bulletin (Brain Res Bull) Vol. 87 Issue 6 Pg. 504-10 (Apr 10 2012) ISSN: 1873-2747 [Electronic] United States
• PMID: 22421165 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• 4-cyano-1-(2-iodophenyl)-5-(4-methoxyphenyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide
• Dopamine Antagonists
• Iodine Radioisotopes
• Pyrazoles
• Receptor, Cannabinoid, CB1
• Receptors, Dopamine D2
• Receptors, Dopamine D3
• Thiram
• Raclopride

Topics

• Aged
• Autoradiography (methods)
• Case-Control Studies
• Caudate Nucleus (diagnostic imaging, drug effects, metabolism)
• Dopamine Antagonists (pharmacokinetics)
• Female
• Humans
• Iodine Radioisotopes (pharmacokinetics)
• Male
• Parkinson Disease (pathology)
• Protein Binding (drug effects)
• Putamen (diagnostic imaging, drug effects, metabolism)
• Pyrazoles (pharmacokinetics)
• Raclopride (pharmacokinetics)
• Radionuclide Imaging
• Receptor, Cannabinoid, CB1 (antagonists & inhibitors, metabolism)
• Receptors, Dopamine D2 (metabolism)
• Receptors, Dopamine D3 (metabolism)
• Thiram (pharmacokinetics)