Abstract
Repeated administration of Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa, induces profound tolerance that correlates with desensitization and downregulation of CB1 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 [35S]GTPγS binding in brain and spinal cord, and reduced [3H]WIN55,212-2 binding in brain. Interestingly, AEA-treated FAAH−/− mice showed less CB1 receptor downregulation and desensitization than THC-treated mice. Experiments examining tolerance and cross-tolerance indicated that the behavioral effects of THC, a low efficacy CB1 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 CB1 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 CB1 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 CB1 receptor agonists.
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Acknowledgements
These studies were supported by NIH grants R01DA014277, P01DA017259, R01DA15197, R01DA03672, R01DA02396, R01DA015683, P50DA005274, P01DA009789, T32DA007027, and F31DA026279 and The Institute of International Education/Scholar Rescue Funds/New York (RA).
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This research has been supported solely by the National Institutes of Health (NIH). The following authors KWF, JES, RAA, THS, DES, and LJS declare that, except for income received from the primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. AHL, BFC, and AJT report no conflicts of interest with the work presented in this manuscript. AJT was employed by Abbott labs after completion of this work and is currently employed by AMAG Pharmaceuticals. AHL declares that over the past 3 years he has received compensation from Pfizer, Ironwood Pharmaceuticals, and Allergan. In addition, AHL has received funding from Pfizer and Ironwood for contracts unrelated to the research presented in this paper. BFC declares that over the past 3 years, he has received compensation from Pfizer, Activx Biosciences, and aTyr Pharma.
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Falenski, K., Thorpe, A., Schlosburg, J. et al. FAAH−/− Mice Display Differential Tolerance, Dependence, and Cannabinoid Receptor Adaptation After Δ9-Tetrahydrocannabinol and Anandamide Administration. Neuropsychopharmacol 35, 1775–1787 (2010). https://doi.org/10.1038/npp.2010.44
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DOI: https://doi.org/10.1038/npp.2010.44
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