Project 3: Fyn Kinase Inhibitors and Alcohol Drinking Behaviors in Heavy Drinkers Suchitra Krishnan-Sarin, Ph.D. Abstract Historically, development of successful treatments for substance use disorders, including alcohol drinking, has been based on an understanding of the neurochemical mechanisms mediating the condition. CTNA4 has a novel and translational focus on understanding the role of an intracellular signaling mechanism, related to protein tyrosine phosphatases, in mediating alcohol induced disturbances in DA and glutamate signaling, and the relevance of these interactions to alcohol reward and drinking and alcohol habits. This project, P3, which is an important component of the translational CTNA4, will evaluate if a Fyn Kinase inhibitor, Saractinib, alters drinking behavior in heavy drinkers. Saractinib is a Fyn Kinase inhibitior developed by Astra Zeneca that will target NMDA receptor signaling and has been used in multiple studies with healthy control, patients with solid tumors and patients with Alzheimers disease. P3 is inherently innovative in both its conception and application because it identifies an important gap in clinical knowledge ?how to target NMDA receptor function to reduce drinking without increasing positive alcohol effects- and then brings to bear an experiment which combines a novel therapeutic agent and a behavioral science tool, the Alcohol drinking paradigm (ADP) to investigate this question. The project is served by the cores but also supports the goals of the CTNA cores, including the clinical and translational cores, to ask unique questions like the role of ?habit? and novel neuroimaging markers in predicting medication response. P3 will address the primary questions of whether Fyn kinase inhibition with Saractinib, alters alcohol drinking and craving in heavy drinkers using the ADP. It will also evaluate if Saracatinib alters alcohol effects like stimulation and sedation and examine various novel predictors of treatment response including habit, impulsivity, deficiencies in learning in response to rewards/punishment and neuroimaging markers of functional brain connectivity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA012870-18
Application #
9493330
Study Section
Special Emphasis Panel (ZAA1)
Project Start
Project End
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
18
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
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
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

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