Repeated treatment with psychostimulants produces persistent molecular adaptations that result in enhanced control over behavior by rewards and reward-related cues, a process termed incentive sensitization. This process is theorized to contribute to the inflexibility of drug-taking behavior and chronic patterns of recidivism seen in drug dependent individuals. As such, an understanding of neural mechanisms by which degree of incentive salience is scaled would have important implications for the treatment of substance dependence. Because the same receptor systems and nuclei (dopaminergic and glutamatergic interactions within a midbrain-striatal-limbic-forebrain network) that are implicated in progressively elevating behavioral responses to drugs are also implicated in the acquisition of response-outcome (instrumental) and stimulus-outcome (Pavlovian) associations, sensitization of this common neural pathway may underlie the alterations in these forms reward-related learning that repeated exposure to psychostimulants can cause. Specifically, it is thought that dopaminergic transmission arising from the ventral tegmental area conveys incentive salience to rewards and cues, and that NMDA-dependent plasticity within these neurons modulates degree of salience attribution. To explore this hypothesis, we will first determine the role of NMDA-mediated plasticity in dopamine neurons in appetitive associative learning by restricting the loss of NMDA receptors exclusively to dopamine neurons and examining differences in instrumental and Pavlovian learning. We will also inducibly inhibit NMDA receptor expression in all cell types in the ventral tegmental area via virai transfection to control for compensatory gene regulation in the constitutive model and characterize the role of plasticity in non-dopamine ventral tegmental cells in reward-related learning. This design will allow insights into the role that plasticity in dopamine cells plays in basic associative learning and provide the comprehensive characterization these models and their associated controls that is necessary before utilizing them to investigate the role of NMDA-mediated plasticity in incentive sensitization. Characterization ofthe plastic mechanisms contributing to reward-related learning and the elevation of control over behavior of drugs and drug-associated cues will provide an important step in understanding how to this control could be lowered form its pathological levels in substance dependent individuals and will therefore have important implications for reducing recidivistic behavior.
|James, Alex S; Chen, Jane Y; Cepeda, Carlos et al. (2013) Opioid self-administration results in cell-type specific adaptations of striatal medium spiny neurons. Behav Brain Res 256:279-83|