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Molecular Pharmacology

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Research ArticleArticle

Preservation of Striatal Cannabinoid CB1 Receptor Function Correlates with the Antianxiety Effects of Fatty Acid Amide Hydrolase Inhibition

Silvia Rossi, Valentina De Chiara, Alessandra Musella, Lucia Sacchetti, Cristina Cantarella, Maura Castelli, Francesca Cavasinni, Caterina Motta, Valeria Studer, Giorgio Bernardi, Benjamin F. Cravatt, Mauro Maccarrone, Alessandro Usiello and Diego Centonze
Molecular Pharmacology August 2010, 78 (2) 260-268; DOI: https://doi.org/10.1124/mol.110.064196
Silvia Rossi
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Valentina De Chiara
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Alessandra Musella
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Lucia Sacchetti
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Cristina Cantarella
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Maura Castelli
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Francesca Cavasinni
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Caterina Motta
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Valeria Studer
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Giorgio Bernardi
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Benjamin F. Cravatt
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Mauro Maccarrone
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Alessandro Usiello
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Diego Centonze
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Abstract

The endocannabinoid anandamide (AEA) plays a crucial role in emotional control, and inhibition of its degradation by the fatty acid amide hydrolase (FAAH) has a potent antianxiety effect. The mechanism by which the magnification of AEA activity reduces anxiety is still largely undetermined. By using FAAH mutant mice and both intraperitoneal and intracerebroventricular administration of the FAAH inhibitor (3′-(aminocarbonyl)[1,1′-biphenyl]-3-yl)-cyclohexylcarbamate (URB597), we found that enhanced AEA signaling reversed, via central cannabinoid CB1 receptors (CB1Rs), the anxious phenotype of mice exposed to social defeat stress. This behavioral effect was associated with preserved activity of CB1Rs regulating GABA transmission in the striatum, whereas these receptors were dramatically down-regulated by stress in control animals. The hypothalamic-pituitary-adrenal (HPA) axis was not involved in the antistress effects of FAAH inhibition, although the HPA axis is a biological target of endogenous AEA. We also provided some physiological indications that striatal CB1Rs regulating GABA synapses are not the receptor targets of FAAH inhibition, which rather resulted in the stimulation of striatal CB1Rs regulating glutamate transmission. Collectively, our findings suggest that preservation of cannabinoid CB1 receptor function within the striatum is a possible synaptic correlate of the antianxiety effects of FAAH inhibition.

Footnotes

  • This investigation was supported by the Italian Ministero dell'Università e della Ricerca [Grant 2006064219-003].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.064196.

  • ABBREVIATIONS:

    AEA
    anadamide
    CB1R
    cannabinoid CB1 receptor
    sEPSC
    spontaneous excitatory postsynaptic current
    EPM
    elevated plus maze
    FAAH
    fatty acid amide hydrolase
    sIPSC
    spontaneous inhibitory postsynaptic current
    OFT
    open-field test
    URB597
    (3′-(aminocarbonyl)[1,1′-biphenyl]-3-yl)-cyclohexylcarbamate
    HU210
    (6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol
    MK-801
    (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate
    DMSO
    dimethyl sulfoxide
    WT
    wild type
    AM251
    1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide
    RU486
    17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one
    BAPTA
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid.

  • Received February 15, 2010.
  • Accepted April 27, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (2)
Molecular Pharmacology
Vol. 78, Issue 2
1 Aug 2010
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Research ArticleArticle

Preservation of Striatal Cannabinoid CB1 Receptor Function Correlates with the Antianxiety Effects of Fatty Acid Amide Hydrolase Inhibition

Silvia Rossi, Valentina De Chiara, Alessandra Musella, Lucia Sacchetti, Cristina Cantarella, Maura Castelli, Francesca Cavasinni, Caterina Motta, Valeria Studer, Giorgio Bernardi, Benjamin F. Cravatt, Mauro Maccarrone, Alessandro Usiello and Diego Centonze
Molecular Pharmacology August 1, 2010, 78 (2) 260-268; DOI: https://doi.org/10.1124/mol.110.064196

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Research ArticleArticle

Preservation of Striatal Cannabinoid CB1 Receptor Function Correlates with the Antianxiety Effects of Fatty Acid Amide Hydrolase Inhibition

Silvia Rossi, Valentina De Chiara, Alessandra Musella, Lucia Sacchetti, Cristina Cantarella, Maura Castelli, Francesca Cavasinni, Caterina Motta, Valeria Studer, Giorgio Bernardi, Benjamin F. Cravatt, Mauro Maccarrone, Alessandro Usiello and Diego Centonze
Molecular Pharmacology August 1, 2010, 78 (2) 260-268; DOI: https://doi.org/10.1124/mol.110.064196
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