Tonic and Phasic Glutamate Release in Incentive Salience and Cocaine Reinforcemen

The proposed career development plan is designed to provide the PI with a unique skill set and experience to meet the short-term goal of becoming a productive, independent researcher and long-term goal of becoming a significant contributor to the understanding and treatment of substance abuse disorders. The plan will be carried out at the University of Kentucky, an institution with a rich history of interdisciplinary substance abuse research. The PI will be mentored by Dr.Michael Bardo and co-mentored by Dr. Greg Gerhardt, established experts in neuropsychopharmacology and neurochemistry, respectively. The plan proposes to use enzyme-based microelectrode arrays to uncover the role of sub-second tonic/phasic mesocorticolimbic glutamate release in individual differences in incentive salience/value attribution to reward-related cues and cocaine reinforcement in a preclinical rat model. When a stimulus reliably predicts reward, some animals attribute incentive value to the stimulus, and thus will approach and contact it (sign-trackers); other animals use the stimulus as a simple signal of forthcoming reward, and thus will approach the receptacle into which reward will be delivered (goal-trackers). Recently, it has been demonstrated that differences in sign and goal tracking are related to novelty seeking, impulsivity, initial vulnerability to cocaine reinforcement, and relapse vulnerability. In addition to mesocorticolimbic dopamine, stimulus-reward learning and drugs of abuse are known to alter mesocorticolimbic glutamate signaling. The overall proposed hypothesis is that differences in incentive value attribution are mediated by differential mesocorticolimbic glutamate release upon cue exposure; this differential release is then exacerbated by repeated cocaine self-administration, giving rise to differential substance abuse vulnerability and relapse. Specific Aim 1 will determine if second-by-second tonic/phasic glutamate signaling is differentially affected by food-associated cues in sign- vs. goal-tracking animals. Specific Aim 2 will determine the role of dopaminergic receptor function on the expression of sign-/goal-tracking, and underlying tonic/phasic glutamate signaling. Specific Aim 3 will determine if second-by-second tonic and phasic glutamatergic signaling in sign- and goal-tracking animals changes differentially with repeated cocaine self-administration. Specific Aim 4 will then determine the role of dopaminergic receptor function on cocaine self-administration and tonic/phasic glutamate signaling in sign- and goal-trackers. Collectively, these results will provide insight into the role of tonic/phasic glutamate signaling in stimulus-reward learning, incentive value attribution to reward-associated stimuli, and cocaine reinforcement, while providing the PI with unique training in neuropsychopharmacology and neurochemistry by experts in both fields. PUBLIC HEALTH RELEVANCE: The proposed studies will provide insight into the underlying mechanisms that accompany individual differences in substance abuse disorders that may aid in the development of novel therapies for abuse disorders involving stimulants.