Discriminative stimulus functions of methanandamide and a dagger(9)-THC in rats: tests with aminoalkylindoles (WIN55,212-2 and AM678) and ethanol

The aim of the study was to characterize in vivo the aminoalkylindoles WIN55,212-2 (WIN) and AM678 (naphthalen-1-yl(1-pentyl-1H-indol-3-yl)methanone) as cannabinoid receptor (CB1R) ligands using drug discrimination. Tests also involved a dagger(9)-tetrahydrocannabinol (THC) and R-(+)-methanandamide (mAEA), a metabolically stable analog of the endogenous ligand anandamide, as well as the CB1R selective antagonist/inverse agonist rimonabant; tests with ethanol assessed pharmacological specificity. We used two different drug discriminations (mAEA and THC) allowing us to explore potential differences in CB1R activation which could be attributed to variations in their respective CB1R signaling mechanisms. There were two concurrently trained groups of rats. One group discriminated between i.p. injected vehicle and 10 mg/kg mAEA. The other group was trained to discriminate between vehicle and 1.8 mg/kg THC. Dose generalization curves for AM678, WIN55,212-2, THC, and mAEA suggested the following rank order of potency: AM678 > WIN55,212-2 a parts per thousand yenaEuro parts per thousand THC > mAEA in both drug discrimination groups. Challenge by 1 mg/kg rimonabant resulted in shifts to the right of the generalization curves for the two aminoalkylindoles (4.4-fold for AM678 and 11.3-fold for WIN in the mAEA group, whereas for the THC group, the corresponding values were 13 and 2.6, respectively), suggesting surmountable antagonism. Ethanol did not generalize in either of the two groups, suggesting pharmacological specificity. Data are congruent with the general observation that there is substantial overlap in the discriminative stimulus effects of CB1R ligands across different chemical classes. However, the quantitative differences in the interactions between the two aminoalkylindoles and rimonabant in the two discrimination groups suggest subtle variations in the ligand-receptor activation(s).