Incentive salience is the motivational value attributed to a reward-predicting stimulus. Only stimuli that have acquired incentive salience become desirable and able to bias our attention and elicit approach towards them. These incentive stimuli have the ability to significantly influence our daily behavior. In the case of addiction, drug-associated stimuli (conditioned stimuli, CS) that acquire incentive salience can trigger powerful craving and motivate drug-seeking/taking behaviors. As the primary issue in the treatment of addiction is the tendency of addicts to relapse, and relapse is believed to be triggered in part by drug-associated stimuli, it is important to understand the genetic basis underlying the attribution of incentive salience. Pavlovian Conditioned Approach (PCA) is a behavioral paradigm used in rats to reliably assess their propensity towards Pavlovian sign-tracking (or autoshaping). Sign-tracking behaviors consist of approach and interaction with a reward-paired CS (sign) and only occur as a result of the attribution of incentive salience to the cue. Performance in the PCA paradigm can be scored as a quantitative trait and has been shown to be both highly heritable and variable in Sprague-Dawley (SD) rats. We will perform the first large-scale genome-wide association study (GWAS) for this trait on a sample of approximately 3,000 outbred SD rats that have been phenotyped for sign-tracking through PCA. To obtain genotypes for the 3,000 rats, we will utilize genotype-by-sequencing (GBS), a reduced-representation sequencing approach being optimized for rats in Dr. Palmer's (sponsor) lab. Due to the extensive population structure observed in SD rat populations, analysis will be done using a mixed model with a random term containing relatedness matrices based on the SNP genotypes. This is an unprecedentedly large sample for such as genetic study in rats or mice, and therefore provides us with outstanding power. This study will provide us with insights into the molecular mechanisms underlying the attribution of incentive salience and may have important implications for future drug-abuse research.
Addiction is a prevalent disorder, characterized by a high rate of relapse and a strong, negative impact on the quality of life of those affected. It is thought that variation in the amount of motivational value (incentive salience) attributed to discrete, reward-predicting cues plays a large role in an individual's vulnerability to developing and relapsing into addiction. It is therefore the goal of this proposal to identify genetic factors influencing the attribution of incentive salience to conditioned cues, providing us with novel insights into the disease pathology, and potentially leading to innovative therapies for the treatment of addiction.
