ABSTRACT
Cannabinoid CB1 receptor antagonist/inverse agonists are becoming increasingly recognized for their potential therapeutic utility as appetite suppressants. In the current paper we characterize the biochemical and behavioral effects of AM 1387, which is a novel CB1 antagonist. AM 1387 exhibited binding affinity and selectivity for the CB1 over the CB2 receptor. Moreover, AM 1387 decreased GTPgammaS (EC50: 22.82 nM) and increased forskolin-stimulated cAMP (EC50: 274.6 nM), as did the CB1 inverse agonist AM 251 (GTPgammaS EC50: 25.82 nM; cAMP EC50: 363.8 nM), indicating that AM1387 also has inverse agonist properties in vitro. In the behavioral characterization in rats, AM 1387 suppressed lever pressing for food on two operant schedules (fixed-ratio 1 and 5). Timecourse of the effect on fixed-ratio 5 responding was then determined, and the half-life (t1/2=4.87 h) was found to be threefold shorter than what has been shown for SR 141716A, and fourfold shorter than AM 251. Finally, AM 1387 was found to suppress food intake using three diets of differing macronutrient composition and palatability. It was concluded that AM 1387 may be a useful tool for examining the effects of CB1 receptor antagonism or inverse agonism on food intake.
Subject(s)
Eating/drug effects , Feeding Behavior/drug effects , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Animals , Brain/metabolism , Cell Line , Conditioning, Operant , Cyclic AMP/metabolism , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , In Vitro Techniques , Male , Mice , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Reinforcement, Psychology , Spleen/metabolismABSTRACT
AM 411 ((-)-1-adamantyl-Delta8-tetrahydrocannabinol) is a novel full agonist at cannabinoid CB1 receptors. The present studies were conducted to provide behavioral characterization of this compound in rats. It was hypothesized that AM 411 should produce behavioral effects similar to known cannabinoid agonists, and that these effects should be inhibited by co-treatment with a CB1 antagonist. In Experiments 1 and 2, AM 411 dose-dependently produced behaviors consistent with CB1 agonism, including analgesia, hypothermia, catalepsy and reductions in locomotion, which were blocked by a CB1-selective antagonist. In Experiment 3, AM 411 produced a dose-dependent suppression of lever-pressing on a fixed-ratio 5 (FR5) schedule, a task known to be sensitive to administration of CB1 agonists. Detailed analysis of the temporal patterns of operant responding showed that AM 411 altered the distribution of interresponse times. Experiment 4 showed that AM 411 decreased relative interior activity in the open field, which is suggestive of an anxiogenic effect. It is concluded that AM 411 produces CB1 agonist-like behavior with potency between that of WIN 55,212-2 and AM 356. AM 411 could be a useful tool for understanding the behavioral and neural effects of CB1 receptor stimulation.
