title: The anandamide transport inhibitor AM404 reduces ethanol self-administration.
abstract: The endocannabinoid system mediates in the pharmacological actions of ethanol and genetic studies link endocannabinoid signaling to alcoholism. Drugs activating cannabinoid CB1 receptors have been found to promote alcohol consumption but their effects on self-administration of alcohol are less clear because of the interference with motor performance. To avoid this problem, a novel pharmacological approach to the study of the contribution of the cannabinoid system in alcoholism may be to use drugs that locally amplify the effects of alcohol on endogenous cannabinoids. In the present study we addressed this model by studying the effects of the anandamide transport inhibitor N-(4-hydroxyphenyl) arachidonoyl-ethanolamide (AM404) on both ethanol self-administration and reinstatement of alcohol-seeking behavior in rats. The results show that AM404 significantly reduced ethanol self-administration in a dose-dependent manner but failed to modify reinstatement for lever pressing induced by the stimulus associated with alcohol. This effect was not due to a motor depressant effect and was not related to a decrease in general motivational state, as it was not effective in other reward paradigms such as lever pressing for a saccharin solution. The mechanism of action of AM404 does not involve cannabinoid CB1 receptors as the CB1-selective antagonist SR141716A did not block the reduction of ethanol self-administration induced by the anandamide uptake blocker. Moreover, 3-(1,1-dimethylheptyl)-(-)-11-hydroxy-delta 8-tetrahydrocannabinol (HU-210), a classical cannabinoid receptor agonist, did not affect ethanol self-administration. The effects of AM404 are not mediated by either vanilloid VR1 receptors or cannabinoid CB2 receptors because it is not antagonized by either the VR1 receptor antagonist capsazepine or the CB2 antagonist AM630. These results indicate that AM404 may be considered as an innovative approach to reduce alcohol consumption.
authors.affiliation: Fundación IMABIS (The European TARGALC Consortium), Hospital Carlos Haya, Avenida Carlos Haya s/n, 7 Planta, Pabellón A, 29010 Málaga, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cippitelli
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Bilbao
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Gorriti
authors.forename: Miguel
authors.initials: M
authors.lastname: Navarro
authors.forename: Maurizio
authors.initials: M
authors.lastname: Massi
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
mesh_terms: D000428:Alcohol Drinking / Q000523:psychology; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D003864:Depression, Chemical; D063388:Endocannabinoids; D000431:Ethanol / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects; D007035:Hypothermia / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors; D012054:Reinforcement, Psychology; D012439:Saccharin / Q000494:pharmacology; D012646:Self Administration; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors
chemical_list: D001095:Arachidonic Acids; D002492:Central Nervous System Depressants; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D000431:Ethanol; D012439:Saccharin; C071423:capsazepine; D002211:Capsaicin; C078814:anandamide; C107594:N-(4-hydroxyphenyl)arachidonylamide