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A "Targeted" Approach to Identify the Proteins Underlying the Biobehavioral Mechanisms of Addiction

Stephanie Groman, Department of Psychiatry, Yale University
Not all individuals that use drugs of abuse will develop an addiction. The transition from drug use to abuse and, eventually, to dependence may be mediated by biological factors that impact the likelihood of individuals to develop an addiction. Identification of proteins that mediate addiction vulnerability, therefore, could lead to the development of novel prophylactic treatments for addiction. 

We have been interested in using decision-making as a behavioral biomarker for understanding addiction pathophysiology and recently identified a computationally-derived decision-making parameter that predicts future drug-taking behaviors. Specifically, the ability of rats to use positive outcomes to guide their decision-making prior to any drug use predicted future drug-taking behaviors. Using this behavioral biomarker in drug-naïve and drug-exposed animals, we conducted a pilot study using label-free proteomics and identified three protein targets as potential addiction susceptibility proteins: sorting nexin 1 (Snx1), ryanodine receptor 2 (Ryr2), and ataxin 2-like (Atxn2l). Remarkably, genes encoding these same proteins have been linked to addiction in humans. These exciting results suggest that differential expression of these proteins may underlie addiction vulnerability and Aim 1 of this proposal will test this hypothesis by examining decision-making processes and expression of Snx1, Ryr2, and Atxn2l proteins in animals exposed to morphine during gestation – a known risk factor for addiction.

Self-administration of drugs of abuse, however, disrupts decision-making processes, regardless of pre-existing decision-making abilities. We have found that the drug-induced decision-making deficits are due to reductions in the ability of rats to use negative outcomes to guide their decision-making, suggesting that the behavioral processes that mediate an indivuial's risk for developing an addiction differ from the behavioral processes that are disrupted by drug use. Indeed, our label-free proteomic study identified a single protein responsible for the drug-induced decision-making deficits: ras-related protein Rab3B. It is unclear, however, if prenatal exposure to morphine modulates drug-induced changes in decision-making and Rab3B expression. In Aim 2 of this proposal, decision-making will be assessed in rats exposed to morphine during gestation before and after they are trained to self-administer methamphetamine (or saline). Expression of Rab3B will be quantified using targeted proteomics to determine if expression of Rab3B is differentially affected by drugs of abuse in addiction vulnerable populations.

The proteomic data collected in this proposal will provide the experimental evidence needed to support our discovery-based results that have implicated specific protein targets in different aspects of addiction pathophysiology. We believe that these data will lead to the development of therapeutic tools that can modulate the expression of addiction-risk proteins and, consequently, attenuate addiction liability.