, Volume 198, Issue 4, pp 449–460 | Cite as

Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat

  • Andrea Cippitelli
  • Nazzareno Cannella
  • Simone Braconi
  • Andrea Duranti
  • Andrea Tontini
  • Ainhoa Bilbao
  • Fernando Rodríguez DeFonseca
  • Daniele Piomelli
  • Roberto Ciccocioppo
Original Investigation



A major clinical concern with the use of cannabinoid receptor 1 (CB1) direct agonists is that these compounds increase alcohol drinking and drug abuse-related behaviours. As an alternative approach, CB1-receptor-mediated activity can be facilitated by increasing anandamide levels with the use of hydrolase fatty acid amide hydrolase (FAAH) inhibitors.


Using the selective FAAH inhibitor URB597, we investigated whether activation of the endogenous cannabinoid tone increases alcohol abuse liability, as what happens with the CB1 receptor direct agonists.

Materials and methods

URB597 was tested on alcohol self-administration in Wistar rats and on homecage alcohol drinking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. In Wistar rats, URB597 effects on alcohol-induced anxiety and on stress-, yohimbine- and cue-induced reinstatement of alcohol seeking were also evaluated. For comparison, the effect of the CB1 receptor antagonist rimonabant on ethanol self-administration was also tested.


Under our experimental condition, intraperitoneal (IP) administration of URB597 (0.0, 0.3 and 1.0 mg/kg) neither increased voluntary homecage alcohol drinking in msP rats nor facilitated fixed ratio 1 and progressive ratio alcohol self-administration in nonselected Wistars. In the reinstatement tests, the compound did not have effects on cue-, footshock stress- and yohimbine-induced relapse. Conversely, URB597 completely abolished the anxiogenic response measured during withdrawal after an acute IP administration of alcohol (3.0 g/kg). Rimonabant (0.0, 0.3, 1.0 and 3.0 mg/kg) significantly reduced ethanol self-administration.


Results demonstrate that activation of the endocannabinoid anandamide system by selective inhibition of FAAH does not increase alcohol abuse risks but does reduce anxiety associated to alcohol withdrawal. We thus can speculate that medication based on the use of endocannabinoid system modulators such as URB597 may offer important advantages compared to treatment with direct CB1 receptor activators.


Anandamide Cannabinoids URB597 FAAH Alcohol drinking Relapse Alcohol self-administration 



This work was supported by the Italian MUR (Ministero dell’Università e della Ricerca), the University of Urbino, the Plan Nacional Sobre Drogas, REDES TEMATICAS RD06/001 and the 5th Framework Programme, grants TARGALC QLRT-2001-01048. The authors have no financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.


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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Andrea Cippitelli
    • 1
  • Nazzareno Cannella
    • 1
  • Simone Braconi
    • 1
  • Andrea Duranti
    • 2
  • Andrea Tontini
    • 2
  • Ainhoa Bilbao
    • 3
  • Fernando Rodríguez DeFonseca
    • 3
  • Daniele Piomelli
    • 4
  • Roberto Ciccocioppo
    • 1
  1. 1.Department of Experimental Medicine and Public HealthUniversity of CamerinoCamerinoItaly
  2. 2.Institute of Medicinal ChemistryUniversity of Urbino “Carlo Bo”UrbinoItaly
  3. 3.Fundación IMABISHospital Carlos Haya de MálagaMalagaSpain
  4. 4.Department of Pharmacology360 MSRII, University of CaliforniaIrvineUSA

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