Differences in the relative potency of SR 141716A and AM 251 as antagonists of various in vivo effects of cannabinoid agonists in C57BL/6J mice
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Although the cannabinoid CB(1) antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR 141716A) blocks many of the in vivo effects of cannabinoids, the antagonist activity of SR 141716A is limited under some conditions. The general aims of this study were to: 1) examine whether the limited antagonist activity of SR 141716A generalizes to the cannabinoid CB(1) antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM 251); and 2) examine mechanisms by which cannabinoids produce hypothermia, catalepsy, and hypoactivity in C57BL/6J mice. SR 141716A and AM 251 were administered alone and in combination with the cannabinoid agonists triangle up(9)-tetrahydrocannabinol (triangle up(9)-THC) and R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)-methyl]pyrrolol-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone (WIN 55212-2). triangle up(9)-THC and WIN 55212-2 produced catalepsy, hypothermia, and hypoactivity with similar potency; WIN 55212-2 produced greater hypothermia than triangle up(9)-THC, otherwise differences in maximal effect were not detected in the other assays. When administered alone, the antagonists did not produce catalepsy or alter body temperature and they decreased locomotor activity. SR 1417167A and AM 251 blocked catalepsy and hypothermia, and partially attenuated hypoactivity, produced by triangle up(9)-THC and WIN 55212-2. While the antagonists were equipotent in blocking agonist-induced hypothermia, SR 141716A was 6-fold more potent than AM 251 in blocking agonist-induced catalepsy. The results demonstrate that SR 141716A and AM 251 have strikingly similar behavioral activity, i.e., they block some and not other in vivo effects of cannabinoid agonists, and further demonstrate differences in the maximum effect of cannabinoid agonists that might be related to differences in agonist efficacy. While the results strongly suggest that cannabinoid CB(1) receptors mediate the hypothermic and cataleptic effects of cannabinoids, differences in the relative potency of antagonists suggest that mechanisms responsible for these effects are not identical.
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Concomitant administration of AM251 (2 mg/kg i.p.) prevented the effect of FAAH inhibition on social approach in BTBR mice.
“The effect of FAAH inhibition on social approach depended on CB1 receptors and, thus, presumably on anandamide accumulation, because it was prevented by concomitant administration of AM251 (2 mg kg−1, i.p.) (Fig. 1c, d).”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [29]
Neither AM251 (2 mg/kg i.p.) nor URB597 (1 mg/kg i.p.) altered the time spent in the social chamber or the time spent sniffing the target mouse in socially normal C57Bl6J mice.
“We first evaluated maximally effective doses of AM251 (2 mg kg−1, i.p.)29 or URB597 (1 mg kg−1, i.p.)25 in socially normal C57Bl6J mice and found that neither drug altered the two outcome measures of the test, namely the time spent in the social chamber and the time spent sniffing the target mouse (Fig. 1a, b).”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [29]
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Behavioral pharmacology of cannabinoids
Tai, S. (2012) · doi:10.17760/d20002949
- Authors
- McMahon, L. R., & Koek, W.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- McMahon, Lance R.
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2007-08
- Volume
- 569
- Issue
- 1-2
- Pages
- 70-76
- ISSN
- 0014-2999 (ISSN-L)
- PMC
- PMC2043376
- OpenAlex
- W2056524652
- Cited by
- 57
- References
- 25
- Citations by year
- 2024: 2 · 2023: 1 · 2021: 2 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 3 · 2014: 5 · 2013: 3 · 2012: 5
- FWCI
- 3.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service (DA19222, DA15468)
- 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
- SR141716A, AM251, cannabinoid CB1 receptor antagonist, delta-9-tetrahydrocannabinol, WIN 55,212-2, catalepsy, hypothermia, hypoactivity, locomotor activity, C57BL/6J mice
- MeSH terms
- Rimonabant, Animals, Cannabinoids, Catalepsy, Dose-Response Relationship, Drug, Hypothermia, Injections, Intraperitoneal, Mice, Inbred C57BL, Morpholines, Motor Activity, Naphthalenes, Piperidines, Pyrazoles, Dronabinol, Time Factors, Receptor, Cannabinoid, CB1, Benzoxazines, Mice
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