To prevent and treat drug use it is important to identify who is at risk for addiction and why. The goal of this B/START award is to develop a human measure of a risk factor for addiction that has previously only been ex- amined in laboratory animals. Specifically, recent preclinical findings suggest that individuals who attach par- ticularly strong motivational value to cues (i.e. sights, smells or objects) associated with reward are at risk for addiction. In animals this tendency manifests as compulsive approach to cues, or "signs", associated with re- ward, a behavior called "sign-tracking". Importantly, animals that sign-track show addictive tendencies in labo- ratory models of drug-taking and relapse. Sign-tracking also correlates with impulsive action, a known risk fac- tor for addiction. Finally, sign-tracking is based in fundamental differences in the brain's dopamine system, a key neural substrate of addiction. Yet there is a critical barrier to applying this highly promising behavioral indi- cator of addiction risk to predicting and understanding human addiction: There is no validated human measure of this tendency. The objective of this B/START grant is to develop a sensitive behavioral measure of "sign- tracking" in humans. We have developed a procedure that measures responses to cues paired with food re- ward in humans. The procedure quantifies individual differences in the tendency to attach motivational value to cues (i.e. "human sign-tracking") using a composite measure consisting of subjective, psychophysiological and behavioral indices of attraction to cues.
In Aim 1 we will conduct a pilot study to refine this novel measure, in which 40 healthy adults will perform our human sign-tracking task on one occasion and we will adjust parame- ters to optimize conditioning and measurement. Then in Aim 2 we will conduct a validation study in which 100 healthy adults will participate in a two-session study using the final measure of human sign-tracking. At each session, they will complete the sign-tracking task as well as a validated measure of impulsive actions. Within this single efficient design we will examine stability of our measure over two sessions of conditioning (Aim 2a) and its convergent validity with impulsive actions (Aim 2b). Our central hypothesis is that in humans, as in rats, sign-tracking will be a stable individual difference that correlates with a tendency towards impulsive action. The proposed research is significant because we expect it will validate a novel and directly translational behavioral measure of a promising indicator of addiction risk. This has the potential to advance the field in several ways, including improving prediction of addiction risk, providing novel information about behaviors that may mediate between dopamine abnormalities and clinical symptoms of addiction, and suggesting new behavioral targets for intervention. The proposed research is innovative because this is the first attempt to quantify this trait in humans. This grant will form the foundation of a series of future directions, including using the procedure vali- dated here to predict addiction-relevant outcomes such as acute responses to drugs and cue-induced relapse, and examination of the relationship of sign-tracking to dopamine functioning in humans.
In the current study we will develop a novel human measure of sign-tracking, a behavior that has been associated in laboratory animals with addiction risk. This study has the potential to advance the NIH's mission to prevent disease and protect and improve public health by i) helping to identify individuals at risk for drug abuse, ii) providing novel information about behaviors that may contribute to addiction and ii) opening the door to new treatments that focus on the modifiable behavior of sign-tracking.