Independent Scientist Award-KO2: As Co-Director of an Alcoholism Research Center, I have supported my salary since 1991. In July, 1998, the VA will terminate this national program. At that time, I will assume substantial clinical responsibilities unless I find an alternative mechanism to support my salary. This K02 Award would enable me to sustain my research and develop further expertise in areas critical to my research program. My research has focussed on characterizing the clinical significance of glutamate and GABA dysregulation in alcoholism. With NIAAA support, I conducted a study that indicated that the NMDA antagonist, ketamine, had ethanol-like effects and altered reward valence in alcoholic patients. These patients showed blunted dysphoric responses and increased euphoric responses. Thus, NMDA receptor dysregulation may alter the NMDA antagonist component of ethanol response in patients in a manner that promotes relapse. To build towards pharmacotherapy, I have proposed to compare responses to a partial agonist of the strychnine-insensitive glycine (SIGLY) site of the NMDA receptor in recently detoxified alcoholics and controls (Years 1-3) and to determine whether drugs acting at this site modulate ethanol cue-induced craving in patients (Years 4-5). To facilitate these objectives, I will pursue additional training in multivariate statistics and I will work collaboratively to develop methods for assessing craving that are independent of self-report and would be applied to studies in Years 4-5. My other major research focus has been the study of reductions in GABA function in alcoholics using 133I iomazenil single photon emission computerized tomography (SPECT) and magnetic resonance spectroscopy (lH-NMR). Respectively, these techniques measure benzodiazepine/GABA-A receptor density and GABA levels. I have proposed a study that employs both SPECT and 1H-NMR in a longitudinal assessment of the recovery of GABA systems with sobriety. If funded, this study would cover years 1-4 of this K02 period. In year 5, I propose to characterize the activity of the GABA synthetic enzyme, glutamic acid decarboxylase, in alcoholic patients using a 13C-glucose infusion technique. In this work, I focus my career development on gaining further expertise in 1H- and 13C-NMR. As a result, I have developed an educational program designed to facilitate my development in these areas. In summary, this K02 award would foster my academic development and enable me to better contribute to the building of pathophysiologic models of alcoholism that can guide medications development for this disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02AA000261-03
Application #
6371226
Study Section
Special Emphasis Panel (ZAA1-FF (02))
Program Officer
Witt, Ellen
Project Start
1999-07-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
3
Fiscal Year
2001
Total Cost
$104,490
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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D'Souza, Deepak Cyril; Gil, Roberto B; Zuzarte, Edward et al. (2006) gamma-Aminobutyric acid-serotonin interactions in healthy men: implications for network models of psychosis and dissociation. Biol Psychiatry 59:128-37
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Epperson, C Neill; O'Malley, Stephanie; Czarkowski, Kathryn A et al. (2005) Sex, GABA, and nicotine: the impact of smoking on cortical GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopy. Biol Psychiatry 57:44-8
Hoffman, Ralph E; Gueorguieva, Ralitza; Hawkins, Keith A et al. (2005) Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and moderators in a fifty patient sample. Biol Psychiatry 58:97-104
D'Souza, Deepak Cyril; Abi-Saab, Walid Michel; Madonick, Steven et al. (2005) Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol Psychiatry 57:594-608
Jacobsen, Leslie K; D'Souza, D Cyril; Mencl, W Einar et al. (2004) Nicotine effects on brain function and functional connectivity in schizophrenia. Biol Psychiatry 55:850-8
Jacobsen, Leslie K; Mencl, W Einar; Pugh, Kenneth R et al. (2004) Preliminary evidence of hippocampal dysfunction in adolescent MDMA (""ecstasy"") users: possible relationship to neurotoxic effects. Psychopharmacology (Berl) 173:383-90
Lappalainen, Jaakko; Sanacora, Gerard; Kranzler, Henry R et al. (2004) Mutation screen of the glutamate decarboxylase-67 gene and haplotype association to unipolar depression. Am J Med Genet B Neuropsychiatr Genet 124B:81-6
Sanacora, Gerard; Gueorguieva, Ralitza; Epperson, C Neill et al. (2004) Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 61:705-13

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