Behavioral pharmacology of cannabinoids

The development of improved pharmacotherapeutics for treating cannabinoid dependence has presented many challenges. This report will discuss these challenges as well as use an animal model to study cannabinoid dependence by incorporating traditional methodologies (e.g., tetrad assay) and profiling novel cannabinoid ligands with distinct pharmacological properties/modes of action by evaluating their pharmacological effects on CB1-receptor related physiological and behavioral endpoints. Initial steps were made to characterize acutely AM2389, a CB1-receptor agonist, in the tetrad assay (i.e., locomotor activity, paw thermal stimulation, inverted screen test/catalepsy bar test and rectal temperature) as a novel approach for inducing dependence with greater potency and a prolonged functional in vivo duration of action than Δ9-THC. Cannabinoid tolerance was then evaluated with repeated administration of AM2389. Next, the effects of centrally acting antagonists, rimonabant and AM4113, and a neutral antagonist with limited acute brain penetration, AM6545, were characterized behaviorally prior to examining precipitated withdrawal. Antagonist-precipitated withdrawal was induced in cannabinoid-tolerant mice by either rimonabant or AM4113 but not by AM6545. Finally, CB1-receptor antagonist induced precipitated withdrawal was reversed by reinstating either AM2389 or Δ9-THC in cannabinoid-tolerant mice. Overall, these findings suggest that cannabinoid precipitated withdrawal may not be ascribed to the inverse agonist properties of the CB1-receptor antagonist rimonabant, but rather simply to the rapid displacement of the agonist from the CB1-receptor. Furthermore, this cannabinoid withdrawal syndrome is likely centrally mediated, since only the centrally acting CB1-receptor antagonists were able to elicit "withdrawal" responses, i.e., such responses were not induced by the purported peripherally selective CB1-receptor antagonist AM6545.