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


OBJECTIVE
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.


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.


RESULTS
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.


CONCLUSIONS
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.
Cippitelli
Andrea
A
Department of Experimental Medicine and Public Health, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy.
Cannella
Nazzareno
N
Braconi
Simone
S
Duranti
Andrea
A
Tontini
Andrea
A
Bilbao
Ainhoa
A
Defonseca
Fernando Rodríguez
FR
Piomelli
Daniele
D
Ciccocioppo
Roberto
R
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000428:Alcohol Drinking / Q000235:genetics / Q000523:psychology; D000437:Alcoholism / Q000235:genetics / Q000523:psychology*; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001007:Anxiety / Q000523:psychology; D001095:Arachidonic Acids / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology*; D002219:Carbamates / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004597:Electroshock; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D012008:Recurrence; D012055:Reinforcement Schedule; D012646:Self Administration; D013315:Stress, Psychological / Q000523:psychology; D015016:Yohimbine / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
D000317:Adrenergic alpha-Antagonists; D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D015016:Yohimbine; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C078814:anandamide