These studies will identify neurobehavioral mechanisms underlying vulnerability to habitual ethanol-seeking behavior and relapse. We hypothesize that individual differences in the ability of incentive stimuli to control behavior can promote compulsive alcohol drinking in the face of adverse consequences. Our studies will test whether individual variation in the ability of cues to motivate behavior measured by the Pavlovian-to-lnstrumental Transfer (PIT) procedure, will predict habitual ethanol-seeking behavior (i.e., stimulus-response) and cue-induced reinstatement behavior in mice. Animals that show high levels of sucrose PIT will display enhanced ethanol habits measured by insensitivity to outcome devaluation and increased cue-induced reinstatement. Aberrant cognitive flexibility and regulation of control over reward-motivated behavior is central to these preexisting differences in PIT that we argue depend on altered dopaminergic and glutamatergic signaling in regions of the prefrontal cortex (PFC) and striatum. Our published data show that dopaminergic activation of the ventromedial (vm) PFC can restore goal-directed responding in animals that are responding habitually for food. We propose to determine if manipulations of dopaminergic and glutamatergic signaling can reduce habitual ethanol-motivated responding and cue-induced reinstatement in mice that show high levels of sucrose PIT. The role of these signaling pathways will be examined in the vmPFC and dorsal striatum given their known roles in habit formation and in the orbito-frontal cortex and nucleus accumbens, given their role in incentive Pavlovian (stimulus-outcome) learning.
Aim 1 will test the hypothesis that individual variation in sucrose PIT predicts the transition from goal-directed to habitual ethanol-seeking behavior. Alterations in protein expression and activity in cortico-limbic-striatal regions will be examined in mice showing high vs. low levels of PIT and those expressing habitual vs. goal-directed ethanol-seeking behavior.
Aim 2 will examine if individual differences in sucrose PIT predict reinstatement of cue-induced ethanol seeking. We will also determine if indirect stimulation of extra-synaptic metabotropic glutamate receptors with N-acetylcysteine or direct reduction in NMDA activity with memantine can prevent the expression of ethanol habits and reduce cue-induced reinstatement of ethanol seeking. Our proposed studies will provide the first direct investigation of preexisting mechanisms of incentive motivation and their relationship to habitual ethanol-seeking behavior. These data will provide a foundation for understanding potential genetic contributions to habitual ethanol behavior and identify mechanisms of dopaminergic and glutamatergic dysfunction in corticostriatal circuits that may underlie alcoholism vulnerability and relapse.

Public Health Relevance

The proposed studies will investigate how pre-existing individual variation in reward sensitivity promotes habitual ethanol-seeking and cue-induced relapse In animal models. We will identify neural mechanisms of dopaminergic and glutamatergic dysfunction in corticostriatal circuits that underlie the vulnerability to habitual ethanol-seeking behavior and relapse. The goal of these animal studies is to provide a neurobiological basis for the determination and assessment of new targets for treatment of heavy drinking or alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA012870-12
Application #
8378918
Study Section
Special Emphasis Panel (ZAA1-GG)
Project Start
Project End
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
12
Fiscal Year
2012
Total Cost
$202,407
Indirect Cost
$59,767
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Krystal, John H (2016) Neuroethology as a translational neuroscience strategy in the era of the NIMH Research Domain Criteria. Psychophysiology 53:364-6
Clarke, Toni-Kim; Smith, Andrew H; Gelernter, Joel et al. (2016) Polygenic risk for alcohol dependence associates with alcohol consumption, cognitive function and social deprivation in a population-based cohort. Addict Biol 21:469-80
Duman, Ronald S; Aghajanian, George K; Sanacora, Gerard et al. (2016) Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med 22:238-49
Wang, Fan; Xu, Hongqin; Zhao, Hongyu et al. (2016) DNA co-methylation modules in postmortem prefrontal cortex tissues of European Australians with alcohol use disorders. Sci Rep 6:19430
Tsai, Wan-Min; Zhang, Heping; Buta, Eugenia et al. (2016) A modified classification tree method for personalized medicine decisions. Stat Interface 9:239-253
Wrocklage, Kristen M; Schweinsburg, Brian C; Krystal, John H et al. (2016) Neuropsychological Functioning in Veterans with Posttraumatic Stress Disorder: Associations with Performance Validity, Comorbidities, and Functional Outcomes. J Int Neuropsychol Soc 22:399-411
Wang, Qian; Polimanti, Renato; Kranzler, Henry R et al. (2016) Genetic factor common to schizophrenia and HIV infection is associated with risky sexual behavior: antagonistic vs. synergistic pleiotropic SNPs enriched for distinctly different biological functions. Hum Genet :
Steele, Vaughn R; Anderson, Nathaniel E; Claus, Eric D et al. (2016) Neuroimaging measures of error-processing: Extracting reliable signals from event-related potentials and functional magnetic resonance imaging. Neuroimage 132:247-60
Morean, M E; Zellers, S; Tamler, M et al. (2016) Psychometric validation of measures of alcohol expectancies, retrospective subjective response, and positive drinking consequences for use with adolescents. Addict Behav 58:182-7
Arout, Caroline A; Perrino Jr, Albert C; Ralevski, Elizabeth et al. (2016) Effect of Intravenous Ethanol on Capsaicin-Induced Hyperalgesia in Human Subjects. Alcohol Clin Exp Res 40:1425-9

Showing the most recent 10 out of 230 publications