Administrative Core

Leadership

Overview

The CTNA places a high priority on maintaining an efficient flow of information in order to promote the safe and successful completion of proposed studies, to support the initiation of novel pilot studies, to facilitate the career development of trainees and junior faculty affiliated with the Center, and to promote the dissemination of research advances. The Administrative Core provides for the centralized organizational functions of the CTNA. The executive functions, budget functions and data management components are the heart of CTNA, serving as the focus of all activities.

Data Management & Biostatistical Component (DMBC)

The Administrative Core oversees centralized data management for all CTNA components. The Data Management and Biostatistics Component (DMBC) is directed by Dr. Ralitza Gueorguieva. Data are entered using a novel data management system via Teleforms managed by Elaine LaVelle. All members of the DMBC are experienced in study design, preparation of study forms, management of data, preparation of reports related to the progress of each study.

Education Committee

Led by Dr. Ismene Petrakis, the aim of the Education Committee is to insure that alcoholism research training is integrated into all Yale neuroscience training programs in the following ways: 1) to encourage the recruitment of research trainees with alcoholism research interests, 2) to insure that research trainees associated with the CTNA present to an appropriate research audience at least annually, 3) to meet regularly with each alcoholism research trainee to monitor their progress and to provide additional career development support, and 4) to maintain the CNTA website. In addition, the CTNA has a lengthy and detailed website (http://info.med.yale.edu/ctna/index.html) so that any research training, continuing education, and objectives of the CTNA may be achieved to a greater extent through collaboration with neighboring institutions.

Data Safety Monitoring Board (DSMB)

CTNA puts the highest possible emphasis on the protection of subjects participating in its research activities. The establishment of the DSMB within this Center minimizes the exposure of research subjects to procedures that may carry risk. The DSMB is extrinsic to the CTNA infrastructure to provide an additional level of protection for subjects. This step is taken for two reasons, 1) Cutting-edge clinical neuroscience research as it is implemented in the CTNA may involve exposure to radiation (e.g., PET neuroreceptor imaging), drugs that may have unpleasant effects, or procedures that could conceivably worsen the course of alcoholism (e.g., ethanol self-administration in non-treatment-seeking alcoholics). The proposed studies are designed in accord with NIAAA guidelines for alcohol administration, NAMI recommendations regarding the ethical conduct of research, and related recommendations from the ACNP. The inclusion of these technologies in the CTNA followed careful consideration of the potential scientific merit of each study, the risk/benefit issues for research subjects and society, and approval by the Yale-affiliated IRBs (Yale, Columbia, Hartford Hospital and VACHS IRBs). The establishment of the DSMB insures that the clinical studies will not be continued long after the data collected has answered the proposed scientific aims or when it is unlikely to be concluded successfully, thus placing subjects at avoidable potential risk. 2) The collaboration with the Data Management and Biostatistics Component (DMBC) of the Clinical Core provides the Center with an infrastructure that is capable of preparing detailed reports on safety and efficacy for each clinical study every 6 months. This capacity, out of reach for most single-site studies, assures that the DSMB has the information necessary to perform its monitoring functions.

Scientific Advisory Board (SAB)

The SAB reviews all ongoing projects and planned pilot studies to assure that the transdisciplinary goals of the CTNA are maintained. Investigators present an update of each ongoing project to the SAB. Members of the SAB are asked to provide critical assessments and suggestions for continuation, enhancement, change, or closure of projects. The SAB reports to Dr. Krystal to provide guidance on the most appropriate conduct of the CTNA. Selection of SAB members was based on the need for a multidisciplinary group that could provide advice on all aspects of the CTNA.

Family History and Spinophilin Genotype Influence NMDA Receptor Function and Ethanol Response

(I. Petrakis)

This Project builds from our original CTNA Project to explore the hypothesis that individuals with a family history positive for alcohol dependence (FHP), experience an alteration in the reward valence of ethanol (more positive effects and reduced negative effects) compared to family history negative (FHN) age-matched subjects. This project builds on basic science evidence that the discriminative stimulus effects of ethanol reflect a composite of its pharmacologic effects in the brain. Therefore variation in genes that code for key ethanol targets in the brain or downstream signal transduction mechanisms may increase or decrease the risk for alcoholism by altering a component of the discriminative stimulus effects of ethanol. In this case, we are studying the NMDA receptor, an important ethanol target in the brain. This study will test the hypothesis that both ketamine and alcohol response (using the alcohol clamp procedure to minimize pharmacokinetic issues) will be similarly influenced by family history of alcoholism and by the spinophilin SNP, strengthening the hypothesis that the NMDA receptor antagonist component of ethanol action contributes to the abuse liability of ethanol.

