Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids

Paulina Carriba; Oskar Ortiz; Kshitij Patkar; Zuzana Justinova; Jessica Stroik; Andrea Themann; Christa Müller; Anima S. Woods; Bruce T. Hope; Francisco Ciruela; Vicent Casadó; Enric I. Canela; Carme Lluis; Steven R. Goldberg; Rosario Moratalla; Rafael Franco; Sergi Ferré

doi:10.1038/sj.npp.1301375

Striatal adenosine A_2A and cannabinoid CB₁ receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids

Paulina Carriba, Oskar Ortiz, Kshitij Patkar, Zuzana Justinova, Jessica Stroik, Andrea Themann, Christa Müller, Anima S. Woods, Bruce T. Hope, Francisco Ciruela, Vicent Casadó, Enric I. Canela, Carme Lluis, Steven R. Goldberg, Rosario Moratalla, Rafael Franco, Sergi Ferré

Research output: Contribution to journal › Article › peer-review

188 Scopus citations

Abstract

The mechanism of action responsible for the motor depressant effects of cannabinoids, which operate through centrally expressed cannabinoid CB ₁ receptors, is still a matter of debate. In the present study, we report that CB₁ and adenosine A_2A receptors form heteromeric complexes in co-transfected HEK-293T cells and rat striatum, where they colocalize in fibrilar structures. In a human neuroblastoma cell line, CB₁ receptor signaling was found to be completely dependent on A _2A receptor activation. Accordingly, blockade of A_2A receptors counteracted the motor depressant effects produced by the intrastriatal administration of a cannabinoid CB₁ receptor agonist. These biochemical and behavioral findings demonstrate that the profound motor effects of cannabinoids depend on physical and functional interactions between striatal A_2A and CB₁ receptors.

Original language	English (US)
Pages (from-to)	2249-2259
Number of pages	11
Journal	Neuropsychopharmacology
Volume	32
Issue number	11
DOIs	https://doi.org/10.1038/sj.npp.1301375
State	Published - Nov 2007
Externally published	Yes

Keywords

Adenosine A receptor
Cannabinoid CB receptor
Cyclic AMP
Motor activity
Receptor heteromerization
Striatum

ASJC Scopus subject areas

Pharmacology

Access to Document

10.1038/sj.npp.1301375

Cite this

Carriba, P., Ortiz, O., Patkar, K., Justinova, Z., Stroik, J., Themann, A., Müller, C., Woods, A. S., Hope, B. T., Ciruela, F., Casadó, V., Canela, E. I., Lluis, C., Goldberg, S. R., Moratalla, R., Franco, R., & Ferré, S. (2007). Striatal adenosine A_2A and cannabinoid CB₁ receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids. Neuropsychopharmacology, 32(11), 2249-2259. https://doi.org/10.1038/sj.npp.1301375

Carriba, P, Ortiz, O, Patkar, K, Justinova, Z, Stroik, J, Themann, A, Müller, C, Woods, AS, Hope, BT, Ciruela, F, Casadó, V, Canela, EI, Lluis, C, Goldberg, SR, Moratalla, R, Franco, R & Ferré, S 2007, 'Striatal adenosine A_2A and cannabinoid CB₁ receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids', Neuropsychopharmacology, vol. 32, no. 11, pp. 2249-2259. https://doi.org/10.1038/sj.npp.1301375

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abstract = "The mechanism of action responsible for the motor depressant effects of cannabinoids, which operate through centrally expressed cannabinoid CB 1 receptors, is still a matter of debate. In the present study, we report that CB1 and adenosine A2A receptors form heteromeric complexes in co-transfected HEK-293T cells and rat striatum, where they colocalize in fibrilar structures. In a human neuroblastoma cell line, CB1 receptor signaling was found to be completely dependent on A 2A receptor activation. Accordingly, blockade of A2A receptors counteracted the motor depressant effects produced by the intrastriatal administration of a cannabinoid CB1 receptor agonist. These biochemical and behavioral findings demonstrate that the profound motor effects of cannabinoids depend on physical and functional interactions between striatal A2A and CB1 receptors.",

keywords = "Adenosine A receptor, Cannabinoid CB receptor, Cyclic AMP, Motor activity, Receptor heteromerization, Striatum",

author = "Paulina Carriba and Oskar Ortiz and Kshitij Patkar and Zuzana Justinova and Jessica Stroik and Andrea Themann and Christa M{\"u}ller and Woods, {Anima S.} and Hope, {Bruce T.} and Francisco Ciruela and Vicent Casad{\'o} and Canela, {Enric I.} and Carme Lluis and Goldberg, {Steven R.} and Rosario Moratalla and Rafael Franco and Sergi Ferr{\'e}",

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AU - Justinova, Zuzana

AU - Stroik, Jessica

AU - Themann, Andrea

AU - Müller, Christa

AU - Woods, Anima S.

AU - Hope, Bruce T.

AU - Ciruela, Francisco

AU - Casadó, Vicent

AU - Canela, Enric I.

AU - Lluis, Carme

AU - Goldberg, Steven R.

AU - Moratalla, Rosario

AU - Franco, Rafael

AU - Ferré, Sergi

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AB - The mechanism of action responsible for the motor depressant effects of cannabinoids, which operate through centrally expressed cannabinoid CB 1 receptors, is still a matter of debate. In the present study, we report that CB1 and adenosine A2A receptors form heteromeric complexes in co-transfected HEK-293T cells and rat striatum, where they colocalize in fibrilar structures. In a human neuroblastoma cell line, CB1 receptor signaling was found to be completely dependent on A 2A receptor activation. Accordingly, blockade of A2A receptors counteracted the motor depressant effects produced by the intrastriatal administration of a cannabinoid CB1 receptor agonist. These biochemical and behavioral findings demonstrate that the profound motor effects of cannabinoids depend on physical and functional interactions between striatal A2A and CB1 receptors.

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