Chronic FAAH inhibition during nicotine abstinence alters habenular CB1 receptor activity and precipitates depressive-like behaviors

Neuropharmacology. 2017 Feb;113(Pt A):252-259. doi: 10.1016/j.neuropharm.2016.10.007. Epub 2016 Oct 11.


The role of the endocannabinoid system in nicotine addiction is being increasingly acknowledged. Acute inhibition of anandamide (AEA) degradation efficiently reduces nicotine withdrawal-induced affective symptoms in rats and fatty acid amide hydrolase (FAAH), the degradation enzyme of AEA, has been proposed as a possible treatment against nicotine addiction. However, it is unclear whether chronic inhibition of AEA during nicotine abstinence will have beneficial or deleterious affective side-effects. Using a rat model of nicotine addiction, we found that, during abstinence, rats injected daily with a FAAH inhibitor (URB597) developed a depressive-like phenotype. Our results show that in the nicotine abstinent rats, URB597 induced low saccharin consumption, persistent immobility in the forced swim test and increased corticosterone levels in response to stress. In addition, URB597decreased CB1 receptor binding and activity in the habenula, a key structure in the control of nicotine-related emotional states. In contrast, non-treated abstinent rats showed increased CB1 receptor activity and behaviors comparable to controls. No FAAH inhibition-induced alterations were observed in animals that had a previous history of saline self-administration. Taken together, our results suggest that chronic FAAH inhibition prevents the homeostatic adaptations of habenular CB1 receptor function that are necessary for the recovery from nicotine dependence.

Keywords: Abstinence; CB1 receptor; Depressive-like behavior; Habenula; Nicotine; Rat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Amidohydrolases / metabolism*
  • Animals
  • Benzamides / pharmacology
  • Carbamates / pharmacology
  • Depression / metabolism*
  • Depression / psychology
  • Habenula / drug effects
  • Habenula / metabolism*
  • Male
  • Nicotine / administration & dosage*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Self Administration
  • Substance Withdrawal Syndrome / metabolism*
  • Substance Withdrawal Syndrome / psychology


  • Benzamides
  • Carbamates
  • Receptor, Cannabinoid, CB1
  • cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
  • Nicotine
  • Amidohydrolases
  • fatty-acid amide hydrolase