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Expression of GPR55 and either cannabinoid CB1 or CB2 heteroreceptor complexes in the caudate, putamen, and accumbens nuclei of control, parkinsonian, and dyskinetic non-human primates

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Endocannabinoids are neuromodulators acting on specific cannabinoid CB1 and CB2 G-protein-coupled receptors (GPCRs), representing potential therapeutic targets for neurodegenerative diseases. Cannabinoids also regulate the activity of GPR55, a recently “deorphanized” GPCR that directly interacts with CB1 and with CB2 receptors. Our hypothesis is that these heteromers may be taken as potential targets for Parkinson’s disease (PD). This work aims at assessing the expression of heteromers made of GPR55 and CB1/CB2 receptors in the striatum of control and parkinsonian macaques (with and without levodopa-induced dyskinesia). For this purpose, double blind in situ proximity ligation assays, enabling the detection of GPCR heteromers in tissue samples, were performed in striatal sections of control, MPTP-treated and MPTP-treated animals rendered dyskinetic by chronic treatment with levodopa. Image analysis and statistical assessment were performed using dedicated software. We have previously demonstrated the formation of heteromers between GPR55 and CB1 receptor (CB1-GPR55_Hets), which is highly expressed in the central nervous system (CNS), but also with the CB2 receptor (CB2-GPR55_Hets). Compared to the baseline expression of CB1-GPR55_Hets in control animals, our results showed increased expression levels in basal ganglia input nuclei of MPTP-treated animals. These observed increases in CB1-GPR55_Hets returned back to baseline levels upon chronic treatment with levodopa in dyskinetic animals. Obtained data regarding CB2-GPR55_Hets were quite similar, with somehow equivalent amounts in control and dyskinetic animals, and with increased expression levels in MPTP animals. Taken together, the detected increased expression of GPR55-endocannabinoid heteromers appoints these GPCR complexes as potential non-dopaminergic targets for PD therapy.

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Complexes formed by CB1 and GPR55 receptors


CB1 receptors


Complexes formed by CB2 and GPR55 receptors


CB2 receptors


Contrast Limited Adaptive Histogram Equalization


Central nervous system


G-protein-coupled receptors




Parkinson’s disease


In situ proximity ligation assay


Substantia nigra


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This work was supported by grants from Spanish Ministerio de Economía y Competitividad (MINECO) (#BFU2012-37907, #SAF2008-03118-E and #SAF2012-39875-C02-01; they may include EU FEDER funds), Eranet-Neuron (Heteropark), CIBERNED (CB06/05/006), Fundació La Marató de TV3 [20141330 to RF, and 20141331 to JLL] and by Departamento de Salud del Gobierno de Navarra.

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JLL, GN and RF participated in the design of the project and analyzed the results; it is considered that their contribution was similar. EMP and AJR performed the majority of the experiments and took care of animals and measured ad hoc scores; it is considered that their contribution was similar. ER participated in a significant number of experiments. RRS and JL incorporated the software to analyze the PLA results, and actively participated in the PLA data analysis and in providing data for final Figures. JLL did many of the imaging assays in the confocal microscope, took images and participated in data analysis. EMP, JLL and RF wrote the first draft of the manuscript that was further edited by all co-authors, who agreed with submission.

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Correspondence to Eva Martínez-Pinilla, José Luis Lanciego or Rafael Franco.

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The authors declare no conflict of interest.

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All experiments have been performed with approved protocols and under the regional supervision, i.e. strictly following all national and EU regulations.

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Martínez-Pinilla, E., Rico, A.J., Rivas-Santisteban, R. et al. Expression of GPR55 and either cannabinoid CB1 or CB2 heteroreceptor complexes in the caudate, putamen, and accumbens nuclei of control, parkinsonian, and dyskinetic non-human primates. Brain Struct Funct 225, 2153–2164 (2020).

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