Large Receptor Reserve for Cannabinoid Actions in the Central Nervous System
Abstract
The receptor occupancy required to produce cannabinoid effects in the central nervous system was determined in both a neurochemical and a behavioral assay for cannabinoid actions. In the neurochemical experiments, performed on superfused rat hippocampal slices, electrically evoked [3H]acetylcholine release was inhibited by the cannabinoid agonist, WIN 55212 to 2 with an EC50 of 0.005 microM and maximum effect of 79%. In parallel experiments examining binding of the radiolabeled CB1 antagonist [131I]AM 281 (N-(morpholin-4-yl)-5-(4-[131I]iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) to living hippocampal slices, WIN 55212 to 2 inhibited [131I]AM 281 binding with an EC50 of 1.3 microM. From these two sets of data it was determined that 50% of maximal inhibition of [3H]acetylcholine release in hippocampal slices occurs at a receptor occupancy of only 0.13% and 95% of maximal inhibition at a receptor occupancy of 7.5%, suggesting the presence of a receptor reserve that is large compared with other G protein-coupled receptor systems in the central nervous system. In behavioral experiments, WIN 55212 to 2 inhibited spontaneous locomotor activity in mice with an ED50 of 0.3 mg/kg, i. v. In in vivo binding experiments using [131I]AM 281, WIN 55212 to 2 failed to produce significant inhibition of radiotracer binding in the mouse brains, except at very high doses (10 mg/kg or greater, i. v.). By contrast, the CB1 antagonist SR 141716A (10 mg/kg, i.p.), completely abolished specific [131I]AM 281 binding. These experiments suggest that behavioral effects of cannabinoids, like neurochemical effects, are produced at very low receptor occupancy.
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Increased [11C]OMAR VT values are explained to the most part by receptor up-regulation in response to low anandamide levels rather than low receptor occupancy by anandamide.
“The lack of displacement of CB1 radioligands by agonists42–44 which has been attributed to a large receptor reserve45 suggests that increased [11C]OMAR VT values are explained to the most part by receptor up-regulation in response to low anandamide levels rather than low receptor occupancy by anandamide.”
From Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: A positron emission tomography study (2013) · cites this paper as [45]
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- Authors
- Gifford, A. N., Bruneus, M., Gatley, S. J., Lan, R., Makriyannis, A., & Volkow, N. D.
- Affiliations
- University of Connecticut (US)
- Corresponding author
- Gifford, Andrew N.
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 1999-02
- Volume
- 288
- Issue
- 2
- Pages
- 478-483
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2310765948
- Cited by
- 100
- References
- 24
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 5 · 2015: 2 · 2014: 6 · 2013: 8 · 2012: 6
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Journal of Pharmacology and Experimental Therapeutics
- Funders
- National Institute on Drug Abuse (DA12412-01, R29DA012412)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- CB1 receptor, WIN 55,212-2, acetylcholine release, hippocampus, locomotor activity, SR141716A, receptor occupancy, G protein-coupled receptors
- MeSH terms
- Calcimycin, Rimonabant, Acetylcholine, Analgesics, Animals, Behavior, Animal, Cannabinoids, Hippocampus, Iodine Radioisotopes, Ionophores, Kinetics, Male, Morpholines, Motor Activity, Naphthalenes, Piperidines, Pyrazoles, Receptors, Drug, Tritium, Rats, Sprague-Dawley, Radiopharmaceuticals, Receptors, Cannabinoid, Benzoxazines, Mice, Rats
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