The cannabinoids have a long history as drugs of abuse, with profound effects at neurochemical, physiological and behavioral levels. Nevertheless, the molecular mechanisms of action of these drugs are still unknown. An important breakthrough in this field occurred with the discovery that Lambda 9-tetrahydrocannabinol (THC) and its analogs bind to brain membrane receptors which are coupled to G-proteins to inhibit adenylyl cyclase. While these THC receptors are probably not responsible for all CNS actions of cannabinoids, they may help explain some specific neuronal actions of these compounds. Moreover, since many other neurotransmitters and neuromodulators bind to G-protein-coupled receptors, these results suggest that cannabinoids may not simply be exogenous drugs of abuse but also be members of a novel class of neurotransmitters. The current study will explore components of the putative endogenous cannabinoid system in the brain by utilizing a novel class of compounds, the aminoalkylindoles (AAIs). The AAIs, originally synthesized as analgesics, are now known to bind to the same G-protein-coupled receptors as THC. These receptors can be studied by radioreceptor and cerebellar granule cells, and by inhibition of electrically-induced contractions of mouse vas deferens. Moreover, the AAIs contain a series of antagonists which competitively antagonize these receptor actions of THC. These compounds may be the first specific THC antagonists to be reported. This project will focus on THC and AAI actions in cultured cerebellar granule cells, which represent a novel, non-transformed cell culture system for the study of cannabinoid receptors. Other experiments will utilize these different methods of receptor assay, combined with specific AAI/THC antagonists, to isolate endogenous ligands binding to these receptor sites.
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