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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AA020135-02
Application #
8153113
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Grakalic, Ivana
Project Start
2010-12-01
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$42,232
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Barker, Jacqueline M; Taylor, Jane R; Chandler, L Judson (2014) A unifying model of the role of the infralimbic cortex in extinction and habits. Learn Mem 21:441-8
Barker, Jacqueline M; Taylor, Jane R (2014) Habitual alcohol seeking: modeling the transition from casual drinking to addiction. Neurosci Biobehav Rev 47:281-94
Barker, Jacqueline M; Zhang, Huiping; Villafane, J Joshua et al. (2014) Epigenetic and pharmacological regulation of 5HT3 receptors controls compulsive ethanol seeking in mice. Eur J Neurosci 39:999-1008
Barker, Jacqueline M; Zhang, Yuqi; Wang, Fan et al. (2013) Ethanol-induced Htr3a promoter methylation changes in mouse blood and brain. Alcohol Clin Exp Res 37 Suppl 1:E101-7