Methods

This study is a two phased study: Phase I: a double-blind, placebo controlled evaluation of the perceptual, neurophysiologic and cognitive effects of an intravenous (IV) ethanol clamp infusion; and Phase II; a double-blind, placebo controlled evaluation of the perceptual, cognitive, and neurophysiologic effects of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, in healthy individuals at increased familial risk for alcoholism by virtue of a paternal family history of alcohol dependence (family history positive: FHP) and a matched comparison group of individuals without a family history of alcohol dependence (family history negative: FHN). In Phase I, Subjects will complete 2 test days, in randomized, balanced order under double blind conditions. Test days will include an IV “clamping” procedure, where subjects will have an infusion of 6% ethanol infusate for approximately 20-25 minutes until target breathalyzer of 100mg/dl is reached, then infusion will continue “clamped” at the breathalyzer target range for an additional 60 minutes OR a placebo infusion, with a similar 20-25 minute run-in infusion and a “clamped” infusion for 60minutes. Phase II: Subjects will complete 2 test days in a randomized, balanced order under double-blind conditions. Test days will involve the 60-minute intravenous bolus + infusion of placebo or bolus of ketamine (0.23mg/kg x 1 minute) followed by a 60-minute infusion of ketamine 0.0097mg/kg/minute (total dose =0.812 mg/kg). Subjects will participate in Phase I first, followed by Phase II, at least 2 weeks apart. All test days within a Phase are conduced at least 3 days apart.

Results

This project has resulted in several publications. One manuscript characterizes behavioral effects of the GABA-A agonist thiopental and ketamine. Both medications produced cognitive and subjective effects similar to ethanol, highlighting the importance of GABA and NMDA receptor systems to the effects of alcohol intoxication. In a related study, the investigators examined the influence of ketamine and thiopental on ERP response during a visual oddball task. Both drugs attenuated neural response, demonstrating the role of GABA and NMDA mechanisms in processing of novel stimuli. Both of these projects provide a framework for understanding the mechanisms by which altered glutamate and GABA receptor systems may affect cognitive functioning and behavioral response to alcohol among FHP individuals.

Genetics Core

(J. Gelernter)

The goal of the Genetics Core is to support the genetic components of each of the projects participating in this Center to help understand the nature of genetic influences on the phenotypes measured, and to allow for the ascertainment of genetic covariates that might affect those outcomes. We encourage that all subjects be asked to provide a DNA sample. Information on family history and other characteristics will be collected in the Clinical Core to provide the basis for analyses with DNA information.

Specific candidate genes have been identified as potentially important for each of the component projects in the center. We have the goal of sampling DNA from 100% of study subjects. The major function of the Genetics Core is to support genotyping for each of the projects (including pilot projects), for the purpose of identifying genotype/phenotype correlations.

NMDA Antagonist Efficacy in Reducing Human Alcohol Consumption: Impact of Family History

(S. Krishnan-Sarin)

CTNA-1 described evidence that enhanced NMDA receptor function associated with alcohol dependence may increase risk for heavy drinking. This project evaluates the dose-related efficacy of memantine in reducing alcohol consumption in FHP/FHN alcohol dependent patients. It also tests whether memantine, perhaps through “normalizing” NMDA receptor function, reduces alcohol cue-induced craving. Building on previous studies, we will explore the modifying effects of familial alcoholism history. The evaluation of delay discounting, impulsivity and ventral striatal activation in these patients will enable us to explore the hypothesis that normalization of NMDA receptor function in these patients reduces risk for heavy drinking related to disturbances in motivational circuitry common to alcoholism and other substance abuse disorders. In contrast, the ability of memantine to change the subjective response to ethanol will enable CTNA-2 to explore risk factors for alcoholism that may be unique to the pharmacodynamic actions of ethanol. Our pilot data also raise the possibility that spinophilin genotype may influence both common and unique alcoholism risk mechanisms.

Purpose

To evaluate the interactive effects of FH of alcoholism and the NMDA antagonist memantine on alcohol drinking in alcohol dependent heavy drinkers, using a human laboratory alcohol self-administration paradigm. The paradigm, that has been previously used in numerous projects (e.g. O’Malley et al., 2002; Anton et al., 2004; Drobes et al., 2003; Krishnan-Sarin et al, under review) involves administration of a priming drink of alcohol followed by three hour alcohol self-administration session. This double blind, placebo-controlled study will examine the effects of memantine on behavioral measures related to alcohol self-administration in alcohol dependent heavy drinkers with positive or negative family history of alcoholism (FHP and FHN). Within each family history group, subjects will be randomized to one of three doses of memantine (placebo, 20 mg/day or 40 mg/day).

PET Striatum Dopamine Release Deficits With Family History of Alcoholism

(A. Abi-Dargham)

This project is designed to assess effects of alcohol challenge and a monetary incentive delay task (MIDT) on dopamine release as measured with [11C]raclopride displacement.

Alcohol challenge

Each subject received 2 PET scans with [11C]raclopride: one after a placebo drink and one after an alcoholic drink. The alcohol challenge resulted in a significant [11C]raclopride displacement in all striatal subregions for the sample as a whole. The largest change was found in the ventral striatum.

