Modulation of anxiety through blockade of anandamide hydrolysis

By S. Kathuria, S. Gaetani, D. Fegley, F. Valiño, A. Duranti, A. Tontini, M. Mor, G. Tarzia, G. L. Rana, A. Calignano and 5 more. Nature Medicine, 2003

1,036 citations recorded by the source corpus.

The psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol, produces in humans subjective responses mediated by CB1 cannabinoid receptors, indicating that endogenous cannabinoids may contribute to the control of emotion. But the variable effects of Δ9-tetrahydrocannabinol obscure the interpretation of these results and limit the therapeutic potential of direct cannabinoid agonists. An alternative approach may be to develop drugs that amplify the effects of endogenous cannabinoids by preventing their inactivation. Here we describe a class of potent, selective and systemically active inhibitors of fatty acid amide hydrolase, the enzyme responsible for the degradation of the endogenous cannabinoid anandamide. Like clinically used anti-anxiety drugs, in rats the inhibitors exhibit benzodiazepine-like properties in the elevated zero-maze test and suppress isolation-induced vocalizations. These effects are accompanied by augmented brain levels of anandamide and are prevented by CB1 receptor blockade. Our results indicate that anandamide participates in the modulation of emotional states and point to fatty acid amide hydrolase inhibition as an innovative approach to anti-anxiety therapy.

Subfields: Cellular and Molecular Neuroscience, Pharmacology, Toxicology

View Paper: https://www.semanticscholar.org/paper/60abe8a5a986f605cda90072d46992fcad5f969a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. Tamás F. Freund
2. I. Katona
3. P. Pacher
4. S. Batkai
5. George Kunos
6. B. Cravatt
7. Jacqueline L. Blankman
8. G. Simon

In Pharmacology

1. B. Cravatt
2. Tamás F. Freund
3. I. Katona
4. P. Pacher
5. S. Batkai
6. George Kunos
7. Jacqueline L. Blankman
8. G. Simon

In Toxicology

1. B. Cravatt
2. Jonathan Z. Long
3. Tamás F. Freund
4. I. Katona
5. George Kunos

Citations in the corpus

• The endocannabinoid system drives neural progenitor proliferation (2005, neutral): “URB597 and 2AG were from Cayman Chemicals, mouse monoclonal anti-nestin and rabbit polyclonal anti-FAAH antibodies from Chemicon, and rabbit monoclonal anti-Ki-67 (clone SP6) antibody from LabVision.”
• The emerging role of the endocannabinoid system in endocrine regulation and energy balance. (2006, background): “anxiety-like response in different tasks (147).”
• The endocannabinoid system links gut microbiota to adipogenesis (2010, background): “Consistent with the results obtained using the cannabinoid receptor agonist, inhibition of AEA degradation by administration of a potent FAAH inhibitor, URB597 (Kathuria et al, 2003), significantly increased AEA levels (CT: 100±7.4%; URB597: 117.5±4.9; Po0.”
• Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects (2008, background): “Other MAGs, such as mono-palmitoylglycerol (14) (PG) and mono-oleoylglycerol (15) (OG), and their corresponding free fatty acids, palmitic (16) and oleic acid (17), respectively, were not significantly altered in brains from JZL184-treated animals (Supplementary Fig.”
• Neurobiological Interactions Between Stress and the Endocannabinoid System (2016, background): “The putative role of AEA in regulating anxiety was first highlighted by the Piomelli laboratory, who demonstrated that inhibition of AEA-hydrolysis by FAAH resulted in a reduction of anxiety (Kathuria et al, 2003).”
• A Comprehensive Profile of Brain Enzymes that Hydrolyze the Endocannabinoid 2‐Arachidonoylglycerol (2007, background): “Consistent with these previous studies, we observed selective blockade of FP-rhodamine labeling of FAAH and ABHD6 in brain-membrane proteomes treated with URB597 (10 mM) and WWL70 (10 mM), respectively (Figure 5A).”
• The endocannabinoid system and the brain. (2013, background): “The Piomelli group (Kathuria et al. 2003) reported a novel class of potent, selective, and systemically active carbamatebased inhibitors of FAAH, the enzyme responsible for the degradation of anandamide.”
• Role of endogenous cannabinoids in synaptic signaling. (2003, background): “The pharmacological profile of URB597, which is currently under investigation, includes profound antianxiety effects accompanied by modest analgesia (185).”
• The Endocannabinoid System as an Emerging Target of Pharmacotherapy (2006, background): “Surprisingly, the use of cannabinoid receptor antagonists, including SR141716, AM281, AM251, and SR144528, also leads to survival benefits in endotoxic and septic shock or necrotizing pancreatitis (Varga et al., 1998; Smith et al., 2000, 2001; Cainazzo et al., 2002; Kadoi et al., 2005a,b; Matsuda et”