PT  - JOURNAL ARTICLE
AU  - Brian D. Kangas
AU  - Ani S. Zakarian
AU  - Kiran Vemuri
AU  - Shakiru O. Alapafuja
AU  - Shan Jiang
AU  - Spyros P. Nikas
AU  - Alexandros Makriyannis
AU  - Jack Bergman
TI  - Cannabinoid Antagonist Drug Discrimination in Nonhuman Primates
AID  - 10.1124/jpet.119.261818
DP  - 2019 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.119.261818
4099  - http://jpet.aspetjournals.org/content/early/2019/10/22/jpet.119.261818.short
4100  - http://jpet.aspetjournals.org/content/early/2019/10/22/jpet.119.261818.full
AB  - Despite a growing acceptance that withdrawal symptoms can emerge following discontinuation of cannabis products, especially in high intake chronic users, there are no FDA-approved treatment options. Drug development has been hampered by difficulties studying cannabis withdrawal in laboratory animals. One preclinical approach that has been effective in studying withdrawal from several pharmacological classes is antagonist drug discrimination. The present studies were designed to examine this paradigm in squirrel monkeys treated daily with the long-acting CB1 agonist AM2389 (0.01 mg/kg) and trained to discriminate the CB1 inverse agonist/antagonist rimonabant (0.3 mg/kg) from saline. The discriminative-stimulus effects of rimonabant were both dose- and time-dependent and, importantly, could be engendered by discontinuation of agonist treatment. Antagonist substitution tests with the CB1 neutral antagonists AM4113 (0.03-0.3 mg/kg), AM6527 (0.03-1.0 mg/kg), and AM6545 (0.03-1.0 mg/kg) confirmed that the rimonabant discriminative stimulus could be reproduced by CB1 antagonists lacking inverse agonist action. Agonist substitution tests with the phytocannabinoid ∆9-tetrahydrocannabinol (0.1-1.0 mg/kg), synthetic CB1 agonists nabilone (0.01-0.1 mg/kg), AM4054 (0.01-0.03 mg/kg), K2/Spice compound JWH-018 (0.03-0.3 mg/kg), FAAH-selective inhibitors AM3506 (0.3-5.6 mg/kg), URB597 (3.0-5.6 mg/kg), and nonselective FAAH/MGL inhibitor AM4302 (3.0-10.0 mg/kg) revealed that only agonists with CB1 affinity were able to reduce the rimonabant-like discriminative-stimulus effects of withholding daily agonist treatment. Although the present studies did not document physiological disturbances associated with withdrawal, they are consistent with the view that the cannabinoid antagonist drug discrimination paradigm provides a useful screening procedure for examining the ability of candidate medications to attenuate the interoceptive stimuli provoked by cannabis discontinuation.SIGNIFICANCE STATEMENT Despite a growing acceptance that withdrawal symptoms can emerge following the discontinuation of cannabis products, especially in high intake chronic users, there are no FDA-approved pharmacotherapies to assist those seeking treatment. The present studies systematically examined cannabinoid antagonist drug discrimination, a preclinical animal model that is designed to appraise the ability of candidate medications to attenuate the interoceptive effects that accompany abrupt cannabis abstinence.