The risk for alcohol dependence runs in families. A component of this heritable risk for alcoholism iscommon to other addictions, sociopathy, and impulsive behavior. CTNA will explore the hypothesis thatthese Alcoholism 'Common' Risk Factors (ACRF) involve synaptic pathology related to the convergenceof glutamate and dopamine inputs to the ventral striatum and associated 'motivation' circuitry. From acognitive/behavioral neuroscience perspective, evidence for this vulnerability is expressed as generalimpairments in the normal ability to engage motivational circuitry by delayed rewards and punishments,biasing individuals toward immediate rewards, (exemplified by alcohol), and impulsive behavior. Anaspect of this transmitted vulnerability is hypothesized to involve problems in the brain circuitry for rewardand punishment expectation- a 'Reward Deficit Hypothesis.' We will use two distinct but complementarybehavioral tasks, in combination with functional MRI, to quantify responses in motivational circuitry tosituations involving both expectation of and receipt of rewards and punishments, as well as the propensityto take risks on one of the tasks. We will study 80 adult male and female subjects in equal numbers whoare either offspring of an alcoholic parent or are family history negative matched controls. Use of twocomplementary cognitive tasks during functional MRI (fMRI), will dissect functional abnormalities in thecircuits converging on the ventral striatum that may contribute to the vulnerability to alcoholism and otherrisky or impulsive behaviors. The 2 paradigms are: 1) a Monetary Incentive Delay Task, that distinguishesnetworks engaged in motivational (anticipation) and consummatory (outcome) components of rewardprocessing; 2) a Domino Task, that explores anticipatory and consummatory phases of reward processingunder contextual manipulations (uncertainty, social interaction) that promote risk-taking. Subjectiveresponses to tasks will be quantified as an important dependent measure. In synergy within CTNA, we willexplore: (Genetics Core) whether variation in genes that influence dopaminergic and glutamatergicfunction moderate the integrity of motivation circuitry; (Project 3) whether increases in NMDA receptorfunction contribute to functional abnormalities in motivation circuitry; (Project 5) the clinical relevance ofthe functional integrity of motivation circuitry in alcohol dependent subjects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA012870-08
Application #
7622305
Study Section
Special Emphasis Panel (ZAA1-HH (60))
Project Start
2008-06-01
Project End
2011-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
8
Fiscal Year
2008
Total Cost
$103,919
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
Polimanti, R; Kaufman, J; Zhao, H et al. (2018) A genome-wide gene-by-trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus. Mol Psychiatry 23:154-160
Polimanti, R; Kaufman, J; Zhao, H et al. (2018) Trauma exposure interacts with the genetic risk of bipolar disorder in alcohol misuse of US soldiers. Acta Psychiatr Scand 137:148-156
Ide, Jaime S; Zhornitsky, Simon; Chao, Herta H et al. (2018) Thalamic Cortical Error-Related Responses in Adult Social Drinkers: Sex Differences and Problem Alcohol Use. Biol Psychiatry Cogn Neurosci Neuroimaging 3:868-877
D'Souza, Deepak Cyril; Carson, Richard E; Driesen, Naomi et al. (2018) Dose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects. Biol Psychiatry 84:413-421
Polimanti, Renato; Gelernter, Joel; Stein, Dan J (2018) Genetically determined schizophrenia is not associated with impaired glucose homeostasis. Schizophr Res 195:286-289
Foster, Dawn W; Ye, Feifei; O'Malley, Stephanie S et al. (2018) Longitudinal Associations Between Alcohol-Related Cognitions and Use in African American and European American Adolescent Girls. Alcohol Clin Exp Res 42:962-971
Polimanti, Renato; Gelernter, Joel (2018) ADH1B: From alcoholism, natural selection, and cancer to the human phenome. Am J Med Genet B Neuropsychiatr Genet 177:113-125
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

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