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.

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National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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Yale University
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Zhou, Hang; Cheng, Zhongshan; Bass, Nicholas et al. (2018) Genome-wide association study identifies glutamate ionotropic receptor GRIA4 as a risk gene for comorbid nicotine dependence and major depression. Transl Psychiatry 8:208
DeMartini, Kelly S; Schilsky, Michael L; Palmer, Amanda et al. (2018) Text Messaging to Reduce Alcohol Relapse in Prelisting Liver Transplant Candidates: A Pilot Feasibility Study. Alcohol Clin Exp Res 42:761-769
Morean, Meghan E; DeMartini, Kelly S; Foster, Dawn et al. (2018) The Self-Report Habit Index: Assessing habitual marijuana, alcohol, e-cigarette, and cigarette use. Drug Alcohol Depend 186:207-214
Mota, Natalie P; Han, Shizhong; Harpaz-Rotem, Ilan et al. (2018) Apolipoprotein E gene polymorphism, trauma burden, and posttraumatic stress symptoms in U.S. military veterans: Results from the National Health and Resilience in Veterans Study. Depress Anxiety 35:168-177
Leeman, Robert F; Nogueira, Christine; Wiers, Reinout W et al. (2018) A Test of Multisession Automatic Action Tendency Retraining to Reduce Alcohol Consumption Among Young Adults in the Context of a Human Laboratory Paradigm. Alcohol Clin Exp Res 42:803-814
Morean, Meghan E; L'Insalata, Alexa; Butler, Ellyn R et al. (2018) Age at drinking onset, age at first intoxication, and delay to first intoxication: Assessing the concurrent validity of measures of drinking initiation with alcohol use and related problems. Addict Behav 79:195-200
Preller, Katrin H; Burt, Joshua B; Ji, Jie Lisa et al. (2018) Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor. Elife 7:
Zhang, Huiping; Zhou, Hang; Lencz, Todd et al. (2018) Genome-wide association study of cognitive flexibility assessed by the Wisconsin Card Sorting Test. Am J Med Genet B Neuropsychiatr Genet 177:511-519
Vijay, Aishwarya; Cavallo, Dana; Goldberg, Alissa et al. (2018) PET imaging reveals lower kappa opioid receptor availability in alcoholics but no effect of age. Neuropsychopharmacology 43:2539-2547
Polimanti, Renato; Kayser, Manfred H; Gelernter, Joel (2018) Local adaptation in European populations affected the genetics of psychiatric disorders and behavioral traits. Genome Med 10:24

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