Schindler Charles W, Scherma Maria, Redhi Godfrey H, Vadivel Subramanian K, Makriyannis Alexandros, Goldberg Steven R, Justinova Zuzana
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.
Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato, Italy.
Psychopharmacology (Berl). 2016 May;233(10):1867-77. doi: 10.1007/s00213-016-4211-3. Epub 2016 Jan 23.
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.
N-(4-羟基苯基)-花生四烯酸酰胺（AM404）是一种花生四烯酸乙醇胺转运抑制剂，在多种烟草依赖动物模型中显示可降低尼古丁的奖赏和复吸诱导作用。然而，AM404的强化/奖赏作用尚不清楚。
我们研究了AM404是否能维持松鼠猴的自我给药行为或恢复已消退的觅药行为。
在有花生四烯酸乙醇胺或可卡因自我给药史的猴子中，我们用AM404（1-100μg/kg/注射）替代注射。使用10次反应的固定比率程序，AM404维持了自我给药行为。剂量-反应曲线呈倒U形，在10μg/kg/注射剂量时出现峰值反应率。在有花生四烯酸乙醇胺经验的猴子中，我们还证明了另一种花生四烯酸乙醇胺转运抑制剂VDM11的自我给药。除了支持自我给药外，AM404的激发注射（0.03-0.3mg/kg）恢复了先前由大麻素（Δ(9)-四氢大麻酚（THC）或花生四烯酸乙醇胺）或可卡因强化的觅药行为。AM404的自我给药行为以及AM404恢复觅药行为均因大麻素CB1受体拮抗剂/反向激动剂利莫那班（0.3mg/kg）的治疗而降低。此外，脂肪酸酰胺水解酶（FAAH）抑制剂URB597（0.3mg/kg）的治疗增强了AM404的强化作用，表明花生四烯酸乙醇胺在这些作用中起主要作用。最后，AM404（0.3mg/kg）增强了花生四烯酸乙醇胺的强化作用，但未增强可卡因的强化作用。
在非人灵长类动物中，AM4有效强化了自我给药行为，并诱导禁欲猴子恢复觅药行为。这些作用似乎由大麻素CB1受体介导。因此，通过抑制内源性大麻素的膜转运来促进其在全脑作用的化合物可能存在滥用潜力。
