The past 5 years has been the most productive epoch in my career. I supported my salary with an NIAAA Independent Investigator (KO2) Award that markedly reduced my clinical and administrative responsibilities. Consequently, since 1998, I published 128 research papers and reviews including the multicenter VA naltrexone alcohol dependence study, characterization of NMDA receptor function alterations with alcohol dependence and the familial risk for alcoholism, completion of studies exploring roles for glutamate receptor antagonist or glutamate release inhibiting drugs for treating alcohol dependent patients, and completion of an initial characterization of time-dependent changes in the regulation of GABA systems in patients using concurrent measurements of cortical GABA levels with 1H-magnetic resonance spectroscopy (MRS) and GABAA receptor regulation with single photon emission computerized tomography (SPECT). For this work, I received several awards including the Joel Elkes Award (ACNP) and the Hans-Jonas Weitbrecht Scientific Award (Bayer). During this period, I renewed our VA Alcohol Research Center, led the establishment of the NIAAA Center for the Translational Neuroscience of Alcoholism (CTNA), and received funding for two RO 1 grants and a VA Merit Review Grant. I also participated in several national and international committees, served on the Editorial Boards of several journals, and mentored several highly accomplished trainees. Over the next five years, I propose to advance the scientific theme of my KO2 Award: to further characterize alterations in amino acid neurotransmission associated with alcohol dependence. The principal new conceptual and educational focus of this application is to unite psychopharmacologic and neuroimaging techniques that were my focus for the past five years with molecular genetic (candidate gene) and molecular neuroscientific (mRNA expression arrays) techniques that may help to add significant explanatory power to the proposed studies. I also propose to characterize the specificity of alterations in glutamatergic and GABAergic alterations associated with the vulnerability to alcohol dependence by comparing ethanol, sodium pentothal (barbiturate), and ketamine (NMDA receptor antagonist) responses in healthy individuals with and without family histories of ethanol dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Scientist Award (K05)
Project #
5K05AA014906-02
Application #
6923742
Study Section
Special Emphasis Panel (ZAA1-DD (03))
Program Officer
Witt, Ellen
Project Start
2004-07-15
Project End
2009-06-30
Budget Start
2005-07-07
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$183,589
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Gueorguieva, Ralitza; Chekroud, Adam M; Krystal, John H (2017) Trajectories of relapse in randomised, placebo-controlled trials of treatment discontinuation in major depressive disorder: an individual patient-level data meta-analysis. Lancet Psychiatry 4:230-237
Gueorguieva, Ralitza; Wu, Ran; Krystal, John H et al. (2013) Temporal patterns of adherence to medications and behavioral treatment and their relationship to patient characteristics and treatment response. Addict Behav 38:2119-27
Gueorguieva, Ralitza; Wu, Ran; Donovan, Dennis et al. (2012) Baseline trajectories of heavy drinking and their effects on postrandomization drinking in the COMBINE Study: empirically derived predictors of drinking outcomes during treatment. Alcohol 46:121-31
Gunduz-Bruce, Handan; Reinhart, Robert M G; Roach, Brian J et al. (2012) Glutamatergic modulation of auditory information processing in the human brain. Biol Psychiatry 71:969-77
Gomez, Rosane; Behar, Kevin L; Watzl, June et al. (2012) Intravenous ethanol infusion decreases human cortical ?-aminobutyric acid and N-acetylaspartate as measured with proton magnetic resonance spectroscopy at 4 tesla. Biol Psychiatry 71:239-46
Andrews, Melissa M; Meda, Shashwath A; Thomas, Andre D et al. (2011) Individuals family history positive for alcoholism show functional magnetic resonance imaging differences in reward sensitivity that are related to impulsivity factors. Biol Psychiatry 69:675-83
Freeman, Willard M; Vanguilder, Heather D; Guidone, Elizabeth et al. (2011) Plasma proteomic alterations in non-human primates and humans after chronic alcohol self-administration. Int J Neuropsychopharmacol 14:899-911
Gueorguieva, Ralitza; Wu, Ran; Donovan, Dennis et al. (2011) Baseline trajectories of drinking moderate acamprosate and naltrexone effects in the COMBINE study. Alcohol Clin Exp Res 35:523-31
Hallak, Jaime E C; Dursun, Serdar M; Bosi, Daniel C et al. (2011) The interplay of cannabinoid and NMDA glutamate receptor systems in humans: preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects. Prog Neuropsychopharmacol Biol Psychiatry 35:198-202
Krystal, John H; Petrakis, Ismene L; Limoncelli, Diana et al. (2011) Characterization of the interactive effects of glycine and D-cycloserine in men: further evidence for enhanced NMDA receptor function associated with human alcohol dependence. Neuropsychopharmacology 36:701-10

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