1. ¹Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain
2. ²Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain
3. ³Proteomics Laboratory, Department of Health and Human Services, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
4. ⁴Preclinical Pharmacology Section, Department of Health and Human Services, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
5. ⁵Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA
6. ⁶Pharmaceutical Institute, University of Bonn, Bonn, Germany
7. ⁷Neurobiology of Relapse Section, Department of Health and Human Services, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA

Correspondence: Dr S Ferré, Preclinical Pharmacology Section, Department of Health and Human Services, National Institute on Drug Abuse, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224, USA. E-mail: sferre@intra.nida.nih.gov

⁸These authors contributed equally to this work.

Received 3 August 2006; Revised 18 January 2007; Accepted 19 January 2007; Published online 14 March 2007.

Abstract

The mechanism of action responsible for the motor depressant effects of cannabinoids, which operate through centrally expressed cannabinoid CB₁ 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.