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, Diego Centonze

Research output: Contribution to journalArticle

51 Citations (Scopus)

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 intrace-rebroventricular 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-pituitaryadrenal (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.

Original languageEnglish
Pages (from-to)260-268
Number of pages9
JournalMolecular Pharmacology
Volume78
Issue number2
DOIs
Publication statusPublished - Aug 2010

Fingerprint

Corpus Striatum
Cannabinoid Receptor CB1
Anti-Anxiety Agents
gamma-Aminobutyric Acid
Endocannabinoids
Synapses
fatty-acid amide hydrolase
Inhibition (Psychology)
Glutamic Acid
Anxiety
Phenotype

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Preservation of striatal cannabinoid CB1 receptor function correlates with the antianxiety effects of fatty acid amide hydrolase inhibition. / Rossi, Silvia; De Chiara, Valentina; Musella, Alessandra; Sacchetti, Lucia; Cantarella, Cristina; Castelli, Maura; Cavasinni, Francesca; Motta, Caterina; Studer, Valeria; Bernardi, Giorgio; Cravatt, Benjamin F.; Maccarrone, Mauro; Usiello, Alessandro; Centonze, Diego.

In: Molecular Pharmacology, Vol. 78, No. 2, 08.2010, p. 260-268.

Research output: Contribution to journalArticle

Rossi, Silvia ; De Chiara, Valentina ; Musella, Alessandra ; Sacchetti, Lucia ; Cantarella, Cristina ; Castelli, Maura ; Cavasinni, Francesca ; Motta, Caterina ; Studer, Valeria ; Bernardi, Giorgio ; Cravatt, Benjamin F. ; Maccarrone, Mauro ; Usiello, Alessandro ; Centonze, Diego. / Preservation of striatal cannabinoid CB1 receptor function correlates with the antianxiety effects of fatty acid amide hydrolase inhibition. In: Molecular Pharmacology. 2010 ; Vol. 78, No. 2. pp. 260-268.
@article{7def0b3196d3480d97843f0c29bceb65,
title = "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 intrace-rebroventricular 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-pituitaryadrenal (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.",
author = "Silvia Rossi and {De Chiara}, Valentina and Alessandra Musella and Lucia Sacchetti and Cristina Cantarella and Maura Castelli and Francesca Cavasinni and Caterina Motta and Valeria Studer and Giorgio Bernardi and Cravatt, {Benjamin F.} and Mauro Maccarrone and Alessandro Usiello and Diego Centonze",
year = "2010",
month = "8",
doi = "10.1124/mol.110.064196",
language = "English",
volume = "78",
pages = "260--268",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

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

PY - 2010/8

Y1 - 2010/8

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 intrace-rebroventricular 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-pituitaryadrenal (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.

AB - 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 intrace-rebroventricular 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-pituitaryadrenal (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.

UR - http://www.scopus.com/inward/record.url?scp=77954902977&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954902977&partnerID=8YFLogxK

U2 - 10.1124/mol.110.064196

DO - 10.1124/mol.110.064196

M3 - Article

C2 - 20424126

AN - SCOPUS:77954902977

VL - 78

SP - 260

EP - 268

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 2

ER -