Format

Send to

Choose Destination
Psychopharmacology (Berl). 2016 May;233(10):1867-77. doi: 10.1007/s00213-016-4211-3. Epub 2016 Jan 23.

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

Author information

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 Services, 251 Bayview Boulevard, Baltimore, MD, 21224, USA. cschind@helix.nih.gov.
2
Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato, Italy.
3
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.
4
Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
5
Center for Drug Discovery, Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.

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.

KEYWORDS:

AM404; Anandamide; Reinstatement; Rimonabant; Self-administration; Squirrel monkeys

PMID:
26803499
PMCID:
PMC4846479
DOI:
10.1007/s00213-016-4211-3
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center