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 #
2P50AA012870-11
Application #
8128243
Study Section
Special Emphasis Panel (ZAA1-GG (99))
Project Start
Project End
Budget Start
2011-07-15
Budget End
2012-05-31
Support Year
11
Fiscal Year
2011
Total Cost
$201,961
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chang, Fong; Xu, Ke; Huang, Ming-Chyi et al. (2017) Alcohol Triggers Reemergence of Ketamine-Like Experience in a Ketamine Ex-User. J Clin Psychopharmacol 37:110-112
Wang, Qian; Polimanti, Renato; Kranzler, Henry R et al. (2017) 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 136:75-83
Kort, Naomi S; Ford, Judith M; Roach, Brian J et al. (2017) Role of N-Methyl-D-Aspartate Receptors in Action-Based Predictive Coding Deficits in Schizophrenia. Biol Psychiatry 81:514-524
Krystal, John H; Petrakis, Ismene L; O'Malley, Stephanie et al. (2017) NMDA Glutamate Receptor Antagonism and the Heritable Risk for Alcoholism: New Insights from a Study of Nitrous Oxide. Int J Neuropsychopharmacol 20:351-353
Polimanti, Renato; Gelernter, Joel (2017) ADH1B: From alcoholism, natural selection, and cancer to the human phenome. Am J Med Genet B Neuropsychiatr Genet :
Polimanti, Renato; Jensen, Kevin P; Gelernter, Joel (2017) Phenome-wide association study for CYP2A6 alleles: rs113288603 is associated with hearing loss symptoms in elderly smokers. Sci Rep 7:1034
Polimanti, Renato; Agrawal, Arpana; Gelernter, Joel (2017) Schizophrenia and substance use comorbidity: a genome-wide perspective. Genome Med 9:25
Polimanti, Renato; Gelernter, Joel; Stein, Dan J (2017) Genetically determined schizophrenia is not associated with impaired glucose homeostasis. Schizophr Res :
Polimanti, Renato; Wang, Qian; Meda, Shashwath A et al. (2017) The Interplay Between Risky Sexual Behaviors and Alcohol Dependence: Genome-Wide Association and Neuroimaging Support for LHPP as a Risk Gene. Neuropsychopharmacology 42:598-605
Polimanti, Renato; Meda, Shashwath A; Pearlson, Godfrey D et al. (2017) S100A10 identified in a genome-wide gene × cannabis dependence interaction analysis of risky sexual behaviours. J Psychiatry Neurosci 42:252-261

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