High Content Functional Neuroanatomy of Endogenous GPCRs

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Abstract G protein coupled receptors (GPCRs) modulate neuronal excitability and neurotransmitter release, and exert profound effects on neural circuit functions. They play important roles in regulating motivation, reward, pain, negative affect, and stress responses, which are all important in the context of substance use disorders (SUDs). Exogenous ligands for several GPCRs have been shown to modify drug seeking behavior, which has generated interest in GPCRs as targets for the development of pharmacological therapeutics for substance use disorders. There are over 300 different non-sensory GPCRs expressed in mammalian brains, and fundamental questions remain unanswered for all of them. For example, how does a given receptor's ability to activate different G protein subtypes (Gi/o, Gs, Gq, G12/13) vary across neuroanatomical regions, cell types, and subcellular regions? How are these properties altered in response to chronic drug use, chronic stress, or chronic pain? To help answer these questions, we will develop new imaging methods in tissue sections for neuroanatomical measurement of GPCR-mediated G protein activation, with subcellular resolution and G protein subtype specificity. Our methods will only require common neuroscience equipment (cryostats and fluorescence microscopes) and commercially available reagents. They will generate high-content information on many GPCRs in healthy and diseased brains, and accelerate efforts to target GPCRs in addiction.