PROJECT SUMMARY Cannabis sativa/indica (marijuana plant) is the most commonly abused substance in the United States, but is still classified as illegal to possess under federal law. Psychoactive phytocannabinoids such as Δ9- tetrahydrocannabinol (THC) produce their effects on physiology and behavior through activation of CB1 and CB2 receptors. These receptors are part of the endocannabinoid system, one of several lipid signaling systems in the brain/body. Discovery of these mechanisms underlying cannabinoid action and characterization of their effects on physiology and behavior were due, in part, to research conducted in animals, and specifically, in rodent models. Future progress in this area also will involve findings derived from work with these models. Hence, fundamental knowledge of the advantages and limits of the models are crucial. Recently, we discovered an intriguing species X sex interaction in the effects of THC in rats and mice. Briefly, rats exhibited pronounced sex differences in physiological and behavioral responses following THC injection whereas female and male mice showed similar responses. The overall goals of the proposed project are to investigate mechanisms that may underlie these differences and to determine the extent to which a similar profile characterizes THC’s effects on physiology and behavior. Side-by-side comparisons of the physiological (temperature and cardiac and pulmonary function) and behavioral (discriminative stimulus) effects of THC and cannabis extracts will be made in female and male rats and mice. Differences in pharmacokinetics and receptor mechanisms will be characterized following parenteral injection routes of administration for rodent studies and after administration via more translationally relevant inhalational and oral routes of administration. The results of these studies will provide an empirical basis for choice of rodent model with which to investigate mechanisms underlying cannabis use.