Evaluation of the in vivo receptor occupancy for the behavioral effects of cannabinoids using a radiolabeled cannabinoid receptor agonist, R-[125/131I]AM2233 - PubMed (original) (raw)
Evaluation of the in vivo receptor occupancy for the behavioral effects of cannabinoids using a radiolabeled cannabinoid receptor agonist, R-[125/131I]AM2233
Jasbeer Dhawan et al. Synapse. 2006 Aug.
Abstract
G-protein coupled receptors exist in both high and low agonist affinity conformations, with tracer levels of agonist radioligands preferentially binding to the former. The goal of the present study was to characterize the in vivo binding of the aminoalkyindole-based, CB1 receptor agonist, R-[125/131I]AM2233 ((2-[125/131I]iodo-phenyl)-[1-(1-methyl-piperidin-2-yl-methyl)-1H-indol-3-yl]-methanone), and to use this radiotracer to selectively measure the receptor occupancy by the related CB1 receptor agonist, WIN55212-2, to the agonist-preferring affinity state of the receptor. In mouse locomotor assays, both WIN55212-2 and AM2233 (racemic) produced an approximately 60% reduction in activity at 1 mg/kg, (i.v.) and completely inhibited activity at 3 mg/kg, confirming their agonist nature. In ex vivo autoradiography, preferential uptake of R-[131I]AM2233 was apparent in CB1 receptor-rich areas, including globus pallidus, substantia nigra, striatum, cerebellum, and hippocampus. Overall brain uptake of R-[131I]AM2233 was 1.3% injected activity/g at 5 min in mice. Coinjection of 3 mg/kg (i.v.) SR141716A, a CB1 receptor antagonist, with R-[125I]AM2233 inhibited the radiotracer binding almost to nonspecific levels in the striatum, globus pallidus, and substantia nigra, although residual binding to a non-CB1 receptor remained in the hippocampus. In contrast to the effect of SR141716A, coinjection of 10 mg/kg (i.v.) WIN55212-2, a high dose that produced an immediate and profound immobility and catalepsy in the mice, reduced CB1 receptor-specific binding of R-[125I]AM2233 in CB1 receptor-rich areas by only 21-43%. These observations suggest that the behavioral effects of CB1 receptor agonists are manifested with a relatively small fraction of the agonist-preferring affinity state of the receptor occupied.
Similar articles
- Large receptor reserve for cannabinoid actions in the central nervous system.
Gifford AN, Bruneus M, Gatley SJ, Lan R, Makriyannis A, Volkow ND. Gifford AN, et al. J Pharmacol Exp Ther. 1999 Feb;288(2):478-83. J Pharmacol Exp Ther. 1999. PMID: 9918548 - Sphingosine and its analog, the immunosuppressant 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, interact with the CB1 cannabinoid receptor.
Paugh SW, Cassidy MP, He H, Milstien S, Sim-Selley LJ, Spiegel S, Selley DE. Paugh SW, et al. Mol Pharmacol. 2006 Jul;70(1):41-50. doi: 10.1124/mol.105.020552. Epub 2006 Mar 29. Mol Pharmacol. 2006. PMID: 16571654 - Cannabinoids depress excitatory neurotransmission between the subthalamic nucleus and the globus pallidus.
Freiman I, Szabo B. Freiman I, et al. Neuroscience. 2005;133(1):305-13. doi: 10.1016/j.neuroscience.2005.01.058. Neuroscience. 2005. PMID: 15893652 - _R_-2-[131I]Iodophenyl-(1-(1-methylpiperidin-2-ylmethyl)-1_H_-indol-3-yl)methanone.
Leung K. Leung K. 2006 Dec 12 [updated 2008 Feb 12]. In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004–2013. 2006 Dec 12 [updated 2008 Feb 12]. In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004–2013. PMID: 20641836 Free Books & Documents. Review. - Moving around the molecule: relationship between chemical structure and in vivo activity of synthetic cannabinoids.
Wiley JL, Marusich JA, Huffman JW. Wiley JL, et al. Life Sci. 2014 Feb 27;97(1):55-63. doi: 10.1016/j.lfs.2013.09.011. Epub 2013 Sep 23. Life Sci. 2014. PMID: 24071522 Free PMC article. Review.
Cited by
- MAM-2201, One of the Most Potent-Naphthoyl Indole Derivative-Synthetic Cannabinoids, Exerts Toxic Effects on Human Cell-Based Models of Neurons and Astrocytes.
Coccini T, De Simone U, Lonati D, Scaravaggi G, Marti M, Locatelli CA. Coccini T, et al. Neurotox Res. 2021 Aug;39(4):1251-1273. doi: 10.1007/s12640-021-00369-3. Epub 2021 May 4. Neurotox Res. 2021. PMID: 33945101 - The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons.
Murataeva N, Mackie K, Straiker A. Murataeva N, et al. Pharmacol Res. 2012 Nov;66(5):437-42. doi: 10.1016/j.phrs.2012.08.002. Epub 2012 Aug 14. Pharmacol Res. 2012. PMID: 22921769 Free PMC article. - Ligand-binding architecture of human CB2 cannabinoid receptor: evidence for receptor subtype-specific binding motif and modeling GPCR activation.
Pei Y, Mercier RW, Anday JK, Thakur GA, Zvonok AM, Hurst D, Reggio PH, Janero DR, Makriyannis A. Pei Y, et al. Chem Biol. 2008 Nov 24;15(11):1207-19. doi: 10.1016/j.chembiol.2008.10.011. Chem Biol. 2008. PMID: 19022181 Free PMC article. - Baths salts, spice, and related designer drugs: the science behind the headlines.
Baumann MH, Solis E Jr, Watterson LR, Marusich JA, Fantegrossi WE, Wiley JL. Baumann MH, et al. J Neurosci. 2014 Nov 12;34(46):15150-8. doi: 10.1523/JNEUROSCI.3223-14.2014. J Neurosci. 2014. PMID: 25392483 Free PMC article. Review. - Human Astrocyte Spheroids as Suitable In Vitro Screening Model to Evaluate Synthetic Cannabinoid MAM2201-Induced Effects on CNS.
De Simone U, Pignatti P, Villani L, Russo LA, Sargenti A, Bonetti S, Buscaglia E, Coccini T. De Simone U, et al. Int J Mol Sci. 2023 Jan 11;24(2):1421. doi: 10.3390/ijms24021421. Int J Mol Sci. 2023. PMID: 36674936 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources