Endogenous cannabinoids (endocannabinoids) and the CB1 cannabinoid receptor form a signaling system that plays a key role in several forms of short and long term neuronal plasticity. In addition, CB1 receptors are the primary target of cannabis, the most commonly used illicit drug in the US. Despite an increasing awareness of the importance of the cannabinoid signaling system in normal and pathological CNS function, the potential therapies targeting this system, and the social impact of cannabis use, our knowledge of how CB1 receptors and endocannabinoid production is regulated is quite modest. Understanding the control of the endocannabinoid system is vital to the rational assessment of therapies affecting this system, as well as to appreciating the impact of chronic activation of this system (as might happen therapeutically or by excessive cannabis use). In the proposed work we will address three specific aims: Is desensitization of cannabinoid inhibition of neurotransmission due to phosphorylation of the CB1 receptor at residues $426 and $430? Does regulated association of CB1 cannabinoid and D2 dopamine receptors underlie some of the interactions between dopamine and cannabinoid signaling? Which endocannabinoids are secreted by cultured neurons and from where are they released? By accomplishing these specific aims we will have a firm understanding of the molecular events associated with desensitization of CB1 receptor signaling, insight into the interactions between the cannabinoid and dopamine signaling pathways, knowledge of the endocannabinoids released by neurons and the domains of the neuron important in endocannabinoid release. ? ?
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