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Primarily, rats have served as subjects in Δ 9 -tetrahydrocannabinol's (THC) discrimination studies although other species such as monkeys and pigeons have been used. While the introduction of the knockout and transgenic mice has vastly stimulated the study of the discriminative stimulus effects of drugs there is only a single published report of mice trained to discriminate THC. Thus, this study extended those results by providing a systematic replication that THC serves as an effective discriminative stimulus in mice and by further investigating the mechanisms of action involved in the THC discrimination model in the mouse. Male C57BL/6J mice were trained to discriminate 10 mg/kg THC from vehicle in 2-lever drug discrimination. THC fully and dose dependently substituted for itself. Cannabinoid indoles, except one with low cannabinoid CB 1 receptor affinity, substituted for THC. Anandamide failed to substitute for THC when administered alone but completely substituted when administered with the non-specific fatty acid amide hydrolase inhibitor, phenylmethylsulphonyl fluoride. As expected, nicotine failed to substitute for THC. Lastly, the cannabinoid CB 1 receptor antagonist rimonabant blocked THC's discriminative stimulus effects.Taken together these studies demonstrate THC's ability to produce discriminative stimulus effects as well as demonstrate its pharmacological specificity and mechanism of action in a two-lever drug discrimination mouse model.

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Indole derivatives R 0140 1-Pentyl-3-phenylacetylindoles, a New Class of Cannabimimetic Indoles. -A variety of the title indole derivatives (I) (26 examples) are synthesized and their affinities for the cannabinoid CB1 and CB2 receptors are determined. Compounds (Ib) and (Ic) have a 5-fold selectivity for the CB1 receptor with modest affinity for the CB2 receptor. Both compounds are highly efficacious agonists at the CB1 receptor and partial agonists at the CB 2 receptor. -(HUFFMAN*, J. W.; SZKLENNIK, P. V.; ALMOND, A.; BUSHELL, K.; SELLEY, D. E.; HE, H.; CASSIDY, M. P.; WILEY, J. L.; MARTIN, B. R.; Bioorg. Med. Chem. Lett. 15 (2005) 18, 4110-4113; Howard L. Hunter Chem. Lab., Clemson Univ., Clemson, SC 29634, USA; Eng.) -H. Toeppel 49-116