Δ9-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids in mice and rats
- 451 Downloads
Novel cannabinoid compounds continue to be marketed as “legal” marijuana substitutes, even though little is known about their molecular and behavioral effects.
Six of these compounds (ADBICA, ADB-PINACA, THJ-2201, RCS-4, JWH-122, JWH-210) were tested for in vitro and in vivo cannabinoid-like effects to determine their abuse liability.
Binding to and functional activity at CB1 cannabinoid receptors was tested. Locomotor activity in mice was tested to screen for behavioral activity and to identify behaviorally active dose ranges and times of peak effect. Discriminative stimulus effects of the six compounds were tested in rats trained to discriminate Δ9-tetrahydrocannabinol (Δ9-THC).
ADBICA, ADB-PINACA, THJ-2201, RCS-4, JWH-122, and JWH-210 showed high affinity binding at the CB1 receptor at nanomolar affinities (0.59 to 22.5 nM), and all acted as full agonists with nanomolar potencies (0.024 to 111 nM) when compared to the CB1 receptor full agonist CP 55940. All compounds depressed locomotor activity below 50 % of vehicle responding, with depressant effects lasting 1.5 to nearly 4 h. All compounds fully substituted (<80 % Δ9-THC-appropriate responding) for the discriminative stimulus effects of Δ9-THC. 3,4-Methylenedioxy-methamphetamine (MDMA) was tested as a negative control and did not substitute for Δ9-THC (11 % Δ9-THC-appropriate responding).
All six of the compounds acted at the CB1 receptor and produced behavioral effects common to abused cannabinoid compounds, which suggest that these compounds have substantial abuse liability common to controlled synthetic cannabinoid compounds.
KeywordsCannabinoids Drug discrimination Locomotor activity Abuse liability Mouse Rat
Funding was provided by the Addiction Treatment Discovery Program of the National Institute on Drug Abuse for the behavioral data (NIH N01DA-13-8908) and for the in vitro data (N01DA-13-9881). Program staff was involved in selection of compounds and test parameters. The ATDP had no further role in study design; the collection, analysis, and interpretation of data; or the writing of the report. They have granted permission for the submission of this data for publication.
Compliance with ethical standards
All housing and procedures were in accordance with Guidelines for the Care and Use of Laboratory Animals (National Research Council 2011) and were approved by the University of North Texas Health Science Center Animal Care and Use Committee.
- Brents LK, Gallus-Zawada A, Radominska-Pandya A, Vasiljevik T, Prisinzano TE, Fantegrossi WE, Moran JH, Prather PL (2012) Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity. Biochem Pharmacol 83:952–961CrossRefPubMedPubMedCentralGoogle Scholar
- Carvalho AF, Reyes BA, Ramalhosa F, Sousa N, Van Bockstaele EJ (2014) Repeated administration of a synthetic cannabinoid receptor agonist differentially affects cortical and accumbal neuronal morphology in adolescent and adult rats. Brain Struct Funct 2014 Oct 28Google Scholar
- Centers for Disease Control and Prevention (2013) Acute kidney injury associated with synthetic cannabinoid use—multiple states, 2012. Morb Mortal Wkly Rep 62:93–98Google Scholar
- Drug Enforcement Administration, Department of Justice (2013) Establishment of drug codes for 26 substances. Final rule. Federal Register 78(3):664–666Google Scholar
- Drug Enforcement Administration, Department of Justice (2014) National Forensic Laboratory Information System Special Report: synthetic cannabinoids and synthetic cathinones reported in NFLIS, 2010–2013, U.S. Drug Enforcement Administration, Springfield, VAGoogle Scholar
- Huffman JW, Zengin G, Wu MJ, Lu J, Hynd G, Bushell K, Thompson AL, Bushell S, Tartal C, Hurst DP, Reggio PH, Selley DE, Cassidy MP, Wiley JL, Martin BR (2005) Structure-activity relationships for 1-alkyl-3-(1-naphthoyl) indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists. Bioorg Med Chem 13:89–112CrossRefPubMedGoogle Scholar
- Marshell R, Kearney-Ramos T, Brents LK, Hyatt WS, Tai S, Prather PL, Fantegrossi WE (2014) In vivo effects of synthetic cannabinoids JWH-018 and JWH-073 and phytocannabinoid Δ(9)-THC in mice: inhalation versus intraperitoneal injection. Pharmacol Biochem Behav 124:40–47CrossRefPubMedPubMedCentralGoogle Scholar
- National Research Council (2011) Guide for the care and use of laboratory animals. The National Academies Press, WashingtonGoogle Scholar
- Wiley JL, Compton DR, Dai D, Lainton JA, Phillips M, Huffman JW, Martin BR (1998) Structure-activity relationships of indole- and pyrrole-derived cannabinoids.J Pharmacol Exp Ther 285:995–1004Google Scholar
- Wohlfarth A, Scheidweiler KB, Castaneto M, Gandhi AS, Desrosiers NA, Klette KL, Martin TM, Huestis MA (2015) Urinary prevalence, metabolite detection rates, temporal patterns and evaluation of suitable LC-MS/MS targets to document synthetic cannabinoid intake in US military urine specimens. Chem Lab Med 53:423–434Google Scholar
- Young R (2009). Drug Discrimination. in Methods of behavior analysis in neuroscience (2nd edition) Jerry J. Buccafuso (Ed.); CRC Press, Taylor & Francis Group LLC, Boca Raton (http://www.ncbi.nlm.nih.gov/books/NBK5228/)