[Drug discrimination properties and cytotoxicity of the cannabinoid receptor ligands].
The worldwide distribution of smokable herbal mixtures called "Spice" that contain synthetic cannabinoids with a pharmacological activity similar to delta 9-tetrahydrocannabinol (delta 9-THC) has been reported. The synthetic cannabinoids induce behavior and have biochemical properties similar to naturally occurring cannabinoids such as delta 9-THC. In drug discrimination procedures, animal behavior is differentially reinforced depending on the presence or absence of specific drug stimuli. This review seeks to establish an animal model to serve as a discriminative stimulus of the synthetic cannabinoids, to determine whether this discriminative stimulus is identical to that of delta 9-THC. Much data have been obtained in drug discrimination experiments with various synthetic cannabinoids. In the discriminative study, synthetic cannabinoids such as CP-55,940 and WIN-55,212-2 were substituted for delta 9-THC in rats trained to discriminate delta 9-THC from the vehicle. These discriminative effects of synthetic cannabinoids were antagonized by CB1 antagonist SR-141,716A. The discriminative effects of synthetic cannabinoids may overlap with the delta 9-THC cue mediated by CB1 receptors. In in vitro study using NG 108-15 cell lines, synthetic cannabinoids have produced strong cytotoxicities that were suppressed by pretreatment with the CB1 receptor antagonist. Furthermore, pretreatment with caspase inhibitors suppressed these synthetic-cannabinoid-induced cytotoxicities in NG 108-15 cells. These findings indicate that the cytotoxicity of synthetic cannabinoids towards NG 108-15 cells is mediated by the CB1 receptors and further suggest that caspase cascades may play an important role in the cytotoxicities induced by these synthetic cannabinoids. In conclusion, synthetic cannabinoid abuse could be a health hazard for humans.
Department of Drug Dependence Research, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8553, Japan. tomiyama@ncnp.go.jp
Ken-ichi
K
Tomiyama
Masahiko
M
Funada
D000818:Animals; D048588:Benzoxazines / Q000737:chemistry / Q000494:pharmacology; D002186:Cannabinoids / Q000737:chemistry / Q000494:pharmacology*; D003511:Cyclohexanols / Q000737:chemistry / Q000494:pharmacology; D013759:Dronabinol / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D013379:Substrate Specificity
D048588:Benzoxazines; D002186:Cannabinoids; D003511:Cyclohexanols; D008024:Ligands; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol