Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys
- 286 Downloads
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.
KeywordsAnandamide 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).
The authors declare that they have no competing interests.
- Ahn K, Smith SE, Liimatta MB, Beidler D, Sadagopan N, Dudley DT, Young T, Wren P, Zhang Y, Swaney S, Van Becelaere K, Blankman JL, Nomura DK, Bhattachar SN, Stiff C, Nomanbhoy TK, Weerapana E, Johnson DS, Cravatt BF (2011) Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain. J Pharmacol Exp Ther 338:114–124CrossRefPubMedPubMedCentralGoogle Scholar
- Bergman J, Shakiru O, Makriyannis A, Justinova Z, Goldberg SR (2011) Discriminative-stimulus and reinforcing effects of FAAH inhibitors in CB-1 trained subjects. FASEB J 25:796, 794Google Scholar
- Clapper JR, Moreno-Sanz G, Russo R, Guijarro A, Vacondio F, Duranti A, Tontini A, Sanchini S, Sciolino NR, Spradley JM, Hohmann AG, Calignano A, Mor M, Tarzia G, Piomelli D (2010) Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat Neurosci 13:1265–1270CrossRefPubMedPubMedCentralGoogle Scholar
- De Petrocellis L, Bisogno T, Davis JB, Pertwee RG, Di Marzo V (2000) Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity. FEBS Lett 483:52–56CrossRefPubMedGoogle Scholar
- Fegley D, Kathuria S, Mercier R, Li C, Goutopoulos A, Makriyannis A, Piomelli D (2004) Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172. Proc Natl Acad Sci U S A 101:8756–8761CrossRefPubMedPubMedCentralGoogle Scholar
- Fu J, Bottegoni G, Sasso O, Bertorelli R, Rocchia W, Masetti M, Guijarro A, Lodola A, Armirotti A, Garau G, Bandiera T, Reggiani A, Mor M, Cavalli A, Piomelli D (2012) A catalytically silent FAAH-1 variant drives anandamide transport in neurons. Nat Neurosci 15:64–69CrossRefPubMedCentralGoogle Scholar
- Gamaleddin I, Guranda M, Scherma M, Fratta W, Makriyannis A, Vadivel SK, Goldberg SR, Le Foll B (2013) AM404 attenuates reinstatement of nicotine seeking induced by nicotine-associated cues and nicotine priming but does not affect nicotine- and food-taking. J Psychopharmacol 27:564–571CrossRefPubMedPubMedCentralGoogle Scholar
- Justinova Z, Mangieri RA, Bortolato M, Chefer SI, Mukhin AG, Clapper JR, King AR, Redhi GH, Yasar S, Piomelli D, Goldberg SR (2008a) Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates. Biol Psychiatry 64:930–937CrossRefPubMedPubMedCentralGoogle Scholar
- Justinova Z, Mascia P, Secci ME, Redhi GH, Piomelli D, Goldberg SR (2014) The FAAH inhibitor PF-04457845 has THC-like rewarding and reinstatement effects in squirrel monkeys and increases dopamine levels in the nucleus accumbens shell in rats. FASEB J 28:838.6Google Scholar
- Justinova Z, Panlilio LV, Moreno-Sanz G, Redhi GH, Auber A, Secci ME, Mascia P, Bandiera T, Armirotti A, Bertorelli R, Chefer SI, Barnes C, Yasar S, Piomelli D, Goldberg SR (2015) Effects of fatty acid amide hydrolase (FAAH) inhibitors in non-human primate models of nicotine reward and relapse. Neuropsychopharmacology 40:2185–2197CrossRefPubMedGoogle Scholar
- National Research Council (2003) Guidelines for the care and use of mammals in neuroscience and behavioral research. The National Academies Press, Washington, D.CGoogle Scholar
- Scherma M, Justinova Z, Zanettini C, Panlilio LV, Mascia P, Fadda P, Fratta W, Makriyannis A, Vadivel SK, Gamaleddin I, Le Foll B, Goldberg SR (2012) The anandamide transport inhibitor AM404 reduces the rewarding effects of nicotine and nicotine-induced dopamine elevations in the nucleus accumbens shell in rats. Br J Pharmacol 165:2539–2548CrossRefPubMedPubMedCentralGoogle Scholar
- Solinas M, Tanda G, Justinova Z, Wertheim CE, Yasar S, Piomelli D, Vadivel SK, Makriyannis A, Goldberg SR (2007) The endogenous cannabinoid anandamide produces delta-9-tetrahydrocannabinol-like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase but not by inhibition of anandamide transport. J Pharmacol Exp Ther 321:370–380CrossRefPubMedGoogle Scholar
- Wiskerke J, Irimia C, Cravatt BF, De Vries TJ, Schoffelmeer AN, Pattij T, Parsons LH (2012) Characterization of the effects of reuptake and hydrolysis inhibition on interstitial endocannabinoid levels in the brain: an in vivo microdialysis study. ACS Chem Neurosci 3:407–417CrossRefPubMedPubMedCentralGoogle Scholar