The regulation of basal ganglia glutamate levels by endogenous cannabinoids is poorly understood. It is known that marijuana suppresses glutamate release in vitro by activating cannabinoid CB1 receptors. This regulation undoubtedly indicates that CB1 receptors are therapeutically relevant in alleviating basal ganglia pathologies caused by an augmentation in extracellular glutamate. Unfortunately, any beneficial effects of marijuana in the clinical management of glutamate-mediated disorders are limited by its potential to produce psychotropic effects. One solution to the problem of marijuana-based therapeutics is the pharmacological manipulation of endogenous cannabinoids which mimic the biological actions of marijuana. The identification of mechanisms that regulate the uptake and metabolism of endogenous cannabinoids has led to the development of novel drugs which inhibit these molecular processes. It is now established that these drugs (endocannabinoid inactivation inhibitors) increase endogenous cannabinoid levels in the rat brain. Despite this, the regulation of extracellular glutamate by the endogenous cannabinoid system, and the significance of this regulation, has not been elucidated. One of the reasons is a lack of studies in behaving animals. The proposed research will fill this gap in our knowledge by determining the effects of endogenous cannabinoids and endocannabinoid inactivation inhibitors on extracellular glutamate in the striatum of behaving rats. The three Specific Aims to be tested are: (1) To determine if CB1 receptor activation by endogenous cannabinoids inhibits striatal glutamate levels; (2) To compare the effects of three classes of cannabinoid drugs (direct cannabinoid agonists, endogenous cannabinoids, and endocannabinoid inactivation inhibitors) on striatal glutamate levels; (3) To identify specific brain regions in which CB1 receptor activation suppresses striatal glutamate. The overall hypothesis to be tested is that CB1 receptor activation by exogenous and endogenous cannabinoids blocks striatal glutamate levels supplied by vesicular and nonvesicular release. The combined results from these studies will elucidate important interactions between cannabinoid CB1 receptors and cellular mechanisms of glutamate release and delineate the effect of endocannabinoid inactivation inhibitors on basal ganglia glutamate levels. The potential of marijuana to produce psychotropic side effects limits its usefulness in the clinical management of glutamate-mediated disorders. An attractive alternative to marijuana-based therapeutics is a new class of drugs which increases the levels of endogenous cannabinoids, substances which mimic the biological actions of marijuana. This application will determine the role of the endogenous cannabinoid system, and the relevance of drugs which increase endogenous cannabinoid levels, in the regulation of basal ganglia glutamate levels in conscious animals. Our outcomes will be a first step in determining whether blocking endocannabinoid inactivation offers any therapeutic advantage over direct activation of cannabinoid receptors with marijuana. ? ? ?
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