May 11-13, 1998
Washington, DC

 U.S. Department of Health and Human Services
Public Health Service
National Institutes of Health

NEUROSCIENCE AND BEHAVIOR PROGRAM

MOLECULAR AND CELLULAR EFFECTS OF ALCOHOL

ADDICTION AND OTHER BEHAVIORS IN ANIMAL MODELS

STUDIES OF ACUTE AND CHRONIC EFFECTS OF ALCOHOL IN HUMANS

COGNITIVE/BEHAVIORAL/STRUCTURAL DEFICITS

APPENDICES

The National Institute on Alcohol Abuse and Alcoholism's (NIAAA) Subcommittee for the Review of the Extramural Research Portfolio for Neuroscience and Behavior met on 11-13 May 1998. The charge to the Subcommittee was to examine the appropriateness of the breadth, coverage, and balance of the neuroscience and behavior research portfolio, identifying research areas that are well covered and others which are either under-investigated or which otherwise warrant significantly increased attention. The Subcommittee was asked also to provide specific advice and guidance on the scope and direction of the Institute's extramural research activities in the neuroscience and behavior area.

The Subcommittee for the Review of the Extramural Research Portfolio for Neuroscience and Behavior consisted of two NIAAA Advisory Council co-chairs and an advisory group of 18 individuals. Fifteen of these individuals have demonstrated expertise in alcohol-related areas and three individuals have demonstrated expertise in non-alcohol-related areas (see Appendix A).

The review process was initiated by having experts (see Appendix B) in neuroscience and behavior prepare written assessments of the state of knowledge, gaps in knowledge, and research opportunities. NIAAA program staff (see Appendix C) presented the current extramural portfolio, categorized into the areas of basic neuroscience research, molecular adaptive responses, neuroendocrine system, studies of the acute and chronic effects of alcohol in animals and in humans, cognitive/behavioral/structural deficits in humans, and training and career development. All information was shared with experts, selected NIAAA staff, and the co-chairs and advisory group before the meeting.

A summary of FY97 awards in neuroscience and behavior is detailed below.

*Seven of 14 centers have neuroscience and behavior components; five of these estimate > 50% is invested in neuroscience and behavior.

 On 11-13 May 1998, experts and NIAAA program staff made abbreviated presentations of their material followed by discussion among all of the participants, including representatives from other NIH Institutes and guests (see Appendix D). After completing this process, the co-chairs and advisory group, with input from the experts, delineated the following list of research priorities, in order of importance.

1. Increase emphasis on mechanisms associated with various models of neuroadaptation (sensitization, tolerance, dependence, withdrawal, recovery), at multiple levels of analysis, i.e.,molecular, cellular, and whole animal, including human and nonhuman primates.

2. Emphasis on new genetic techniques that have great potential for understanding the effects of alcohol on brain and behavior. Techniques include transgenics, knockouts, knockins, antisense oligonucleotides, tissue-specific expression, and viral-mediated genetransfer. Enhance development and availability of these genetically altered animals may have to be subsidized by NIAAA.

3. Increase emphasis on delineating the cellular and molecular mechanisms of neuropathophysiology and neuropathology resulting from exposure to ethanol. This should be accomplished in areas of the brain previously demonstrated to be highly sensitive to the effects of ethanol, e.g., hippocampus, frontal cortex, cerebellum, accumbens, hypothalamus, and ventral tegmental region.

4. Some of the research questions in neuroscience and behavior require collaborations by experts in a number of different disciplines. Moreover, involving the best and most appropriate scientists often requires inter-institution collaboration. Consequently, NIAAA is encouraged to use whatever funding mechanism(s) that will facilitate such collaborative studies.

   Other areas mentioned, in order of importance included:

5. Support multisite, prospective longitudinal studies designed to examine vulnerability and protective effects of alcohol on brain and behavior. Specified individuals should be examined longitudinally with the techniques of imaging, electrophysiology, and neuropsychology. Alcohol, other drugs, and neuroendocrine challenges should be conducted when ethically appropriate.

6. Effects of ethanol on intracellular signaling systems is under represented in the portfolio, especially given the recent explosion of information on intracellular signaling.

7. Increase the number of animal neurobehavioral phenotypes studied, e.g., animal analog of impulsive or disinhibited behaviors, and their interactions with alcohol.

8. Develop and enhance availability of new imaging techniques, with consideration of a dedicated imaging center.

These areas of importance were derived from a list of 22. The remaining 14 are listed by topic without regard to priority.

