Clinical Core

Leadership

The Clinical Core has established common methodologies to facilitate cognitive and clinical research domains and allow us to compare and pool data across projects for secondary analyses to help us define issues of vulnerability. All subjects enrolled in a CTNA project or pilot study will complete the Clinical Core assessment battery. We also provide training in key assessments such as the timeline follow-back and the SCID and help promote recruitment into studies.

Activities

The CTNA Clinical Core serves an important function as the central resource for the diverse clinical projects and pilots. It represents the distinct advantage of an Alcohol Research Center over a cluster of individual grants. The opportunity to fund a central facility with a distinguished leader provides a programmatic method to define needs and assign resources to address central issues. The central components of the Clinical Core are oversight of subject recruitment and clinical assessments for all clinical projects, data management (Directed by Elaine LaVelle) and data analysis (Directed by Dr. Ralitza Gueorguieva and Brian Pittman).

The specific aims for the Clinical Core are:

Centralized monitoring of subject recruitment to: 1) Enhance the efficiency of enrollment into each project, including pilots; and 2) Update the Principal Investigators (PIs), the Scientific Advisory Board, and the Data Safety Monitoring Board of progress on the protocols.
Central oversight of assessments to: 1) Provide efficiency in training and assessment; 2) Maintain consistency in the administration of assessments; 3) Enhance the ability of investigators to pool data across studies; 4) Insure that validated and current assessment tools are used; and 5) Support secondary analyses utilizing core assessments.
Central provision of Data Management and Biostatistics support to: 1) Provide design and analytical expertise to meet the goals of the CTNA scientific agenda; 2) Provide state-of-the-art methods for data management; 3) Generate randomization lists and assess randomization implementation; 4) Interface with specialized data analysis expertise related to particular technologies associated with the CTNA, including genetics and imaging; 5) Prepare reports related to the progress of clinical studies for the Data Safety Monitoring Board; and 6) Provide statistical support for all investigators.

CTNA-1 Projects

Project 1: PI: Eric Nestler MD, PhD, TRANSCRIPTION FACTORS, GLUTAMATERGIC FUNCTION, ETHANOL REWARD, AND ADAPTATION TO CHRONIC ETHANOL
Dr. Nestler has focused his work on a systematic mapping of ?FosB induction in brain by chronic alcohol administration, using several methods of alcohol exposure. He has characterized the specific cell types within these regions where this alcohol induction of ?FosB occurs, in the search for target genes for ?FosB, and hence for alcohol. The data indicate that alcohol-induced accumulation of ?FosB in nucleus accumbens, dorsal striatum, amygdale, and prefrontal cortex.
Working in collaboration with George Koob (Scripps Research Institute) and Adron Harris (University of Texas at Austin), they found that ?FosB may reduce the effects of alcohol on balance, while enhancing the anxiolytic effects of alcohol.
Project 2: PI: Joel Gelernter MD, GUIDED FAMILY-CONTROLLED LINKAGE DISEQUILIBRIUM SCAN FOR ALCOHOL DEPENDENCE AND PFC-RELATED ENDOPHENOTYPES
Dr. Gelernter performed SNP-based fine-mapping of regions of chromosome 1 and 11 that show linkage disequilibrium with alcohol dependence. He collaborated with other CTNA investigators to identify genetic association with EtOH-related endophenotypes.
Project 3: PI: Graeme Mason PhD, 13C MRS MEASUREMENT OF GLUTAMATE NEUROTRANSMITTER CYCLING IN INDIVIDUALS WITH FAMILIAL VULNERABILIUTY TO ALCOHOLISM, RECENTLY DETOXIFIED ALCOHOLICS, LONG-TERM SOBER ALOCHOLICS, AND HEALTHY INDIVIDUALS
Dr. Mason developed 13C and 1H MRS GABA acquisition measurements in order to assess the rate of GABA synthesis in individual subjects.
Project 4: PI: Anissa Abi-Dargham MD, PRESYNAPTIC AND POSTSYNAPTIC 5-HT RECEPTOR ABNORMALITIES IN ALCOHOLISM: A PET STUDY
Dr. Abi Dargham’s protocol focused on a comparison of serotonin transporter binding potential (BP) between alcohol dependent subjects and healthy controls. It combined [11C]WAY100635 and [11C]DASB, as a superior tracer for the serotonin transporter Alcohol dependent subjects were found to have a decrease in D2 receptor availability in the ventral and dorsal regions of the striatum compared to healthy controls and the reduction in striatal D2 receptors correlated with the daily intake of alcohol.
Project 5: PI: Ismene Petrakis MD, ALTERED NMDA RECEPTOR FUNCTION WITH FAMILIAL ALCOHOLISM RISK
Dr. Petrakis found that people with a family history of alcoholism (FHP) have altered sensitivity to the behavioral effects of ethanol, and are at higher risk of developing alcoholism, relative to healthy individuals without a family history (FHN). She found that FHP individuals have an altered response to the NMDA antagonist, ketamine, compared to FHN individuals. This project was expanded for CTNA-2.
Project 6: PI: Suchitra Krishnan-Sarin PhD, DIFFERENTIAL INTERFERENCE WITH ETHANOL SELF-ADMINISTRATION BY NALTREXONE IN ALCOHOLIC INDIVIDUALS WITH OR WITHOUT FAMILIAL ALCOHOLISM
This project utilized the laboratory paradigm for detecting the effects of opiate antagonists on alcohol drinking. Dr. Krishnan-Sarin found that the effect of naltrexone on drinking occurs primarily in FHP subjects. This project was expanded to include memantine as a treatment group for CTNA2.
Pilot 7: PI: William Corbin PhD, ACUTE EFFECTS OF ALCOHOL ON INFORMATION PROCESSING AND BEHAVIORAL CONTROL
Dr. Corbin studied the effects of alcohol on inhibition of behavioral response, and the relation between behavioral inhibition and risk factors for alcohol-related problems. He found a trend toward alcohol impairment on sensitivity to the stimuli presented in the task (go and stop signals). This effect is apparent despite attempts among participants in the alcohol condition to slow themselves down to compensate for impairment.
Pilot 8: PI: Jane Taylor PhD, BEHAVIORAL AND MOLECULAR CONSEQUENCES OF CHRONIC ETHANOL ADMINISTRATION IN THE RAT.
Dr. Taylor examined how molecular adaptations in the mesocorticolimbic structures contribute to neurocognitive effects of ethanol. Pilot work focused on spinophillin, the controller of protein phosphatase 1 (PP1) that is an antagonist of NMDA activity through inhibition of channel conductance. This project investigated how regulatory mechanisms affect incentive learning and cognitive/ibhibitory functions in alcoholism.
Pilot 9: PI: Julie Staley PhD, [123I]5-IA-85830 SPECT IMAGING OF ß2-NICOTINIC ACETYLCHOLINE RECEPTORS IN ALCOHOLISM
Dr. Staley studied whether thalamic and cortico-limbic ß2 nicotine acetylcholine receptors (ß2~nAChR) are increased during sobriety in alcohol-dependent nonsmokers with a family history of alcoholism. She used SPECT imaging of ß ß2~nAChR to assess adaptations during the early development of sobriety.

