Cannabinoid Withdrawal Produces Altered Somatic and Emotionality-related Behavior in Mice

Cannabis sativa is the most commonly abused illicit drug in the United States. An estimated 9 percent of those who use cannabis will develop some level of cannabinoid use disorder (CUD). Although behavioral therapy has some success in treating CUD, many users still relapse. Moreover, there are no FDA approved pharmacological treatments available to complement behavioral therapy. The need for appropriate treatments highlights the need for nonhuman animal models to test target compounds. The current study aimed to (1) evaluate the MAGL inhibitor JZL184 as a possible treatment for cannabinoid withdrawal, and (2) to develop a spontaneous model of cannabinoid withdrawal in mice. Mice were treated with the primary psychoactive component of cannabis, Delta 9-tetrahydrocannabinol (THC; 50 mg/kg) or vehicle for 5.5 days. On the 6th day, withdrawal was precipitated using the cannabinoid receptor antagonist rimonabant (3 mg/kg), and behavior was scored in marble burying and somatic signs tests. THC withdrawal significantly decreased marble burying, however, JZL184 pretreatment did not attenuate withdrawal-related changes marble burying. JZL184 attenuated withdrawal-induced somatic behaviors as demonstrated in previous studies. A second set of experiments was used to evaluate spontaneous (i.e., not precipitated) THC withdrawal, as measured through marble burying and somatic signs. THC withdrawal caused significant increases in paw tremors and head twitches 24--48 h after abstinence, and JZL184 significantly attenuated these somatic signs of withdrawal. These data support the use of endocannabinoid manipulation to reduce symptoms of THC withdrawal