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      Striatal Adenosine A2A and Cannabinoid CB1 Receptors Form Functional Heteromeric Complexes that Mediate the Motor Effects of Cannabinoids

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          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 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 A2A 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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          Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers.

          Francisco Ciruela, Vicent Casadó, Ricardo J Rodrigues … (2006)
          The functional role of heteromers of G-protein-coupled receptors is a matter of debate. In the present study, we demonstrate that heteromerization of adenosine A1 receptors (A1Rs) and A2A receptors (A2ARs) allows adenosine to exert a fine-tuning modulation of glutamatergic neurotransmission. By means of coimmunoprecipitation, bioluminescence and time-resolved fluorescence resonance energy transfer techniques, we showed the existence of A1R-A2AR heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A1R and A2AR are colocalized in the same striatal glutamatergic nerve terminals. Radioligand-binding experiments in cotransfected cells and rat striatum showed that a main biochemical characteristic of the A1R-A2AR heteromer is the ability of A2AR activation to reduce the affinity of the A1R for agonists. This provides a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. Furthermore, it is also shown that A1R-A2AR heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A1R-A2AR heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.
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            Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice.

            C Ledent, G Vassart, J-F Aubert … (1999)
            The function of the central cannabinoid receptor (CB1) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive role of the CB1 receptor in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced. These observations suggest that the CB1 receptor is involved in the motivational properties of opiates and in the development of physical dependence and extend the concept of an interconnected role of CB1 and opiate receptors in the brain areas mediating addictive behavior.
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              Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia.

              Sergi Ferré, Kjell Fuxe, Bertil B. Fredholm … (1997)
              Increasing evidence suggests that antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the basal ganglia are involved in the motor depressant effects of adenosine receptor agonists and the motor stimulant effects of adenosine receptor antagonists, such as caffeine. The GABAergic striatopallidal neurons are regulated by interacting adenosine A2A and dopamine D2 receptors. On the other hand, the GABAergic striatonigral and striatoentopeduncular neurons seem to be regulated by interacting adenosine A1 and dopamine D1 receptors. Furthermore, behavioural studies have revealed interactions between adenosine A2A and dopamine D1 receptors that occur at the network level. These adenosine-dopamine receptor-receptor interactions might offer new therapeutic leads for basal ganglia disorders.
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                Author and article information

                Journal
                Title: Neuropsychopharmacology
                Abbreviated Title: Neuropsychopharmacol
                Publisher: Springer Science and Business Media LLC
                ISSN (Print): 0893-133X
                ISSN (Electronic): 1740-634X
                Publication date Created: November 2007
                Publication date (Electronic): March 14 2007
                Publication date (Print): November 2007
                Volume: 32
                Issue: 11
                Pages: 2249-2259
                Article
                DOI: 10.1038/sj.npp.1301375
                PubMed ID: 17356572
                SO-VID: d27df515-a81b-412f-8cc0-b1d2676372dd
                Copyright © © 2007
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                http://www.springer.com/tdm

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