When separated by sex, males still showed statistically significant [11C]raclopride displacement in all striatal ROI, with the greatest change also in the ventral striatum, while women only showed significant [11C]raclopride displacement in the ventral striatum and the precommissural putamen. Ventrostriatal dopamine release in men, but not in women, showed a significant positive correlation to alcohol-induced measures of subjective activation. Furthermore, we found a significant negative correlation between drinking frequency and ventrostriatal [11C]raclopride displacement in men.

MIDT

In parallel with the alcohol challenge study we also examined the effect of the Monetary Incentive Delay Task (MIDT) (Knutson et al. 2000), a task classically used in fMRI to measure activation related to reward, on [11C]raclopride binding across the striatal substructures measured with PET. This work is in collaboration with Godfrey Pearlson. This work is ongoing.

Pilot Core

Pilot 1: P. Lombroso. The Role of STEP in Mediating the Inhibitory Effects of ETOH
The goal of this pilot study was to test the hypothesis that STEP mediates the inhibitory effects of ethanol on hippocampal long-term potentiation. Consistent with our hypothesis, STEP knockout mice did not show significant ethanol-induced decease in long-term potentiation as wild type mice did. This enhanced acquisition of instrumental ethanol habit. These results support our hypothesis that STEP is an essential tyrosine phosphatase that mediates at least some of the inhibitory effects of ethanol on NMDA-induced neuroplasticity in the hippocampus. Ongoing experiments are examining the consumption of ethanol by wild-type and STEP knockout mice, as well as acquisition of instrumental ethanol habit.
Pilot 2: D. Small. Neurobiological mechanisms of satiety for alcohol consumption
This pilot study uses a novel paradigm to examine fMRI response to alcohol anticipation and consumption in reward networks following an intravenous alcohol “clamp” that will maintain a steady blood alcohol concentration during scanning. In order to examine alcohol satiety in relationship to familial alcoholism risk, FHP and FHN young adults will be given the opportunity to sip alcohol from a gustometer during fMRI scanning, following the administration of an intoxicating dose of ethanol.
Pilot 3: J. Kaufman. Genetic Predictors of Reward-Pathway Activation
The goal of this pilot study was to examine the role of GABRA2 genotype in moderating reward circuitry activation in children. A multimodal imaging protocol was implemented and included: functional imaging utilizing a reward task adapted for use in young children, resting state connectivity, and structural imaging. Preliminary results indicated increased functional connectivity between the nucleus accumbens and inferior frontal gyrus among children with the cc genotype as compared to those with the tt genotype.

Ventral Striatal Functional Deficits and Familial Alcoholism Risk

(G. Pearlson)

This study will determine whether FHP healthy subjects and FHP alcohol dependent patients show deficits in ventral striatal activation associated with the anticipation of reward. Both data from Hommer’s NIAAA lab and CTNA-1 fMRI data reviewed above predict that these deficits may contribute to the common risk for alcoholism, impulsivity, and sociopathy. The study will explore whether (1) deficits in ventral striatal activation in the FHP healthy subjects related to increased NMDA receptor function or spinophilin genotype; (2) spinophilin genotype is related to ventral striatal activation deficits in alcohol dependent patients;

We will use two distinct but complementary behavioral tasks, in combination with functional MRI, to quantify responses in motivational circuitry to situations involving both expectation of and receipt of rewards and punishments, as well as the propensity to take risks on one of the tasks. We will study 80 adult male and female subjects in equal numbers who are either offspring of an alcoholic parent or are family history negative matched controls. Use of two complementary cognitive tasks during functional MRI (fMRI), will dissect functional abnormalities in the circuits converging on the ventral striatum that may contribute to the vulnerability to alcoholism and other risky or impulsive behaviors. The 2 paradigms are: 1) a Monetary Incentive Delay Task, that distinguishes networks engaged in motivational (anticipation) and consummatory (outcome) components of reward processing; 2) a Domino Task, that explores anticipatory and consummatory phases of reward processing under contextual manipulations (uncertainty, social interaction) that promote risk-taking.

Results

During reward anticipation, fMRI data confirmed blunted nucleus accumbens activation in family history positive (FHP) subjects who themselves have had no current or prior histories of alcohol abuse or dependence.

In addition, we found abnormal activation in nucleus accumbens and additional reward-associated brain regions during additional task phases, most notably excessive task-related activation in the FHP group during the A1 (prospect of reward), phase of the MID task.

We further found significant correlations between abnormal nucleus accumbens activation during reward anticipation and prospect and specific impulsivity constructs. Interestingly, diminished activation during the A2 (reward anticipation) phase was significantly correlated with the same impulsivity factor associated with diminished activation during this same task phase in a population of cocaine abusers we are examining in a separate study. Similarly, we observed correlations between nucleus accumbens activation and additional impulsivity factors during the outcome of reward phase in the FHP. Overall, results demonstrate that sensitivity of the reward circuit in general, including NAcc, is functionally compromised in FHP individuals.