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Preservation of striatal cannabinoid CB1 receptor function correlates with the antianxiety effects of fatty acid amide hydrolase inhibition.

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.

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  • Authors+Show Affiliations

    ,

    Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.

    , , , , , , , , , , , ,

    Source

    Molecular pharmacology 78:2 2010 Aug pg 260-8

    MeSH

    Amidohydrolases
    Animals
    Anti-Anxiety Agents
    Corpus Striatum
    Enzyme Inhibitors
    Mice
    Receptor, Cannabinoid, CB1

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    20424126

    Citation

    Rossi, Silvia, et al. "Preservation of Striatal Cannabinoid CB1 Receptor Function Correlates With the Antianxiety Effects of Fatty Acid Amide Hydrolase Inhibition." Molecular Pharmacology, vol. 78, no. 2, 2010, pp. 260-8.
    Rossi S, De Chiara V, Musella A, et al. Preservation of striatal cannabinoid CB1 receptor function correlates with the antianxiety effects of fatty acid amide hydrolase inhibition. Mol Pharmacol. 2010;78(2):260-8.
    Rossi, S., De Chiara, V., Musella, A., Sacchetti, L., Cantarella, C., Castelli, M., ... Centonze, D. (2010). Preservation of striatal cannabinoid CB1 receptor function correlates with the antianxiety effects of fatty acid amide hydrolase inhibition. Molecular Pharmacology, 78(2), pp. 260-8. doi:10.1124/mol.110.064196.
    Rossi S, et al. Preservation of Striatal Cannabinoid CB1 Receptor Function Correlates With the Antianxiety Effects of Fatty Acid Amide Hydrolase Inhibition. Mol Pharmacol. 2010;78(2):260-8. PubMed PMID: 20424126.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Preservation of striatal cannabinoid CB1 receptor function correlates with the antianxiety effects of fatty acid amide hydrolase inhibition. AU - Rossi,Silvia, AU - De Chiara,Valentina, AU - Musella,Alessandra, AU - Sacchetti,Lucia, AU - Cantarella,Cristina, AU - Castelli,Maura, AU - Cavasinni,Francesca, AU - Motta,Caterina, AU - Studer,Valeria, AU - Bernardi,Giorgio, AU - Cravatt,Benjamin F, AU - Maccarrone,Mauro, AU - Usiello,Alessandro, AU - Centonze,Diego, Y1 - 2010/04/27/ PY - 2010/4/29/entrez PY - 2010/4/29/pubmed PY - 2010/8/4/medline SP - 260 EP - 8 JF - Molecular pharmacology JO - Mol. Pharmacol. VL - 78 IS - 2 N2 - 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. SN - 1521-0111 UR - https://www.unboundmedicine.com/medline/citation/20424126/Preservation_of_striatal_cannabinoid_CB1_receptor_function_correlates_with_the_antianxiety_effects_of_fatty_acid_amide_hydrolase_inhibition_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=20424126 DB - PRIME DP - Unbound Medicine ER -