Protein Mechanisms of Drug Use Susceptibility

Although many people will use a drug of abuse at least once in their lifetime, only a subset of these individuals will develop an addiction. This suggests that some individuals may be more susceptible to developing an addiction compared to others and, importantly, if we can identify the neurobiological mechanisms that mediate this susceptibility, then we may be able to prevent addiction. My laboratory is focused on identifying the protein mechanisms that mediate susceptibility to drug use in rodent models. Our ongoing work – in collaboration with the Yale/NIDA Neuroproteomics Center – uses a reinforcement-learning platform to isolate protein targets that are disrupted by chronic exposure to drugs of abuse from those that influence early-stage drug use. Our goal is to generate mechanistic bridges between proteins and complex behavioral phenotypes. Through a funded NIDA K01 award (DA051598; Mentor: Angus Nairn) we are 1) using novel viral approaches to investigate the role of three proteins (ATXN2L, SNX1, and RYR2) we hypothesize to mediate drug use susceptibility, 2) determining how these proteins and others are altered in a genetic rat model of addiction susceptibility, and 3) identifying the protein mechanisms that are altered in an environmental rat model of addiction susceptibility. This work, collectively, will identify novel biomarkers of addiction susceptibility that can be used to identify at risk humans. A second interest of the laboratory is understanding the neurodevelopmental mechanisms that influence addiction susceptibility. Through pilot funding provided by the Yale/NIDA Neuroproteomics Center we have recently completed a study investigating the protein mechanisms underlying age-related changes in decision-making. Our preliminary data suggests that decision-making improves during adolescence in the rat and that this improvement is associated with changes in the expression of perineuronal net proteins. We hypothesize, therefore, that alterations in the expression of perineuronal net proteins during adolescence could impact susceptibility to drug use in adulthood by altering the formation of neural circuits, and our ongoing work is testing these hypotheses. We plan to integrate our collaborative work with the Yale/NIDA Neuroproteomics Center with magnetic resonance measurements at the University of Minnesota Magnetic Resonance Research Center (MRRC) in order to identify a non-invasive neuroimaging measure that could be used to assess addiction susceptibility in humans.