The psychoactive component of marijuana, ?9-tetrahydrocannabinol, binds to and activates cell surface receptors called cannabinoid receptors. Activation of these receptors produces intense responses in humans, which suggest that endogenous cannabinoid (endocannabinoid) substances may contribute in important ways to brain functions as diverse as appetite, mood and pain. Two such substances are anandamide and 2- arachidonoylglycerol (2-AG), lipid-derived compounds that are released from neural cells and activate cannabinoid receptors with high affinity. Anandamide and 2-AG undergo a rapid deactivation process, which contributes to arrest of their biological actions. In the case of anandamide, this process is thought to consist of two steps, transport into cells and intracellular hydrolysis by the enzyme fatty-acid amide hydrolase (FAAH). By contrast, much less is known about 2-AG deactivation. Previous work in our lab has provided evidence that the enzyme monoacylglycerol lipase (MGL) - a presynaptic serine hydrolase that converts 2-AG into arachidonic acid and glycerol - participates in 2-AG hydrolysis. Based on these results, we hypothesize that MGL is an essential component of the physiological mechanism by which 2-AG is deactivated at brain synapses. Our first objective is to discover potent and selective inhibitors of MGL activity. In our initial studies, we have identified two promising leads, which will be optimized through a series of experimental and computational approaches, including structure-activity relationships, site-directed mutagenesis, mass spectrometry and molecular modeling. Our second objective is to characterize 2-AG transport into neurons and define the role of MGL in this process. We will combine pharmacological and genetic strategies to test the hypothesis that MGL- mediated hydrolysis provides the driving force for neuronal 2-AG internalization. Finally, we will use MGL inhibitors and mutant mice that overexpress MGL in the forebrain to determine whether 2-AG hydrolysis terminates the behavioral effects of endogenous 2-AG. We will focus our attention on two behaviors - feeding and stress-coping responses - in which as-yet-unidentified endocannabinoid signals are thought to play a crucial role. These studies will help uncover the functions served by the endocannabinoid system in the brain and may open innovative avenues for the treatment of neuropsychiatric and substance abuse disorders.
Marijuana works by mimicking important transmitter substances in the brain, called endocannabinoids. The objective of our research is to understand how these transmitters are produced and eliminated, and discover innovative medicines that target these processes.
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