# Presentation: 747560

## Mechanisms of 

**Mechanisms of **
**Endocannabinoid Inactivation:**
**Functional Consequences **
- Daniele Piomelli
- University of California, Irvine
- SfN, November 7, 2003

## Endocannabinoid signaling

**E**

**E**

**Endocannabinoid signaling**

**Synapse**

**E**

## Endocannabinoid deactivation

**Anandamide**
**2-AG**

**Endocannabinoid deactivation**

## Design of endocannabinoid transport inhibitors

***Beltramo et al., Science, 1997***
***Piomelli et al., PNAS, 1999***

## AM404 inhibits anandamide transport 

**in FAAH-deficient mice**

***Fegley et al., submitted***

## AM404 inhibits anandamide transport 

**AM404 inhibits anandamide transport **
**in FAAH-deficient mice**

## AM404 protects anandamide from inactivation

**AM404 protects anandamide from inactivation**
**in FAAH-deficient mice**

## AM1172: a transport inhibitor 

**AM1172: a transport inhibitor **
**not hydrolyzed by FAAH **

## Endocannabinoid transport inhibition 

**increases brain levels of anandamide**

***Giuffrida et al., submitted***

## Dopamine D2-receptor activation 

**Dopamine D****2****-receptor activation **
**of anandamide release**

***Giuffrida et al., Nat. Neurosci., 1999***

## Inhibition of endocannabinoid transport

**Inhibition of endocannabinoid transport**
**reduces amphetamine hyperactivity**

***Giuffrida et al., submitted***

## -

**Dopamine**

**D****2****R**

**D****1****R**

**CB****1****R**

**Psychomotor activity**

**+**

**Inactivation**

**Regulation of dopamine transmission by**
**endocannabinoid transport inhibition**

***Giuffrida et al., Nat. Neurosci., 1999***

## Conclusions

** ****AM404 protects anandamide from deactivation by inhibiting endocannabinoid transport**
** ****AM404 reduces psychostimulant drug actions by elevating brain endocannabinoid levels**
** ****Endocannabinoid transport might serve as target for the therapy of psychostimulant dependence or withdrawal **

## Endocannabinoid signaling

**E**

**E**

**Endocannabinoid signaling**

**Synapse**

**E**

## Design of carbamate inhibitors of FAAH

**Design of carbamate inhibitors of FAAH**

## Inhibition of brain FAAH activity in vivo

**ID****50****= 0.60 mg/kg**

**ID****50****= 0.15 mg/kg**

**Inhibition of brain FAAH activity *****in vivo***

***Kathuria et al., Nature Medicine, 2003***

## Effect on brain endocannabinoid levels

**Effect on brain endocannabinoid levels**

## Negative

**Negative**
**Negative**
**Weak**
**Weak**

**Catalepsy**
**Hypothermia**
**Stimulation of feeding**
**Analgesia**
**Hypolocomotion**

**Pharmacological actions of FAAH inhibitors:**
**lack of cannabinoid-like activity **

## Slide 19

## Anxiolytic-like effects of FAAH inhibitors:

**Isolation-induced vocalizations**

***Kathuria et al., Nature Medicine, 2003***

## Conclusions

** ****URB597  is a potent, selective and systemically active FAAH inhibitor**
** ****URB597 does not produce overt cannabinoid-like effects, but has anxiolytic-like properties that are mediated by its ability to elevate brain anandamide levels**
** ****FAAH may serve as target for the treatment of anxiety and depression**

## Thanks to:

**All the members of my lab, but particularly****:**
**Darren Fegley**
**Jin Fu**
**Silvana Gaetani**
**Andrea Giuffrida**
**Satish Kathuria**
**Jesse Lo Verme**
**Fariba Oveisi**

**All our collaborators, but particularly:**
**V. Cuomo (Rome, Italy) **
**F. Rodríguez de Fonseca (Malaga, Spain)**
**G. Tarzia, A. Duranti, A. Tontini (Urbino, Italy)**
**M.Mor (Parma, Italy)**

**NIDA for financial support**