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Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice.
Drug Alcohol Depend 2018; 191:14-24DA

Abstract

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.

Authors+Show Affiliations

Department of Psychology, West Virginia University, 1124 Life Sciences Building, P.O. Box 6040, Morgantown, WV 26506-6040, USA.Department of Psychology, West Virginia University, 1124 Life Sciences Building, P.O. Box 6040, Morgantown, WV 26506-6040, USA; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, 1112 East Clay Street, McGuire Hall, Box 980613, Richmond, VA 23298-0524, USA.Department of Psychology, West Virginia University, 1124 Life Sciences Building, P.O. Box 6040, Morgantown, WV 26506-6040, USA; Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, 1101 East Marshall Street, Box 980551, Richmond, VA 23298-0551, USA.Department of Physiology, Pharmacology and Neuroscience, West Virginia University School of Medicine, P.O. Box 9229, Health Sciences North Morgantown, WV 26506-9229, USA.Department of Psychology, West Virginia University, 1124 Life Sciences Building, P.O. Box 6040, Morgantown, WV 26506-6040, USA.Department of Psychology, West Virginia University, 1124 Life Sciences Building, P.O. Box 6040, Morgantown, WV 26506-6040, USA.Department of Physiology, Pharmacology and Neuroscience, West Virginia University School of Medicine, P.O. Box 9229, Health Sciences North Morgantown, WV 26506-9229, USA.Department of Psychology, West Virginia University, 1124 Life Sciences Building, P.O. Box 6040, Morgantown, WV 26506-6040, USA. Electronic address: sgkinsey@mail.wvu.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30071445

Citation

Trexler, Kristen R., et al. "Novel Behavioral Assays of Spontaneous and Precipitated THC Withdrawal in Mice." Drug and Alcohol Dependence, vol. 191, 2018, pp. 14-24.
Trexler KR, Nass SR, Crowe MS, et al. Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice. Drug Alcohol Depend. 2018;191:14-24.
Trexler, K. R., Nass, S. R., Crowe, M. S., Gross, J. D., Jones, M. S., McKitrick, A. W., ... Kinsey, S. G. (2018). Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice. Drug and Alcohol Dependence, 191, pp. 14-24. doi:10.1016/j.drugalcdep.2018.05.029.
Trexler KR, et al. Novel Behavioral Assays of Spontaneous and Precipitated THC Withdrawal in Mice. Drug Alcohol Depend. 2018 Oct 1;191:14-24. PubMed PMID: 30071445.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2018/07/07/ PY - 2017/11/06/received PY - 2018/05/15/revised PY - 2018/05/28/accepted PY - 2018/8/3/pubmed PY - 2018/11/28/medline PY - 2018/8/3/entrez KW - Cannabinoid withdrawal KW - Cannabis use disorder KW - Drug dependence KW - Marijuana KW - Stress SP - 14 EP - 24 JF - Drug and alcohol dependence JO - Drug Alcohol Depend VL - 191 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. SN - 1879-0046 UR - https://www.unboundmedicine.com/medline/citation/30071445/Novel_behavioral_assays_of_spontaneous_and_precipitated_THC_withdrawal_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0376-8716(18)30360-0 DB - PRIME DP - Unbound Medicine ER -