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FAAH-/- mice display differential tolerance, dependence, and cannabinoid receptor adaptation after delta 9-tetrahydrocannabinol and anandamide administration.
Neuropsychopharmacology. 2010 Jul; 35(8):1775-87.N

Abstract

Repeated administration of Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa, induces profound tolerance that correlates with desensitization and downregulation of CB(1) cannabinoid receptors in the CNS. However, the consequences of repeated administration of the endocannabinoid N-arachidonoyl ethanolamine (anandamide, AEA) on cannabinoid receptor regulation are unclear because of its rapid metabolism by fatty acid amide hydrolase (FAAH). FAAH(-/-) mice dosed subchronically with equi-active maximally effective doses of AEA or THC displayed greater rightward shifts in THC dose-effect curves for antinociception, catalepsy, and hypothermia than in AEA dose-effect curves. Subchronic THC significantly attenuated agonist-stimulated [(35)S]GTP gamma S binding in brain and spinal cord, and reduced [(3)H]WIN55,212-2 binding in brain. Interestingly, AEA-treated FAAH(-/-) mice showed less CB(1) receptor downregulation and desensitization than THC-treated mice. Experiments examining tolerance and cross-tolerance indicated that the behavioral effects of THC, a low efficacy CB(1) receptor agonist, were more sensitive to receptor loss than those of AEA, a higher efficacy agonist, suggesting that the expression of tolerance was more affected by the intrinsic activity of the ligand at testing than during subchronic treatment. In addition, the CB(1) receptor antagonist, rimonabant, precipitated a markedly reduced magnitude of withdrawal in FAAH(-/-) mice treated subchronically with AEA compared with mice treated repeatedly with THC. The findings that repeated AEA administration produces lesser adaptive changes at the CB(1) receptor and has reduced dependence liability compared with THC suggest that pharmacotherapies targeting endocannabinoid catabolic enzymes are less likely to promote tolerance and dependence than direct acting CB(1) receptor agonists.

Authors+Show Affiliations

Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA 23298, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20357755

Citation

Falenski, Katherine W., et al. "FAAH-/- Mice Display Differential Tolerance, Dependence, and Cannabinoid Receptor Adaptation After Delta 9-tetrahydrocannabinol and Anandamide Administration." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 35, no. 8, 2010, pp. 1775-87.
Falenski KW, Thorpe AJ, Schlosburg JE, et al. FAAH-/- mice display differential tolerance, dependence, and cannabinoid receptor adaptation after delta 9-tetrahydrocannabinol and anandamide administration. Neuropsychopharmacology. 2010;35(8):1775-87.
Falenski, K. W., Thorpe, A. J., Schlosburg, J. E., Cravatt, B. F., Abdullah, R. A., Smith, T. H., Selley, D. E., Lichtman, A. H., & Sim-Selley, L. J. (2010). FAAH-/- mice display differential tolerance, dependence, and cannabinoid receptor adaptation after delta 9-tetrahydrocannabinol and anandamide administration. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 35(8), 1775-87. https://doi.org/10.1038/npp.2010.44
Falenski KW, et al. FAAH-/- Mice Display Differential Tolerance, Dependence, and Cannabinoid Receptor Adaptation After Delta 9-tetrahydrocannabinol and Anandamide Administration. Neuropsychopharmacology. 2010;35(8):1775-87. PubMed PMID: 20357755.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FAAH-/- mice display differential tolerance, dependence, and cannabinoid receptor adaptation after delta 9-tetrahydrocannabinol and anandamide administration. AU - Falenski,Katherine W, AU - Thorpe,Andrew J, AU - Schlosburg,Joel E, AU - Cravatt,Benjamin F, AU - Abdullah,Rehab A, AU - Smith,Tricia H, AU - Selley,Dana E, AU - Lichtman,Aron H, AU - Sim-Selley,Laura J, Y1 - 2010/03/31/ PY - 2010/4/2/entrez PY - 2010/4/2/pubmed PY - 2010/9/21/medline SP - 1775 EP - 87 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 35 IS - 8 N2 - Repeated administration of Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa, induces profound tolerance that correlates with desensitization and downregulation of CB(1) cannabinoid receptors in the CNS. However, the consequences of repeated administration of the endocannabinoid N-arachidonoyl ethanolamine (anandamide, AEA) on cannabinoid receptor regulation are unclear because of its rapid metabolism by fatty acid amide hydrolase (FAAH). FAAH(-/-) mice dosed subchronically with equi-active maximally effective doses of AEA or THC displayed greater rightward shifts in THC dose-effect curves for antinociception, catalepsy, and hypothermia than in AEA dose-effect curves. Subchronic THC significantly attenuated agonist-stimulated [(35)S]GTP gamma S binding in brain and spinal cord, and reduced [(3)H]WIN55,212-2 binding in brain. Interestingly, AEA-treated FAAH(-/-) mice showed less CB(1) receptor downregulation and desensitization than THC-treated mice. Experiments examining tolerance and cross-tolerance indicated that the behavioral effects of THC, a low efficacy CB(1) receptor agonist, were more sensitive to receptor loss than those of AEA, a higher efficacy agonist, suggesting that the expression of tolerance was more affected by the intrinsic activity of the ligand at testing than during subchronic treatment. In addition, the CB(1) receptor antagonist, rimonabant, precipitated a markedly reduced magnitude of withdrawal in FAAH(-/-) mice treated subchronically with AEA compared with mice treated repeatedly with THC. The findings that repeated AEA administration produces lesser adaptive changes at the CB(1) receptor and has reduced dependence liability compared with THC suggest that pharmacotherapies targeting endocannabinoid catabolic enzymes are less likely to promote tolerance and dependence than direct acting CB(1) receptor agonists. SN - 1740-634X UR - https://www.unboundmedicine.com/medline/citation/20357755/FAAH_/__mice_display_differential_tolerance_dependence_and_cannabinoid_receptor_adaptation_after_delta_9_tetrahydrocannabinol_and_anandamide_administration_ L2 - http://dx.doi.org/10.1038/npp.2010.44 DB - PRIME DP - Unbound Medicine ER -