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Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys.
Psychopharmacology (Berl) 2016; 233(10):1867-77P

Abstract

RATIONALE

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.

OBJECTIVES

We investigated whether AM404 maintains self-administration behavior or reinstates extinguished drug seeking in squirrel monkeys.

METHODS AND RESULTS

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.

CONCLUSIONS

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+Show Affiliations

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.Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato, Italy.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.Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.Center for Drug Discovery, Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.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.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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26803499

Citation

Schindler, Charles W., et al. "Self-administration of the Anandamide Transport Inhibitor AM404 By Squirrel Monkeys." Psychopharmacology, vol. 233, no. 10, 2016, pp. 1867-77.
Schindler CW, Scherma M, Redhi GH, et al. Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys. Psychopharmacology (Berl). 2016;233(10):1867-77.
Schindler, C. W., Scherma, M., Redhi, G. H., Vadivel, S. K., Makriyannis, A., Goldberg, S. R., & Justinova, Z. (2016). Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys. Psychopharmacology, 233(10), pp. 1867-77. doi:10.1007/s00213-016-4211-3.
Schindler CW, et al. Self-administration of the Anandamide Transport Inhibitor AM404 By Squirrel Monkeys. Psychopharmacology (Berl). 2016;233(10):1867-77. PubMed PMID: 26803499.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys. AU - Schindler,Charles W, AU - Scherma,Maria, AU - Redhi,Godfrey H, AU - Vadivel,Subramanian K, AU - Makriyannis,Alexandros, AU - Goldberg,Steven R, AU - Justinova,Zuzana, Y1 - 2016/01/23/ PY - 2015/09/11/received PY - 2016/01/06/accepted PY - 2016/1/25/entrez PY - 2016/1/25/pubmed PY - 2017/2/23/medline KW - AM404 KW - Anandamide KW - Reinstatement KW - Rimonabant KW - Self-administration KW - Squirrel monkeys SP - 1867 EP - 77 JF - Psychopharmacology JO - Psychopharmacology (Berl.) VL - 233 IS - 10 N2 - RATIONALE: 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. OBJECTIVES: We investigated whether AM404 maintains self-administration behavior or reinstates extinguished drug seeking in squirrel monkeys. METHODS AND RESULTS: 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. CONCLUSIONS: 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. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/26803499/Self_administration_of_the_anandamide_transport_inhibitor_AM404_by_squirrel_monkeys_ L2 - https://dx.doi.org/10.1007/s00213-016-4211-3 DB - PRIME DP - Unbound Medicine ER -