• Torbjörn U C Järbe, Brian J LeMay, V Kiran Vemuri, Subramanian K Vadivel, Alexander Zvonok, and Alexandros Makriyannis.
• Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA. t.jarbe@neu.edu
• Psychopharmacology (Berl.). 2011 Aug 1; 216 (3): 355-65.

RationaleDiscovery of an endocannabinoid signaling system launched the development of the blocker rimonabant, a cannabinoid CB1 receptor (CB(1)R) antagonist/inverse agonist. Due to untoward effects, this medication was withdrawn and efforts have been directed towards discovering chemicals with more benign profiles.ObjectiveThis study aims to comparatively evaluate new ligands using a rimonabant discriminated drinking aversion procedure.MethodsRats discriminated between rimonabant (5.6 mg/kg) and vehicle. The 30 min saccharin (0.1%) drinking after rimonabant pretreatment was followed by injection of lithium chloride (120 mg/kg) in the experimental animals. After vehicle pretreatment, experimental animals were given i.p. NaCl (10 ml/kg). Postdrinking treatment for controls was NaCl, irrespective of pretreatment condition (rimonabant or vehicle).ResultsThe 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 mg/kg), AM1346 (1-10 mg/kg) did not substitute. The rimonabant-induced conditioned suppression of saccharin drinking was attenuated when CB(1)R agonists AM5983 (0.01-1 mg/kg) and THC (10 mg/kg), but not the CB(1)R agonist AM1346 (0.1-18 mg/kg), were combined with rimonabant (5.6 mg/kg). 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.ConclusionA 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.

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