Derived from the plant Cannabis sativa, marijuana is a widely used drug that is primarily known for its psychoactive properties. The primary psychoactive component, delta-9-tetrahydrocannabinol (delta-9-THC), is responsible for its many behavioral and physiological effects which include analgesia as well as changes in memory, cognition, psychomotor skills, mood, perception and immunosuppression. Structure activity relationship (SAR) studies combined with the recent cloning of a G protein-coupled cannabinoid receptor identified in regions of the brain suggests that cannabimimetic agents mediate their CNS effects through specific receptor- ligand interactions. The overall goal of this project is to investigate the mechanisms by which cannabinoid compounds produce immune inhibition by testing the following hypothesis: Immunosuppression by cannabimimetic agents is mediated through a G-protein coupled cannabinoid receptor present on lymphoid cells which when stimulated by cannabimimetic agents produces an intracellular increase in cAMP. The basis for this proposal are five key observations from work in our laboratory supporting the role for a cannabinoid receptor in immunosuppression: (1) [3H]-CP-55,940, demonstrates a high degree of specific binding to lymphoid cells in radioligand binding studies; (2) SAR studies demonstrate that synthetic cannabinoid compounds have a similar rank order of immunoinhibitory potency to that reported with respect to their CNS related effects; (3) cannabinoids demonstrate enantioselective immunosuppression; (4) delta-9- THC and CP-55,940 markedly enhance forskolin-induced intracellular cAMP in lymphoid cells; (5) T-cells are more sensitive to immune inhibition by delta-9-THC than B-cells and macrophages which supports a cAMP-associated mechanism of immunosuppression. Our hypothesis will be tested using the following specific aims: (1) Changes in the phenotypic composition of murine spleen cells isolated from delta-9-THC-treated mice will be characterized by fluorescence activated cell sorting (FACS) analysis; (2) Enantioselective immune inhibition by cannabinoid agents will be further characterized; (3) Cannabinoid receptors on mouse and human lymphoid cells will be verified for the presence of unique regions of mRNA associated with the putative receptor as well as the expression of this receptor using radioligand studies; (4) Modulation of intracellular cAMP through a G protein-coupled mechanism by cannabimimetic agents will be characterized in mouse spleen cells; and (5) the effects of cannabinoids on human lymphoid cell immune function and modulation of cAMP will be investigated.
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