A Highly Precise Platform Technology for Controlling Diverse Clinical Targets in Addiction

About This Grant

Project Summary Addiction is a debilitating disorder that affects ~20 million people and incurs an annual economic burden of $740 billion in the United States alone. However, despite intensive drug discovery efforts, we still lack highly effective therapies for addiction, emphasizing the need for a better understanding of the pathophysiology of the disease and a paradigm-shift in drug design. Towards this end, recent technological advances in neuroscience have allowed us to interrogate the neural circuits that underlie addiction with high precision. We can map the spatial organization of neural circuits, detect and manipulate the firing of selected neurons, and measure the dynamics of neural signal release. However, what is missing is a deep understanding of the molecular effects of neural signals once they are released — rather than simply connecting one neuron to another, neural signals encode complex information by controlling multiple, functionally distinct receptors and their various downstream signaling molecules at once. For example, the neuromodulator dopamine plays key roles in addiction by dynamically activating five G protein-coupled dopamine receptors, which have diverse functions across the brain and periphery, engage numerous downstream signaling proteins, and are associated with varying clinical potential and risk. Thus, the next frontier in addiction research is to uncover the functional role and therapeutic value of specific populations of neural signaling proteins. The goal of this proposal is to develop and apply a highly precise platform technology called Tag-Guided Drug to better understand the functional role of selected populations of neural signaling proteins in addiction. Tag-Guided Drug combines the doseability and reversibility of conventional drugs with the molecular, spatial, and cellular specificity of genetic targeting. We developed a Tag-Guided Drug for dopamine D2 receptor, a putative target for treatment of addiction. We will use the D2R Tag-Guided Drug to better understand the functional role of D2 receptor in a mouse model of cocaine addiction and, in parallel, develop a pipeline for generating Tag-Guided Drugs for other clinically relevant neural signaling proteins, including various G protein-coupled receptors (GPCRs) and intracellular signaling proteins. Overall, Tag-Guided Drug is highly innovative and has major implications for neuroscience, addiction, and biological sciences as a whole.