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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 (838.6)
Author(s) -
Justinova Zuzana,
Mascia Paola,
Secci Maria,
Redhi Godfrey,
Piomelli Daniele,
Goldberg Steven
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.838.6
Subject(s) - nucleus accumbens , pharmacology , anandamide , cannabidiol , dopamine , cannabinoid , endocannabinoid system , dopaminergic , cannabinol , psychology , chemistry , cannabinoid receptor , agonist , medicine , neuroscience , cannabis , psychiatry , receptor
FAAH inhibitors (like URB597), that increase brain levels of anandamide, OEA and PEA, show promise for treatment of several neuropsychiatric disorders, including addiction. We previously showed that URB597, unlike THC and anandamide, is not rewarding in squirrel monkeys (Justinova et al., 2008). Here we assessed abuse liability of the FAAH inhibitor PF‐04457845, currently in clinical testing for treatment of cannabis withdrawal. In squirrel monkeys trained to self‐administer anandamide (FR10 schedule, 60‐s timeout), PF‐04457845 maintained higher numbers of self‐administered injections per session and higher rates of responding than vehicle at doses of 3 and 10 µg/kg/injection. The cannabinoid CB 1 inverse agonist/antagonist rimonabant (0.3 mg/kg, i.m.) blocked self‐administration of the peak dose of PF‐04457845 (10 µg/kg/injection). In abstinent monkeys that had previously self‐administered THC, PF‐04457845 caused moderate reinstatement of drug‐seeking behavior over a narrow dose range. In rats, PF‐04457845, unlike URB597, significantly increased extracellular dopamine levels in the accumbens shell, but similarly to URB597 did not show THC‐like subjective effects. Thus, FAAH inhibitors can produce a spectrum of outcomes ranging from no evidence of rewarding, reinstatement or dopaminergic effects (URB597) to significant self‐administration, reinstatement and accumbal dopamine release (PF‐04457845).