, Volume 233, Issue 10, pp 1867–1877 | Cite as

Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys

  • Charles W. SchindlerEmail author
  • Maria Scherma
  • Godfrey H. Redhi
  • Subramanian K. Vadivel
  • Alexandros Makriyannis
  • Steven R. Goldberg
  • Zuzana Justinova
Original Investigation



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.

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.


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.


Anandamide AM404 Self-administration Reinstatement Rimonabant Squirrel monkeys 



This research was supported by the Intramural Research Program of NIDA, NIH and by NIDA grants R01DA003801 and R01DA007215 (to Dr. Makriyannis). We thank Dr. Daniele Piomelli for providing URB597 and NIDA Drug Supply Program for providing THC and rimonabant.

We dedicate this paper to our colleague and friend Steven R. Goldberg who passed away suddenly on November 25, 2014.

Compliance with ethical standards

The facilities were fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC), and experiments were conducted in accordance with guidelines of the Institutional Animal Care and Use Committee of the Intramural Research Program, National Institute of Drug Abuse, National Institutes of Health, and the Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (National Research Council 2003).

Competing interests

The authors declare that they have no competing interests.


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Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2016

Authors and Affiliations

  • Charles W. Schindler
    • 1
    Email author
  • Maria Scherma
    • 2
  • Godfrey H. Redhi
    • 1
  • Subramanian K. Vadivel
    • 3
  • Alexandros Makriyannis
    • 4
  • Steven R. Goldberg
    • 1
  • Zuzana Justinova
    • 1
  1. 1.Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human ServicesBaltimoreUSA
  2. 2.Department of Biomedical Sciences, Section of Neuroscience and Clinical PharmacologyUniversity of CagliariMonserratoItaly
  3. 3.Center for Drug Discovery, Department of Pharmaceutical SciencesNortheastern UniversityBostonUSA
  4. 4.Center for Drug Discovery, Departments of Pharmaceutical Sciences and Chemistry and Chemical BiologyNortheastern UniversityBostonUSA

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