Central mediation and differential blockade by cannabinergics of the discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats.
Discovery of an endocannabinoid signaling system launched the development of the blocker rimonabant, a cannabinoid CB1 receptor (CB(1)R) antagonistinverse agonist. Due to untoward effects, this medication was withdrawn and efforts have been directed towards discovering chemicals with more benign profiles. This study aims to comparatively evaluate new ligands using a rimonabant discriminated drinking aversion procedure. Rats discriminated between rimonabant (5.6 mgkg) and vehicle. The 30 min saccharin (0.1%) drinking after rimonabant pretreatment was followed by injection of lithium chloride (120 mgkg) in the experimental animals. After vehicle pretreatment, experimental animals were given i.p. NaCl (10 mlkg). Postdrinking treatment for controls was NaCl, irrespective of pretreatment condition (rimonabant or vehicle). The centrally acting neutral CB(1)R antagonist AM4113, but not the limited brain penetrating CB(1)R neutral antagonist AM6545, substituted for rimonabant. The CB(1)R agonists THC (1-10 mgkg), AM1346 (1-10 mgkg) did not substitute. The rimonabant-induced conditioned suppression of saccharin drinking was attenuated when CB(1)R agonists AM5983 (0.01-1 mgkg) and THC (10 mgkg), but not the CB(1)R agonist AM1346 (0.1-18 mgkg), were combined with rimonabant (5.6 mgkg). By varying the injection-to-test interval, we gauged the relative duration of the cueing effects of rimonabant, and the in vivo functional half-life was estimated to be approximately 1.5 h. A neutral CB(1)R antagonist (AM4113) produced cueing effects similar to those of rimonabant and generalization likely was centrally mediated. The functional cueing effects of rimonabant are relatively short-acting, pharmacologically selective, and differentially blocked by cannabinergics.