Acute and Repeated Effects of Synthetic Cannabinoid Agonism and Cannabinoid Receptor 1 Positive Allosteric Modulation

Abstract

Recent years have seen a rise in the diversity and use of synthetic cannabinoids. Currently, there is little known about the effects of specific synthetic cannabinoid compounds. As such, little research has been done evaluating the acute and chronic effects of synthetic cannabinoid administration or the development of tolerance and withdrawal. The present study aimed, in part, to evaluate the acute and repeated effect of a third-generation synthetic cannabinoid, AB-FUBINACA. Mice were treated with AB-FUBINACA (0.1-3 mg/kg, i.p.) or vehicle and were tested repeatedly in the tetrad battery of assays, which included tests of catalepsy, antinociception, hypothermia, and locomotor activity. A second group of mice was injected with AB-FUBINACA (3 mg/kg, s.c.) twice daily for 6 days and were tested daily in tetrad. On the 6 th day, withdrawal was precipitated using the cannabinoid receptor antagonist rimonabant (3 mg/kg), and behavior was scored in the somatic signs of withdrawal tests. AB-FUBINACA exhibited classic acute cannabinoid effects in the tetrad but showed a lack of tolerance and cross-tolerance to THC (50 mg/kg, i.p.). Further, precipitated withdrawal from AB-FUBINACA was of a much smaller magnitude than what is typical of other phyto-and synthetic cannabinoids. Another aspect of cannabinoid research that has been largely overlooked is the use of assays that are able to detect spontaneous (i.e., abstinence-induced) withdrawal. Previous research has demonstrated that spontaneous withdrawal can be detected with certain assays, like the somatic signs of withdrawal and tail suspension tests. To determine whether an anhedonia test would detect signs of spontaneous withdrawal, mice were trained to consume a sweetened condensed milk mixture over 9 days. During the final 6 days of training, mice were injected twice daily with THC (10 or 50 mg/kg, s.c.) or vehicle. On the 9 th day, injections were stopped and mice were tested again at 12h and 36h abstinence. No changes were observed as a result of spontaneous withdrawal from THC.