Elucidating the Role of the Paraventricular Nucleus of the Thalamus and Cortico-Thalamic Circuitry in Cocaine-Seeking Behavior

Abstract

Relapse continues to be one of the biggest problems in the treatment of addiction. This is due, at least in part, to the transformation of cues that are associated with the drug-taking experience into powerful motivators that can in turn elicit drug-seeking behaviors even when one desires to remain abstinent. However, the extent to which a cue can attain such motivational value varies between individuals, and only when it is attributed with incentive salience does it gain inordinate control over behavior. We use an animal model that allows us to study individual variation in the propensity to attribute incentive salience to reward-paired cues. In this model, sign-trackers (STs) are those rats that attribute incentive salience to a reward-predicting cue and will approach and manipulate the cue upon its presentation; whereas goal-trackers (GTs) assign only predictive value to the cue and go to the location of reward delivery upon cue presentation. Relative to GTs, STs are more susceptible to cocaine-primed and to cue-induced reinstatement of drug-seeking behavior. The paraventricular nucleus of the thalamus (PVT) is a brain region known to mediate individual differences in incentive salience attribution as well as drug-seeking behavior in various cocaine relapse models. In this dissertation, I present data showing that transient inactivation of the PVT prior to a test for cue-induced reinstatement selectively enhances drug-seeking behavior in GTs, without affecting behavior in STs. These data suggest that, in GTs, the PVT acts to attenuate the incentive motivational properties of a cocaine-cue during a test of cue-induced reinstatement. In a subsequent study I assessed the role of the cortical projections from the prelimbic cortex (PrL) to the PVT in mediating cue-induced and cocaine-primed drug-seeking behavior. Inhibiting this pathway prior to a test for cue-induced reinstatement selectively decreases drug-seeking behavior in STs, without affecting behavior in GTs. However, drug-seeking behavior in either phenotype is not affected if this pathway is inhibited prior to cocaine-primed reinstatement. It appears, therefore, that the PrL-PVT circuit acts to enhance the incentive motivational value of a cocaine-cue selectively in STs, and does not mediate drug-seeking behavior to cocaine alone. Taken together, this work highlights the complex role of the PVT and its associated circuitry in mediating individual differences cue-reward learning and relapse propensity.