In the last decade, considerable strides have been taken toward understanding the neurobiological basis of substance abuse. The recent discovery of the cannabinoid receptor distribution in the mammalian forebrain and cerebellum presents the intriguing possibility that there are endogenous cannabinoid-like substances in the mammalian brain. There is increasing evidence that many cannabinoid receptor mediated effects occur via G-protein coupling of this receptor to intracellular second messenger systems. The electrophysiological consequences of cannabinoid receptor occupancy have not been determined, and there is currently no data which relates the electrophysiological effects of cannabinoids to the well established G-protein-coupled second messenger changes in neurons and glial cells. The studies proposed here are designed to identify and characterize the effects of cannabinoid receptor occupancy on electrical and biochemical processes in cultured central nervous system neurons and glia from hippocampus, cerebral cortex, cerebellum, and NG108-15 neuroblastoma x glioma cells. Each of the cell types to be investigated have been demonstrated to express cannabinoid receptors and have been previously shown to be influenced by cannabinoids or cannabinoid analogs by several different investigators. Electrophysiological studies will characterize ionic currents gated by cannabinoid receptor occupancy, and determine whether the cannabinoid current requires coupling via a second-messenger cascade between the cannabinoid receptor and a membrane conductance mechanism. These studies will also examine interactions between cannabinoid receptor activation and other neurotransmitter, neuromodulator systems. Additional studies will measure cannabinoid receptor binding and effects on adenylyl cyclase in the same cells, and characterize effects of chronic exposure to cannabinoids on these systems.
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