Dopamine, often celebrated as the brain's "pleasure chemical," captures more fascination than any other neurotransmitter. Cocaine's euphoric and addictive effects stem from its ability to elevate dopamine levels. Unfortunately, no effective medical treatment exists for cocaine addiction, largely because we lack a complete understanding of how cocaine influences its target.
Using the world’s most powerful microscope, we recently captured the first-ever visual insight into how cocaine interacts with its target protein, the dopamine transporter (DAT). Now, we aim to deepen this understanding by exploring how this protein regulates dopamine, how it is inhibited by a range of other ligands with a variety of physiological effects and why some of these drugs do not elicit cocaine-like euphoric effects even though they also bind DAT.
This research will uncover the molecular basis of a battery of ligands binding to DAT, shedding light on how these drugs impact dopamine signaling. Ultimately, our findings aim to guide the design of targeted treatments for cocaine addiction, addressing a critical unmet medical need.