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Research ArticleArticle

Evidence for a New G Protein-Coupled Cannabinoid Receptor in Mouse Brain

Christopher S. Breivogel, Graeme Griffin, Vincenzo Di Marzo and Billy R. Martin
Molecular Pharmacology July 2001, 60 (1) 155-163; DOI: https://doi.org/10.1124/mol.60.1.155
Christopher S. Breivogel
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Graeme Griffin
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Vincenzo Di Marzo
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Billy R. Martin
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Abstract

The purpose of these studies was to support the hypothesis that an undiscovered cannabinoid receptor exists in brain. [35S]GTPγS binding was stimulated by anandamide and WIN55212-2 in brain membranes from both CB1 +/+and CB1 −/− mice. In contrast, a wide variety of other compounds that are known to activate CB1receptors, including CP55940, HU-210, and Δ9-tetrahydrocannabinol, failed to stimulate [35S]GTPγS binding in CB1 −/−membranes. In CB1 −/− membranes, SR141716A affected both basal and anandamide- or WIN55212-2-induced stimulation of [35S]GTPγS binding only at concentrations greater than 1 μM. In CB1 +/+ membranes, SR141716A inhibited only 84% of anandamide and 67% of WIN55212-2 stimulated [35S]GTPγS binding with an affinity appropriate for mediation by CB1 receptors (K B ≈ 0.5 nM). The remaining stimulation seemed to be inhibited with lower potency (IC50 ≈ 5 μM) similar to that seen in CB1 −/− membranes or in the absence of agonist. Further experiments determined that the effects of anandamide and WIN55212-2 were not additive, but that the effect of μ opioid, adenosine A1, and cannabinoid ligands were additive. Finally, assays of different central nervous system (CNS) regions demonstrated significant activity of cannabinoids in CB1 −/− membranes from brain stem, cortex, hippocampus, diencephalon, midbrain, and spinal cord, but not basal ganglia or cerebellum. Moreover, some of these same CNS regions also showed significant binding of [3H]WIN55212-2, but not [3H]CP55940. Thus anandamide and WIN55212-2 seemed to be active in CB1 −/− mouse brain membranes via a common G protein-coupled receptor with a distinct CNS distribution, implying the existence of an unknown cannabinoid receptor subtype in brain.

Footnotes

  • Send reprint requests to: Dr. Billy R. Martin, Ph.D., Department of Pharmacology and Toxicology, Virginia Commonwealth University, P. O. Box 980613, Richmond VA, 23298-0613. E-mail:martinb{at}hsc.vcu.edu

  • ↵1 Current address: Dr. Christopher S. Breivogel, Ph.D., School of Pharmacy, Campbell University, P.O. Box 1090, Buies Creek, NC 27506.

  • This work was supported by National Istitute on Drug Abuse Training Grant DA07027 (C.S.B.) and Grants DA09789 and DA03672 (B.R.M.). V.D.M. was the recipient of a Human Frontier Science Program short-term fellowship.

  • Abbreviations

    THC
    tetrahydrocannabinol
    GTPγS
    guanosine-5′-O-(3-thiotriphosphate)
    CNS
    central nervous system
    DAMGO
    [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
    PIA
    N6-(2-phenylisopropyl)adenosine
    BSA
    bovine serum albumin
    ANOVA
    analysis of variance
    • Received October 31, 2000.
    • Accepted March 28, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Molecular Pharmacology: 60 (1)
    Molecular Pharmacology
    Vol. 60, Issue 1
    1 Jul 2001
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    Research ArticleArticle

    Evidence for a New G Protein-Coupled Cannabinoid Receptor in Mouse Brain

    Christopher S. Breivogel, Graeme Griffin, Vincenzo Di Marzo and Billy R. Martin
    Molecular Pharmacology July 1, 2001, 60 (1) 155-163; DOI: https://doi.org/10.1124/mol.60.1.155

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    Research ArticleArticle

    Evidence for a New G Protein-Coupled Cannabinoid Receptor in Mouse Brain

    Christopher S. Breivogel, Graeme Griffin, Vincenzo Di Marzo and Billy R. Martin
    Molecular Pharmacology July 1, 2001, 60 (1) 155-163; DOI: https://doi.org/10.1124/mol.60.1.155
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