Prashant Donthamsetti, assistant professor of pharmacology and member of the Vanderbilt Brain Institute, has been awarded a highly competitive National Institutes of Health Director’s Pioneer Award from the National Institute on Drug Abuse. This prestigious award, part of the NIH High-Risk, High-Reward Research Program, will provide $2,375,000 in support of Donthamsetti’s research into next-generation strategies for understanding and treating addiction.
The NIH Director’s Pioneer Award supports exceptionally creative scientists pursuing bold new directions in research with the potential for unusually broad impact. The program is designed to fund high-risk, high-reward projects that push the boundaries of traditional scientific thinking. With this award, Donthamsetti joins an elite group of investigators recognized for pushing the boundaries of neuroscience and drug discovery. His work has the potential to redefine how we understand and treat addiction and to inspire a new generation of molecularly targeted brain therapeutics.
Addiction remains a pressing public health crisis, affecting roughly 20 million people in the U.S. and costing the economy over $740 billion annually. Despite decades of research and drug development, effective treatments remain limited. “To move the needle on addiction therapies, we need a paradigm shift,” Donthamsetti said. “We need to go beyond mapping neural circuits and start decoding what neural signals actually do at the molecular level.”
Donthamsetti’s lab is tackling that challenge with a new platform called Tag-Guided Drug, which merges the precision of genetic targeting with the flexibility and reversibility of conventional pharmacology. Tag-Guided Drug will allow Donthamsetti’s team to selectively target specific receptor populations, not just where they are but also in how they signal, to unlock a deeper understanding of their functional roles in addiction-related behaviors.
While modern neuroscience has enabled researchers to map brain circuits and manipulate specific neurons, there remains a major blind spot: how neuromodulators like dopamine interact with complex networks of receptors and intracellular signaling proteins across the brain. Dopamine is central to addiction biology and acts through five distinct G protein-coupled receptors, each with different downstream effects and clinical relevance. In the current project, Donthamsetti will apply this novel approach to the dopamine D2 receptor, a GPCR and a key player in the brain’s reward system—and a promising target for addiction treatment. Using a mouse model of cocaine addiction, his lab will evaluate how selectively modulating D2R signaling affects behavior. At the same time, they will expand the platform to build similar tools for other critical GPCRs and intracellular proteins, laying the groundwork for a new class of precision therapies for neurological and psychiatric diseases.
“This award is designed for researchers who are not afraid to think big and take scientific risks,” said Lisa Monteggia, Barlow Family Director of the Vanderbilt Brain Institute and the Lee E. Limbird Professor of Pharmacology. “Dr. Donthamsetti embodies that spirit, and we’re incredibly proud to have him driving this kind of transformative science at Vanderbilt.”