title: Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys.
abstract: N-(4-hydroxyphenyl)-arachidonamide (AM404) is an anandamide transport inhibitor shown to reduce rewarding and relapse-inducing effects of nicotine in several animal models of tobacco dependence. However, the reinforcing/rewarding effects of AM404 are not clear.
  
  
  
  We investigated whether AM404 maintains self-administration behavior or reinstates extinguished drug seeking in squirrel monkeys.
  
  
  
  In monkeys with a history of anandamide or cocaine self-administration, we substituted injections of AM404 (1-100 μg/kg/injection). Using a 10-response, fixed-ratio schedule, self-administration behavior was maintained by AM404. Dose-response curves had inverted U shapes, with peak response rates occurring at a dose of 10 μg/kg/injection. In anandamide-experienced monkeys, we also demonstrated self-administration of another anandamide transport inhibitor VDM11. In addition to supporting self-administration, priming injections of AM404 (0.03-0.3 mg/kg) reinstated drug-seeking behavior previously reinforced by cannabinoids (∆(9)-tetrahydrocannabinol (THC) or anandamide) or cocaine. Both AM404 self-administration behavior and reinstatement of drug seeking by AM404 were reduced by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist rimonabant (0.3 mg/kg). Moreover, the reinforcing effects of AM404 were potentiated by the treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.3 mg/kg) suggesting a major role of anandamide in these effects. Finally, AM404 (0.3 mg/kg) potentiated the reinforcing effects of anandamide but not those of cocaine.
  
  
  
  In non-human primates, AM404 effectively reinforced self-administration behavior and induced reinstatement of drug-seeking behavior in abstinent monkeys. These effects appeared to be mediated by cannabinoid CB1 receptors. Therefore, compounds that promote actions of endocannabinoids throughout the brain by inhibiting their membrane transport may have a potential for abuse.
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 251 Bayview Boulevard, Baltimore, MD, 21224, USA. cschind@helix.nih.gov.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Schindler
authors.affiliation: Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Scherma
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
authors.forename: Godfrey H
authors.initials: GH
authors.lastname: Redhi
authors.affiliation: Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
authors.forename: Subramanian K
authors.initials: SK
authors.lastname: Vadivel
authors.affiliation: Center for Drug Discovery, Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Justinova
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D063388:Endocannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009538:Nicotine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012054:Reinforcement, Psychology; D012201:Reward; D000077285:Rimonabant; D012453:Saimiri; D012646:Self Administration
chemical_list: D001095:Arachidonic Acids; D001549:Benzamides; D063387:Cannabinoid Receptor Antagonists; D002219:Carbamates; D063388:Endocannabinoids; C462953:N-(2-methyl-3-hydroxyphenyl)-5,8,11,14-eicosatetraenamide; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; D009538:Nicotine; D013759:Dronabinol; D003042:Cocaine; D000077285:Rimonabant; C078814:anandamide; C107594:N-(4-hydroxyphenyl)arachidonylamide
keywords: AM404; Anandamide; Reinstatement; Rimonabant; Self-administration; Squirrel monkeys