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Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents.
Eur J Pharmacol. 2014 Aug 15; 737:97-105.EJ

Abstract

The mechanism through which marijuana produces its psychoactive effects is Δ(9)-tetrahydrocannabinol (THC)-induced activation of cannabinoid CB1 receptors. These receptors are normally activated by endogenous lipids, including anandamide and 2-arachidonoyl glycerol (2-AG). A logical "first step" in determination of the role of these endocannabinoids in THC׳s psychoactive effects is to investigate the degree to which pharmacologically induced increases in anandamide and/or 2-AG concentrations through exogenous administration and/or systemic administration of inhibitors of their metabolism, fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), respectively, share THC׳s discriminative stimulus effects. To this end, adult male mice and rats were trained to discriminate THC (5.6 and 3mg/kg, respectively). In Experiment 1, exogenous administration of anandamide or 2-AG did not substitute for THC in mice nor was substitution enhanced by co-administration of the FAAH or MAGL inhibitors, URB597 and N-arachidonyl maleimide (NAM), respectively. Significant decreases in responding may have prevented assessment of adequate endocannabinoid doses. In mice trained at higher baseline response rates (Experiment 2), the FAAH inhibitor PF3845 (10mg/kg) enhanced anandamide substitution for THC without producing effects of its own. The MAGL inhibitor JZL184 increased brain levels of 2-AG in vitro and in vivo, increased THC-like responding without co-administration of 2-AG. In rats, neither URB597 nor JZL184 engendered significant THC-appropriate responding, but co-administration of these two enzyme inhibitors approached full substitution. The present results highlight the complex interplay between anandamide and 2-AG and suggest that endogenous increases of both endocannabinoids are most effective in elicitation of THC-like discriminative stimulus effects.

Authors+Show Affiliations

RTI International, Research Triangle Park, NC 27709-2194, USA; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA. Electronic address: jwiley@rti.org.Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.

Pub Type(s)

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

Language

eng

PubMed ID

24858366

Citation

Wiley, Jenny L., et al. "Endocannabinoid Contribution to Δ9-tetrahydrocannabinol Discrimination in Rodents." European Journal of Pharmacology, vol. 737, 2014, pp. 97-105.
Wiley JL, Walentiny DM, Wright MJ, et al. Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents. Eur J Pharmacol. 2014;737:97-105.
Wiley, J. L., Walentiny, D. M., Wright, M. J., Beardsley, P. M., Burston, J. J., Poklis, J. L., Lichtman, A. H., & Vann, R. E. (2014). Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents. European Journal of Pharmacology, 737, 97-105. https://doi.org/10.1016/j.ejphar.2014.05.013
Wiley JL, et al. Endocannabinoid Contribution to Δ9-tetrahydrocannabinol Discrimination in Rodents. Eur J Pharmacol. 2014 Aug 15;737:97-105. PubMed PMID: 24858366.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents. AU - Wiley,Jenny L, AU - Walentiny,D Matthew, AU - Wright,M Jerry,Jr AU - Beardsley,Patrick M, AU - Burston,James J, AU - Poklis,Justin L, AU - Lichtman,Aron H, AU - Vann,Robert E, Y1 - 2014/05/22/ PY - 2014/01/30/received PY - 2014/05/13/revised PY - 2014/05/14/accepted PY - 2014/5/27/entrez PY - 2014/5/27/pubmed PY - 2015/2/14/medline KW - 2-Arachidonoylglycerol KW - Anandamide KW - JZL184 KW - PF3845 KW - URB597 KW - Δ(9)-tetrahydrocannabinol SP - 97 EP - 105 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 737 N2 - The mechanism through which marijuana produces its psychoactive effects is Δ(9)-tetrahydrocannabinol (THC)-induced activation of cannabinoid CB1 receptors. These receptors are normally activated by endogenous lipids, including anandamide and 2-arachidonoyl glycerol (2-AG). A logical "first step" in determination of the role of these endocannabinoids in THC׳s psychoactive effects is to investigate the degree to which pharmacologically induced increases in anandamide and/or 2-AG concentrations through exogenous administration and/or systemic administration of inhibitors of their metabolism, fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), respectively, share THC׳s discriminative stimulus effects. To this end, adult male mice and rats were trained to discriminate THC (5.6 and 3mg/kg, respectively). In Experiment 1, exogenous administration of anandamide or 2-AG did not substitute for THC in mice nor was substitution enhanced by co-administration of the FAAH or MAGL inhibitors, URB597 and N-arachidonyl maleimide (NAM), respectively. Significant decreases in responding may have prevented assessment of adequate endocannabinoid doses. In mice trained at higher baseline response rates (Experiment 2), the FAAH inhibitor PF3845 (10mg/kg) enhanced anandamide substitution for THC without producing effects of its own. The MAGL inhibitor JZL184 increased brain levels of 2-AG in vitro and in vivo, increased THC-like responding without co-administration of 2-AG. In rats, neither URB597 nor JZL184 engendered significant THC-appropriate responding, but co-administration of these two enzyme inhibitors approached full substitution. The present results highlight the complex interplay between anandamide and 2-AG and suggest that endogenous increases of both endocannabinoids are most effective in elicitation of THC-like discriminative stimulus effects. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/24858366/Endocannabinoid_contribution_to_Δ9_tetrahydrocannabinol_discrimination_in_rodents_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(14)00375-6 DB - PRIME DP - Unbound Medicine ER -