title: Evaluation of the abuse potential of AM281, a new synthetic cannabinoid CB1 receptor antagonist.
abstract: AM281 (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide) is a new synthetic cannabinoid CB1 receptor antagonist. Similar to other cannabinoid antagonists, AM281 has been suggested to have therapeutic indications. However, recent reports have suggested that cannabinoid CB1 receptor antagonists may share similar behavioral effects with other drugs of abuse such as cocaine and amphetamine. These reports cast doubts on the safety profile of AM281. Thus, in the present study we evaluated the abuse potential (rewarding and reinforcing effects) of AM281 through two of the most widely used animal models for assessing the abuse potential of drugs: the conditioned place preference (CPP) and self-administration (SA) tests. Experiments were performed in Sprague-Dawley rats in various dosages [CPP (0.1, 0.5 or 2.5mg/kg), SA (0.005, 0.025 or 0.1mg/kg/infusion)]. We also delved into the consequences of repeated drug exposure on the subsequent response to the drug. Thus, parallel experiments were carried out in rats pretreated with AM281 for 7 or 14 days. Our findings indicated that AM281, at any dose, did not induce CPP and SA in drug-naïve rats. Interestingly, significant CPP (0.5mg/kg of AM281), but not SA, was observed in 14 days pretreated rats. These observations suggest that AM281 per se has no or minimal rewarding and reinforcing properties, but alterations in neuronal functions and behavior due to repeated AM281 exposure may contribute in part to the abuse potential of this drug. In view of this finding, we advocate the careful use, monitoring, and dispensation of AM281.
authors.affiliation: Uimyung Research Institute for Neuroscience, School of Pharmacy, Sahmyook University, 26-21 Kongreung-2-dong, Hwarangro-815 Nowon-gu, Seoul 139-742, Republic of Korea.
authors.forename: Chrislean Jun
authors.initials: CJ
authors.lastname: Botanas
authors.affiliation: Uimyung Research Institute for Neuroscience, School of Pharmacy, Sahmyook University, 26-21 Kongreung-2-dong, Hwarangro-815 Nowon-gu, Seoul 139-742, Republic of Korea.
authors.forename: June Bryan
authors.initials: JB
authors.lastname: de la Peña
authors.affiliation: Uimyung Research Institute for Neuroscience, School of Pharmacy, Sahmyook University, 26-21 Kongreung-2-dong, Hwarangro-815 Nowon-gu, Seoul 139-742, Republic of Korea.
authors.forename: Irene Joy
authors.initials: IJ
authors.lastname: Dela Pena
authors.affiliation: Uimyung Research Institute for Neuroscience, School of Pharmacy, Sahmyook University, 26-21 Kongreung-2-dong, Hwarangro-815 Nowon-gu, Seoul 139-742, Republic of Korea.
authors.forename: Reinholdgher
authors.initials: R
authors.lastname: Tampus
authors.affiliation: Uimyung Research Institute for Neuroscience, School of Pharmacy, Sahmyook University, 26-21 Kongreung-2-dong, Hwarangro-815 Nowon-gu, Seoul 139-742, Republic of Korea.
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Center for Safety Pharmacology, Korea Institute of Toxicology, Daejeon 305-343, Republic of Korea.
authors.forename: Seong Shoon
authors.initials: SS
authors.lastname: Yoon
authors.affiliation: Center for Safety Pharmacology, Korea Institute of Toxicology, Daejeon 305-343, Republic of Korea.
authors.forename: Joung-Wook
authors.initials: JW
authors.lastname: Seo
authors.affiliation: Center for Safety Pharmacology, Korea Institute of Toxicology, Daejeon 305-343, Republic of Korea.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Jeong
authors.affiliation: Uimyung Research Institute for Neuroscience, School of Pharmacy, Sahmyook University, 26-21 Kongreung-2-dong, Hwarangro-815 Nowon-gu, Seoul 139-742, Republic of Korea. Electronic address: cheongjh@syu.ac.kr.
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Cheong
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D012054:Reinforcement, Psychology; D012646:Self Administration; D019966:Substance-Related Disorders
chemical_list: D063387:Cannabinoid Receptor Antagonists; D009025:Morpholines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C109925:AM 281
keywords: AM281; Abuse potential; Cannabinoid antagonist; Conditioned place preference; Self-administration