Date of Graduation
Eberly College of Arts and Sciences
Steven G. Kinsey
David P. Siderovski
Cole M. Vonder Haar
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 6th 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 9th 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.
Despite recent increases in attention to cannabinoid use disorders, there remains a need for pharmacological interventions. ZCZ011 is a CB1 positive allosteric modulator that increases the effect of CB1 agonists bound at the orthosteric site. We hypothesized that ZCZ011 significantly attenuates behavioral signs of cannabinoid withdrawal. Mice were administered ∆9-THC (10 mg/kg, b.i.d., s.c.) or vehicle for six days, then withdrawal was precipitated using rimonabant (3 mg/kg, i.p.). As previously reported, ∆9-THC withdrawal induced paw tremors and head twitches. Acute ZCZ011 (≥10 mg/kg, i.p.) significantly attenuated paw tremors and head twitches. ZCZ011 (≥10 mg/kg, i.p.) was also administered to mice subjected to spontaneous THC withdrawal. ZCZ011 reduced spontaneous THC withdrawal-induced head twitches and paw tremors. An additional group of mice was injected with ZCZ011 (10 mg/kg, i.p.) or one of its enantiomers, ZCZ011 A or ZCZ011 B prior to precipitated THC withdrawal. Both ZCZ011 10 mg/kg or either enantiomer alone attenuated paw tremors and head twitches.
Trexler, Kristen R., "Acute and Repeated Effects of Synthetic Cannabinoid Agonism and Cannabinoid Receptor 1 Positive Allosteric Modulation" (2019). Graduate Theses, Dissertations, and Problem Reports. 4040.