• There should be an increased emphasis on training in the neurosciences, especially mentored training.
• Develop and increase availability, at reduced cost, of alcohol-related ligands and reagents.
• NIAAA should assist investigators in gaining access to alcohol-related investigational new drugs.
• Develop an informatics type of database for alcohol research, including information on molecular, cellular, genetic, behavioral, and pathologic effects of alcohol. Each database would be designed to provide information in a format that would be useful to investigators addressing specific and complex questions.
• Enhance support for alcohol-related neuroendocrine research at all levels of analysis. Representative topics include responses to stress and alcohol/neuroendocrine/immune interactions.
• Dose-response relationships are particularly informative. It is noted that the effects of moderate doses of alcohol on the CNS are under investigated, particularly in animal models and humans.

• Effects of ethanol on lipid-protein interactions should be emphasized, while effects of ethanol on lipids alone are of more limited value. Particular importance should be placed on the identification of proteins with reasonable sensitivity to ethanol that can readily be studied in the presence of different lipids.
• Develop a program for the structural analyses of ethanol/protein interactions, including molecular modeling as well as physical measurements. This could be accomplished by establishing dedicated groups with equipment and facilities or by supplementing existing grants to allow incorporation of structural initiatives.

• Increase utilization of nonhuman primate models, including studies of the effects of alcohol on adolescent and aged animals.
• Increase support for neurobiological studies of acute and chronic alcohol exposure in adolescent animals.

• Establish an alcoholic brain bank, perhaps by supplementing an existing bank. Accurate information on diagnoses and current drug use and concomitant medical conditions are essential. Antemortem brain structure/function studies would be valuable.
• Studies of alcohol-related nosology and concomitant comorbidity with other psychiatric and brain disorders, including dementia, would be informative.
• Increase emphasis on alcohol and sleep research.
• Studies of neurobiological factors associated with relapse are important.

Additional gaps in knowledge and research opportunities were determined by experts in each of the areas covered and are listed in the text of the report.

This overview will provide information on overall programmatic balance of the portfolio, with all analyses based on awards made in FY97. Specific aspects of the portfolio will be presented in other reports. The overall portfolio currently consists of 121 grants at a total cost of $21,677,142. The balance of neuroscience grants to behavior grants is almost equal. Most of the research funded is basic research, with very little of the portfolio considered applied research. Those few grants that are applied research relate to the development of medications at the preclinical or early clinical level.

About 80% of the grants, representing 77% of the awards, used animals and 20% used humans, representing 23% of the awards. About 70% of the grants were in vivo studies, representing 68% of the awards. Animal and human studies represent 62% of the grants, with molecular and cellular studies reflecting the remainder in approximately equal amounts.

The following list of priorities represents common themes among various initiatives.

• Identify relevant targets of ethanol in the brain;
• Identify neural circuits underlying the behavioral effects of ethanol;
• Determine what neurobiological actions of alcohol are responsible for its acute and chronic behavioral effects;
• Determine how the effects of alcohol on the brain and behavior contribute to the development of alcoholism;
• Determine neurobiological and behavioral factors that render adolescents more vulnerable than adults to abuse alcohol and become alcoholic;
• Develop prototypic compounds for potential therapeutic development.

The last recommendation evolves from the need to translate basic research findings into clinical applications. To that end, a Medications Development Working Group was recently formed to determine if research findings from basic preclinical work could provide a basis for developing potential agents for clinical trials to treat alcoholism. A short-term goal is a workshop to bring together individuals from academia, industry, and government to build bridges among the groups, review the process by which compounds are developed into drugs for clinical trials, and solicit ideas about how NIAAA can help facilitate this process.

TRAINING AND CAREER DEVELOPMENT PROGRAMS IN NEUROSCIENCE AND BEHAVIORAL RESEARCH
(Walter A. Hunt, Ph.D.)

Training of new investigators is supported through several mechanisms, depending on the educational level and experience of the applicant. Much of the program is based on individual fellowships and training grants. The remainder of the program supports scientist development awards at different levels of experience.

Forty-six competitive and noncompetitive awards were funded in FY97. Of those, 19 were individual fellowships, 10 were training grants, and 17 were scientist development awards. Thirty awards supported neuroscience research and 16 supported behavioral research.

Individual Fellowships: The balance between predoctoral and postdoctoral awards is fairly even, with a slightly greater number for predoctoral awards. Based on NIH policy, the commitment to individual fellowships relative to training grants should be at least 15% of the available funds. In FY97, the figure for NIAAA was 19%.

Only one of the awards is for a potential clinical researcher. Four involve neurotransmitter receptors, three use genetic approaches, two study ontogenetic differences in the effects of alcohol, three examine the motivational effects of alcohol, four on the central control of alcohol reinforcement, one on stress and neurosteroids, and two are minority predoctoral fellowships.

