Cannabinoid compounds such as delta9-THC and synthetic analogs including desacetyllevonantradol are active in the central nervous system to produce subjective effects in humans and behavioral effects in animal models. Certain of these biological responses can be pharmacologically correlated with the agonist activity of cannabinoid compounds at the cannabinoid receptor. My laboratory has determined that the cannabinoid receptor in brain is coupled to the cyclic AMP second messenger system via G-i to inhibit adenylate cyclase. These studies have utilized the NI8TG2 neuroblastoma cell line as a model system for cellular biology, and rat brain slices and membrane fractions to investigate the cellular mechanism(s) of action of cannabinoid drugs. The goal of this project is to study the regulation of the cannabinoid receptor at the cellular and molecular level, and will be accomplished through the following specific aims: 1. Assess the domains of the cannabinoid receptor that are important for ligand binding and signal transduction; 2. Determine the G protein subtype(s) that couple to the cannabinoid receptor in the brain and neuroblastoma cells; 3. Analyze the role of phosphorylation of the cannabinoid receptor as a regulatory mechanism; and 4. Analyze the role of receptor sequestration and down-regulation as a regulatory mechanism for the cannabinoid receptor. It is expected that these studies of the cellular regulation of the cannabinoid receptor will further our understanding of cannabinoid actions in the central nervous system. Multiple actions of cannabinoid compounds may be mediated by the cannabinoid receptor via multiple G proteins and effectors. Perhaps separation of therapeutic effects such analgesia from the untoward effects such as sedation might be possible based upon regulation of divergent signal transduction mechanisms. The neuron's ability to regulate its response to cannabinoid compounds is based upon the regulation of the receptor by phosphorylation or up- or down- regulation. Neurons may respond to cannabinoid compounds with differing sensitivity as a result of interactions with other neuromodulators. In the intact animal, this modification may result in tolerance to some of the effects of cannabinoid drugs, or an altered responsiveness dependent upon cell type and synaptic inputs.
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