TY - JOUR
T1 - Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice
AU - Trexler, Kristen R.
AU - Nass, Sara R.
AU - Crowe, Molly S.
AU - Gross, Joshua D.
AU - Jones, Margaret S.
AU - McKitrick, Austin W.
AU - Siderovski, David P.
AU - Kinsey, Steven G.
N1 - Funding Information:
This project was supported by The National Institutes of Health [ AR066806 , DA038714 , DA039335 , DA043331 , and GM081741 ]. Sponsors had no role in the design, collection, analysis and interpretation of data, writing of the report, or the decision to submit the article for publication.
Publisher Copyright:
© 2018
PY - 2018/10/1
Y1 - 2018/10/1
N2 - Background: A subset of cannabis users develop some degree of Cannabis Use Disorder (CUD). Although behavioral therapy has some success in treating CUD, many users relapse, often citing altered sleep, mood, and irritability. Preclinical animal tests of cannabinoid withdrawal focus primarily on somatic-related behaviors precipitated by a cannabinoid receptor antagonist. The goal of the present study was to develop novel cannabinoid withdrawal assays that are either antagonist-precipitated or spontaneously induced by abstinence. Methods: C57BL/6 J mice were repeatedly administered the phytocannabinoid Δ9-tetrahydrocannabinol (THC; 1, 10 or 50 mg/kg, s.c.), the synthetic cannabinoid receptor agonist JWH-018 (1 mg/kg, s.c.), or vehicle (1:1:18 parts ethanol:Kolliphor EL:saline, s.c.) for 6 days. Withdrawal was precipitated with the cannabinoid receptor inverse agonist rimonabant (3 mg/kg, i.p.) or elicited via abstinence (i.e., spontaneous withdrawal), and putative stress-related behavior was scored. Classic somatic signs of cannabinoid withdrawal were also quantified. Results: Precipitated THC withdrawal significantly increased plasma corticosterone. Precipitated withdrawal from either THC or JWH-018 suppressed marble burying, increased struggling in the tail suspension test, and elicited somatic withdrawal behaviors. The monoacylglycerol lipase inhibitor JZL184 attenuated somatic precipitated withdrawal but had no effect on marble burying or struggling. Spontaneous THC or JWH-018 withdrawal-induced paw tremors, head twitches, and struggled in the tail suspension test after 24–48 h abstinence. JZL184 or THC attenuated these spontaneous withdrawal-induced behaviors. Conclusion: Outcomes from tail suspension and marble burying tests reveal that THC withdrawal is multifaceted, eliciting and suppressing behaviors in these tests, in addition to inducing well-documented somatic signs of withdrawal.
AB - Background: A subset of cannabis users develop some degree of Cannabis Use Disorder (CUD). Although behavioral therapy has some success in treating CUD, many users relapse, often citing altered sleep, mood, and irritability. Preclinical animal tests of cannabinoid withdrawal focus primarily on somatic-related behaviors precipitated by a cannabinoid receptor antagonist. The goal of the present study was to develop novel cannabinoid withdrawal assays that are either antagonist-precipitated or spontaneously induced by abstinence. Methods: C57BL/6 J mice were repeatedly administered the phytocannabinoid Δ9-tetrahydrocannabinol (THC; 1, 10 or 50 mg/kg, s.c.), the synthetic cannabinoid receptor agonist JWH-018 (1 mg/kg, s.c.), or vehicle (1:1:18 parts ethanol:Kolliphor EL:saline, s.c.) for 6 days. Withdrawal was precipitated with the cannabinoid receptor inverse agonist rimonabant (3 mg/kg, i.p.) or elicited via abstinence (i.e., spontaneous withdrawal), and putative stress-related behavior was scored. Classic somatic signs of cannabinoid withdrawal were also quantified. Results: Precipitated THC withdrawal significantly increased plasma corticosterone. Precipitated withdrawal from either THC or JWH-018 suppressed marble burying, increased struggling in the tail suspension test, and elicited somatic withdrawal behaviors. The monoacylglycerol lipase inhibitor JZL184 attenuated somatic precipitated withdrawal but had no effect on marble burying or struggling. Spontaneous THC or JWH-018 withdrawal-induced paw tremors, head twitches, and struggled in the tail suspension test after 24–48 h abstinence. JZL184 or THC attenuated these spontaneous withdrawal-induced behaviors. Conclusion: Outcomes from tail suspension and marble burying tests reveal that THC withdrawal is multifaceted, eliciting and suppressing behaviors in these tests, in addition to inducing well-documented somatic signs of withdrawal.
KW - Cannabinoid withdrawal
KW - Cannabis use disorder
KW - Drug dependence
KW - Marijuana
KW - Stress
UR - http://www.scopus.com/inward/record.url?scp=85050740590&partnerID=8YFLogxK
U2 - 10.1016/j.drugalcdep.2018.05.029
DO - 10.1016/j.drugalcdep.2018.05.029
M3 - Article
C2 - 30071445
AN - SCOPUS:85050740590
SN - 0376-8716
VL - 191
SP - 14
EP - 24
JO - Drug and Alcohol Dependence
JF - Drug and Alcohol Dependence
ER -