Identification of Neurochemical Antecedents and Consequences of Distinct Learning Processes Relevant to Addiction Liability

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

ABSTRACT Cues or stimuli in the environment can guide behavior in adaptive ways, bringing one in close proximity to valuable resources (i.e. food, water, mates); but they can also elicit maladaptive behavior. For example, in addicts, exposure to cues (e.g. places, paraphernalia) previously associated with drug-taking often leads to relapse, despite the desire to remain abstinent. The ability of such cues to elicit complex emotional and motivational states and gain control over one's behavior occurs via Pavlovian learning mechanisms. Using an animal model that captures individual differences in response to reward cues, we can now study the neural processes underlying aberrant forms of cue-reward learning, bringing us closer to identifying novel targets for the treatment of addiction. When rats are exposed to a Pavlovian conditioning paradigm wherein a discrete cue is repeatedly paired with presentation of a reward, some are ?sign-trackers??those that attribute incentive salience to the cue, and others ?goal-trackers??those that assign only predictive value to the cue. Thus, there is individual variation in the extent to which food cues are attributed with Pavlovian incentive motivational value (?incentive salience?), and this variation predicts the degree to which drug cues will attain control over behavior and the propensity to relapse. Furthermore, this animal model allows us to parse the incentive from the predictive properties of reward cues, and we have used it to demonstrate that distinct neural circuits regulate these different forms of cue-reward learning. In addition, we have shown that dopamine is critical for incentive learning (i.e. sign-tracking), but not predictive learning (i.e. goal-tracking). Most studies to-date, however, have been hampered by the inability to measure neural correlates of these phenotypes prior to learning. That is, rats must first undergo Pavlovian conditioning in order to be characterized as sign- or goal-trackers. Thus, the first Aim of the current proposal is to determine whether there are pre-existing basal differences in neurotransmitter signaling in the nucleus accumbens core that predict those individuals prone to attribute incentive salience to reward cues prior to behavioral testing. To do this, we will use a novel chemical analytical approach (stable-isotope labeling) that will allow us, for the first time, to assess true basal levels of dopamine, norepinephrine, acetylcholine, serotonin, glutamate and GABA in sign- and goal-trackers. The second Aim will use another novel, but different, chemical analytical approach to simultaneously assess up to 50 neurochemicals in the nucleus accumbens core in sign- and goal-trackers. The focus of the second Aim will be on the neurochemical profiles that emerge as a consequence of an individual's associative learning style. Advanced statistical analyses will be applied in order to identify neurochemical profiles that best predict the behavioral phenotypes and to examine the relationship between neurochemicals over the course of learning. This work will highlight specific neural systems that may render an individual more susceptible to control by reward cues and lay the foundation for future studies to identify novel neuromolecular targets for the treatment of addiction.