Objective/Rationale:
Future therapies in Parkinson’s disease (PD) may derive from the existence of intramembrane heteromeric receptor complexes containing the dopamine D2 receptor. The ability of cannabinoids to alter movement, coupled to the localization of cannabinoid CB1
receptors within basal ganglia has encouraged research into use of cannabinoids in the treatment of hypokinetic movement disorders. However, the mechanism of motor depressant effects of cannabinoids remains unresolved. One possible level of modulation between the dopaminergic and cannabinoid system is direct interaction between CB1 cannabinoid and D2 dopamine receptors. Based on recent findings we hypothesize that
CB1/D2 and A2A/CB1 interactions operate in CB1/D2/A2A complexes thereby opening up a new mechanism for the integration of endocannabinoid and dopamine mediated signals.
The major objective of this research is to investigate how dopamine D2 receptor mosaics containing adenosine A2A and CB1 receptors are altered after 6-OHDA-induced degeneration of the nigro-striatal dopamine system, a known model of PD.
Project Description:
Unilateral neurotoxin induced lesioning of the rat nigro-striatal dopamine pathway will be used as the animal model of PD. Striatal tissue from naive (control rats); 6-OHDAtreated or sham-treated rats will be assayed. A detailed biochemical analysis and quantification of CB1, D2 and A2A receptor densities and analysis of their agonist binding characteristics of CB1, D2 and A2A will be performed. Furthermore, an extensive biochemical analysis of agonist modulation of CB1/D2 and CB1/A2A and A2A/D2 receptor
heteromers will be determined to investigate alterations associated with DA denervation. Additionally, an analysis and quantification of CB1, D2 and A2A receptor G-protein coupling will be determined as well as the determination of the specific G-protein isoform and the sub-cellular localization associated with each receptor in striatal tissue.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Data will advance understanding of alterations in dopaminergic signaling in PD and indicate future development of treatments to compensate for reduced DA signaling and hypokinesia. Specifically a complete understanding of the CB1/D2/A2A interactions in receptor mosaics at the level of agonist recognition and G-protein coupling will advance the understanding of the indirect-pathway’s critical role in the control of movement with the possible introduction of CB1 receptor antagonists as a novel strategy for treatment of PD.
Anticipated Outcome:
A report will be delivered giving the identification of the major receptor-receptor interactions in the postulated CB1/D2/A2A receptor mosaics at the recognition and Gprotein coupling level in striatal membranes and how they become altered in a pre-clinical model
of Parkinson’s disease. Such knowledge is crucial for development of optimal treatment strategies against PD with the introduction of CB1 antagonists in combination with A2A antagonists and/or D2 agonists including L-dopa.
Final Outcome
Dr. Fuxe found that loss of dopamine signaling in the 6-OHDA-lesioned pre-clinical model leads to increased density of the CB1 receptor in the striatum. Data point to the use of CB1 receptor antagonists as potential therapeutic targets for PD.