CTNA-2 Pilot Projects

W. Corbin. Effects of Alcohol and Prior Gambling Outcomes on Gambling Behavior.
This project investigated the influence of alcohol consumption and impulsivity on a computerized gambling task. Participants were 126 individuals, all of whom were moderate to heavy drinkers and regular gamblers. Preliminary results demonstrated that participants bet more during the alcohol condition relative to the placebo condition. This research contributes to the understanding gambling behaviors related to pharmacological and cognitive effects of alcohol, and may help identify risk factors and intervention strategies for individuals with problem drinking and gambling behaviors.
S. O’Malley. Targeted Naltrexone for Heavy Alcohol Use in Young Adults.
This pilot project examined the utility of naltrexone administration in reducing heavy drinking among young adults, which is a population in need of more effective treatment strategies. Participants received naltrexone and behavioral counseling for 8 weeks. Following treatment, participants significantly reduced drinks per drinking day, percentage of heavy drinking days, and alcohol-related consequences. These important findings support the use of naltrexone to reduce heavy drinking in young adults.
A. Simen. Epigenetic factors in stress mediated vulnerability to alcohol abuse and dependence.
This pilot project examined the effects of early life maternal separation or restraint stress on prefrontal cortex gene expression and alcohol preference in mice. The investigators developed a new paradigm involving maternal separation and early weaning to reliably produce behavioral changes indicative of stress in mice.
J. Taylor. Analysis of protein expression in a genetic animal model of alcoholism. This pilot project examined differences in protein expression in alcohol preferring rats in order to determine the protein expression changes that correspond to genetic vulnerability. Data have been analyzed for one rat bred to consume large amounts of alcohol and three non-alcohol rats. With this small sample, approximately 20 proteins have been identified as being differentially regulated in the alcohol preferring rat.
R. Duman. Gene Expression Profile of Postmortem, Alcohol-dependent Brains.
This pilot project characterized dorsolateral prefrontal cortex gene expression and the relationship to cellular changes in alcohol dependence. Methodological progress was been made, optimizing collection and analysis of RNA, resulting in a publication on prefrontal cortex gene expression in major depression. Data from alcohol dependent patients are still being analyzed.
G. Mason. Evaluation of Alcohol Effects on Glutamate and GABA neurotransmission in FHP and FHN Subjects using [1H] and [13C] MRS.
This pilot project evaluated changes in brain GABA and glutamate levels and turnover in response to an acute ethanol challenge in family history positive and family history negative healthy adults. This project made significant methodological progress, refining the ethanol clamp procedure for use in the magnet. Using 1H MRS during ethanol infusion, the investigators observed a rise in GABA followed by a return to baseline, as well as a decrease in myo-inositol levels. Data analyses are ongoing.