While some individuals are able to casually use a drug without it interfering with their day-to-day activities, others become addicted, unable to shift their thoughts and actions away from drugs and drug-associated stimuli. The factors underlying these individual differences are not yet known, but one plausible explanation is that individual differences in addiction liability are related to the extent to which reward-related cues come to control behavior. The ability of reward-related stimuli to gain control over behavior can be studied in the laboratory using Pavlovian conditioning procedures. When a discrete cue is reliably paired with the receipt of a reward, it not only serves as a predictor of reward, but can also elicit complex emotional and motivational states. Thus, for some animals, goal-trackers, the reward-related cue serves merely as a predictor, eliciting approach directed toward the location of reward delivery;and for others, sign-trackers, the cue attains motivational value, eliciting approach and consummatory behavior directed towards the cue. Sign-tracking behavior is thought to reflect enhanced attribution of incentive salience to reward-related cues and may therefore be especially relevant to the study of addictive behavior and relapse. The working hypothesis then is that sign-trackers may represent individuals with increased vulnerability to addiction;whereas goal-trackers may represent those that are resilient to the disorder. To test this hypothesis, we will utilize a unique genetic animal model-rats selectively bred on the basis of a novelty-seeking trait but known to diverge on a number of traits relevant to addiction. Bred high-responder rats (bHR) are primarily sign-trackers, exhibiting approach to cues associated with both food and drug (cocaine) reward;and bred low-responder rats (bLR) are almost exclusively goal-trackers, approaching the location of reward delivery. Cross-bred intermediate responders (bIR) behave similarly to commercial rats, with almost equal probability of developing either goal-tracking or sign-tracking behavior. Utilizing all three of these lines will provide a continuum in the population, enabling us to examine the relationship between various traits (e.g. novelty-seeking, sign-tracking) and addiction liability. The following indices of substance abuse vulnerability will be obtained: I) escalation of drug intake during prolonged (5-hr) cocaine self-administration sessions;II) the persistence of drug-taking behavior when the drug is no longer available;III) resistance to extinction;and IV) cue-induced reinstatement (i.e. relapse) following a 30-day abstinence period. From these measures of addictive liability it will be determined whether rats that sign-track are more susceptible to the transition to addiction relative to rats that goal-track. Moreover, the use of the selectively bred rat lines provides enormous potential for future studies to investigate the genetic, molecular and behavioral antecedents to traits relevant to addictive behavior.
The proposed project will examine whether individual differences in the extent to which reward-related cues come to control behavior are related to substance abuse vulnerability. Utilizing selectively bred rat lines, these studies may prove to be very informative in understanding the psychological, neurobiological, and genetic mechanisms that contribute to the development of addiction. Moreover, the proposed animal model may allow us to determine what renders some individuals susceptible to addiction and what protects others from developing the disorder.
| Flagel, Shelly B; Chaudhury, Sraboni; Waselus, Maria et al. (2016) Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model. Proc Natl Acad Sci U S A 113:E2861-70 |
| Flagel, Shelly B; Waselus, Maria; Clinton, Sarah M et al. (2014) Antecedents and consequences of drug abuse in rats selectively bred for high and low response to novelty. Neuropharmacology 76 Pt B:425-36 |
