The recent advances in our understanding of the neurochemical/physiological basis of cannabinoid action provide exciting background material for continuing efforts to further delineate the mechanism of action of cannabimimetic agents. Cannabinoids and cannabimimetics induce their receptor-based effects by modulating the functions of one or more of four known """"""""cannabinoid target proteins"""""""": CB1, CB2, anandamide amidase, and the anandarnide transporter. The overall purpose of the proposed studies is to compare the structure-activity relationships of the subjective effects of delta-9-tetrahydrocannabinol (delta-9-THC) and other cannabimimetics with analogs such as [(R)-methanandamide] and AM-1346 of the putative endogenous cannabinoid receptor ligand anandamide as well as representatives from a second endocannabinoid family discovered in brain, i.e., 2-arachidonyiglycerol (2-AG). Other targets for examination concern the enzymes responsible for the synthesis and degradation of anandamide and the anandamide transporter system involved in reuptake of endocannabinoids. The SAR between chemical structure and drug action reveals the structural requirements for a given drug effect or drug action. Though some studies suggest that delta-9-THC and anandamide as well as (R)-methanandamide share many similar properties, a one-on-one relationship has not been demonstrated. Studies from our own and other laboratories have shown the THC-like properties of synthetic cannabinoids and cannabimimetics are highly dependent on particular structural configurations. The proposed studies investigate structural requirements of anandamide- and 2-AG analogs in comparison to known cannabimimetic compounds. These studies also focus on identifying useful pharmacotherapies for cannabis abuse by effectively blocking the psychoactive, cannabimimetic properties. The present project will utilize drug discrimination procedures with rats as an animal model for assessing the psychoactive properties of delta-9-THC, (R)-methanandamide, and related compounds. Drug discrimination is the most commonly used paradigm for studying the subjective, intoxicating effects of drugs in preclinical psychopharmacology. A special feature of this proposal is the use of different training doses of THC to create different efficacy demands. Additionally, food maintained responding and open-field activity studies will also be conducted. By providing important information on the SAR of endogenous anandamide and exogenous delta-9-THC, as well as potential cannabimimetic antagonists, these studies will not only add to our understanding of the behavioral neurobiology of cannabis abuse and dependence, but may also lead to the development of effective pharmacological treatments.
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