EXOGENOUS/ENDOGENOUS CANNABINOIDS--CHEMISTRY & BEHAVIOR

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This proposal is a request for a RSDA which would facilitate and extend ongoing research concerning cannabinoids and related compounds. 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. The overall purpose of the proposed studied is to compare the structure-activity relationships of the subjective effects of delta9-tetrahydrocannabinol (delta9-THC) and the endogenous cannabinoid receptor ligand anandamide. The SAR between chemical structure and drug action reveals the structural requirements for the stereoselectivity or stereospecificity of a given drug effect or drug action. Though some studies suggest that delta9-THC and anandamide 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. In general, these studies suggest that cannabimimetic activity is stereoselective, i.e., whether the compound is a (+ )- or (-)-enantiomer, methyl group planarity with regard to the cyclohexane ring, and characteristics of the side chain. The pro posed studies investigate, potential stereoselectivity of known cannabimimetic compounds with regard to anandamide. These studies also focus on identifying useful pharmacotherapies for cannabis abuse by effectively blocking the psychoactive, cannabimimetic properties. Though a number of compounds have been identified that have cannabimimetic properties, compounds that effectively block or antagonize the THC cue have not yet been isolated. The present project will primarily utilize drug discrimination procedures with rats as an animal model for assessing the psychoactive properties of delta9-THC, anandamide, and related test compounds. Drug discrimination is the most commonly used paradigm for studying the subjective, intoxicating effects of drugs in preclinical psychopharmacology. The Aims of this proposal will be addressed in a series of 4 main experiments, requiring 5 years for full completion. The overall purpose is to: l) determine if the SAR of delta9-THC and anadamide are similar with regard to subjective discriminative stimulus properties, and 2) explore the potential for antagonism of cannabimimetic effects. By providing important information on the SAR of endogenous anandamide and exogenous delta9-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. Approval of this proposal would create financial stability and ensure that the above goals can be met.