This grant will establish new independent investigator studies on maladaptive neuroplasticity induced by chronic use of the addictive drugs cocaine and heroin. This project will be led by Ethan Anderson, Ph.D.; an energetic, passionate, and productive researcher on a trajectory to develop an independent research position studying drug addiction. This project will take place at the Medical University of South Carolina (MUSC), an institute with a stellar reputation for producing high quality researchers that specialize in drug addiction. Dr. Anderson will be mentored Dr. Chris Cowan and Dr. Peter Kalivas at MUSC. These mentors have successfully trained scientists who have gone on to faculty positions at major universities and are experts in behavioral models of drug addiction, biochemical, molecular, and structural changes in the brain due to chronic drug use, and the generation of novel tools to investigate these mechanisms of addiction. This overall project will employ 2 novel and innovative approaches to investigate and reverse the negative effects of both cocaine and heroin on morphological and behavioral changes underlying addiction. The short-term goals of this project involve 2 aims: 1) Determine the intracellular mechanism of a novel, endogenous anti-addictive signaling pathway through and phospholipase Cᵧ1 (PLC) as a potential new target for reducing opioid use in humans. 2) Reverse cocaine-induced maladaptive changes in synapses in the nucleus accumbens by selectively targeting and optogenetically removing dendritic spines recently activated by cocaine. This will determine whether a direct causal relationship exists between reversal of these morphological brain changes and alterations in addictive behavior. The scientific training program for Dr. Anderson will focus on learning 3 new skills: 1) optogenetics with novel in vivo spine reduction technology, 2) heroin self-administration behavior, and 3) cloning and molecular biological techniques necessary for constructing novel viral vectors. In addition, Dr. Anderson will receive excellent career development training via an outstanding career advisory committee (Drs. Eric Nestler, David Self, Arthur Riegel, and Jacqueline McGinty) and specific individual career training from Drs. Cowan and Kalivas. The individual scientific training will include individual meetings with his mentors to discuss and prepare future R01 applications, presentations at seminars and 1-2 conferences per year, the publication of 1 paper every 1-2 years, and didactic course work in drug addiction and cutting-edge molecular biology. This grant will pave the way for Dr. Anderson to achieve his potential to become a productive, R01 fundable, independent scientist in the field of addiction research by allowing him to learn new scientific skills, produce high-impact data, receive excellent and broad-based training with expertise from his advisors and mentors, and study in the exceptional training grounds of MUSC.