Role of corticostriatal dopamine signaling in response strategy selection.

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DESCRIPTION (provided by applicant): The main objective of this proposal is to combine molecular, pharmacological, and behavioral techniques to investigate the role of corticostriatal dopamine signaling in response strategy selection. Using a rodent model of instrumental habit, we will investigate how behavior is influenced by activity at dopamine D1 and D2 receptors in the dorsolateral striatum and infralimbic cortex, brain regions implicated in stimulus- response habit and goal-directed behavior by infusing receptor agonists and antagonists into these regions. Additionally, we will investigate the role of the kappa opioid system, which is known to interact with alcohol to influence dopamine signaling, in habitual and goal-directed responding for alcohol. We hypothesize based on preliminary data that activity at the D1 and D2 receptors will promote differential response strategies, such that D1 will promote habitual responding and D2 activity will promote goal-directed actions. Additionally, we expect that enhanced kappa opioid receptor activity in the dorsolateral striatum will promote goal-directed behavior by decreasing dopamine signaling in this region, while the converse will be true in the infralimbic cortex: kappa opioid receptor activity here will promote habitual responding by decreasing dopamine activity. We hypothesize that blocking kappa opioid receptor activity in these regions will produce the opposite effects. Finally, we propose that the transition from goal-directed actions to habitual responding will be characterized by changes in kappa opioid receptor activity and expression (as measured by Western blot analyses) in the dorsolateral striatum and infralimbic cortex, and that the time course of these changes will be accelerated in animals receiving alcohol reinforcement as compared to those receiving food reinforcers. The findings of the proposed experiments are expected to help inform clinical research move toward developing efficient and successfully therapies for individuals suffering from alcohol use disorders. PUBLIC HEALTH RELEVANCE: Alcohol use disorders are devastating not only to the individuals struggling with alcoholism, but also to society as a whole. As alcoholics transition from casual drug use to compulsive, habitual drug seeking, they show signs of cognitive-motivational dysfunction, resulting in altered reward processing and decision-making that can have highly maladaptive consequences, including heavy drinking, recidivism, risky reward- motivated behaviors, craving and difficultly in terminating consumption. By understanding how the dopamine system interacts with alcohol to influence habitual drug seeking and taking, we can begin to understand neurobiological mechanisms of behavioral flexibility and identify possible therapies for alcohol use disorders that target the restoration of goal-directed behaviors.