Training Grants: The ten training grants support 55 slots for 21 predoctoral and 34 postdoctoral trainees. The relative balance between neuroscience training slots and behavioral training slots is 26 to 31. Three grants educate trainees in using genetic approaches to discover the mechanisms underlying actions of alcohol on the brain, four deal with basic neurochemical mechanisms, two with neurotoxic actions of alcohol, one with brain imaging, and three with behavioral studies. Two training grants primarily use human subjects.

Scientist Development Awards: Of the 14 grants, most were mentored awards, and almost half were to junior, mentored investigators. All of the mentored awards support investigators in neuroscience research. Only two awards support investigators in clinical research. Most of the these investigators study basic actions of alcohol on neurotransmitter receptors or signal transduction systems. Two grants have behavioral components.

Recruiting efforts involve staff contacts with potential applicants at scientific meetings. In addition, site visits of NIAAA-funded training grants were undertaken to introduce trainees to the grant process and inform them about the benefits of individual fellowships and mentored scientist development awards. These visits resulted in increased applications but have been discontinued because of limited travel funds.

The training programs are fairly mature, with most mechanisms of training adequately represented. However, increased training of clinical investigators could provide an additional pool of needed scientists to pursue alcohol research with human subjects.

Gaps in Knowledge and Research Opportunities (David M. Lovinger, Ph.D.)

• A greater emphasis should be placed on describing alcohol-induced alterations in the molecular structure and dynamics of neural proteins that are sensitive to the effects of alcohol.
• Analysis of relationships between alcohol sensitivity and protein domain structure should be encouraged in order to characterize the molecular sites of alcohol actions
• Changes in protein function associated with exposure to alcohol are important to delineate.
• It is important to determine alcohol effects on synaptic transmission using techniques that infer a pre- or post-synaptic locus of effect. Specific synaptic proteins should be identified.
• A greater emphasis should be placed on discerning the effects of alcohol on the neuro-physiology of the ventral tegmental area, amygdala, hypothalamus, cerebellum, and prefrontal cortex. 

Gaps in Knowledge and Research Opportunities (Steven N. Treistman, Ph.D.)

• Increased emphasis on protein function as the measure of lipid perturbations will be informative.
• The function of a particular protein should be well characterized before attempts are made to assess perturbations of function by alcohol. Ideally, this should include information in native membranes as well as in artificial bilayers.
• Reasonable (physiological) concentrations of alcohol should be used in determining its effects.
• Studies should be integrated across multiple levels of analysis:

Continue to study the significant role of lipids in the compensatory responses of cells exposed to alcohol.

NIAAA BASIC NEUROSCIENCE RESEARCH PORTFOLIO
(Yuan Liu, Ph.D.)

In FY97, the NIAAA Basic Neuroscience Research Program funded 35 extramural grants for a total of $5.5 million. Of these, 30 were basic research project grants, and five were career development awards.

This program supports a wide variety of investigations that explore different effects of alcohol on the brain at multiple levels of analysis and employ a number of different neuroscience techniques. Several different molecular targets are being examined, as are different mechanisms hypothesized to underlie the actions of alcohol in the brain.

• More than half of the total awards in the portfolio examine the acute effects of alcohol on the brain, about one-third study the chronic effects, and the remainder investigate both short- and long-term effects.
• Only a few research projects study directly the mechanisms underlying various phases of alcohol-related problems, including tolerance and withdrawal, whereas the majority of projects study the direct interactions between alcohol and candidate targets.
• About 80% of investigators utilize multi-disciplinary approaches, primarily a combination of electrophysiological and molecular biological techniques.
• The number of grants by level of analysis - molecular, cellular, and neural circuitry - are detailed below. These categories are not mutually exclusive, as some investigators are studying the effects of alcohol at multiple levels.

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• Nearly 80% of the research teams use in vitro preparations. Among the projects studying molecular targets of alcohol, about 80% of the experiment use recombinant receptor-channel proteins.
• Identifying the molecular targets and elucidating the mechanisms underlying the interactions between alcohol and these targets has been the research focus of more than half of the basic neuroscience research portfolio. The grant distribution by molecular target is summarized below.

• Identifying the cellular targets of alcohol and their distribution in the brain is another challenge for alcohol researchers. Major areas of the brain that are under investigation by research projects supported by this program are listed below. (Note: some grants are counted more than once since they are studying multiple regions in the brain).

Alcohol, unlike most other highly abused substances, does not act on a single specific target in the brain. Instead, it interacts with many targets, such as neurotransmitter receptors and voltage-gated ion channels on nerve cells. A major challenge confronting molecular studies is the lack of uniform effects of alcohol on various cell types in different regions in the brain. Several complementary working hypotheses address the cellular and regional specificity of alcohol. The first postulates that alcohol directly interacts with specific amino-acid residues or domains of the target proteins. The second proposes that expressions of particular receptor subunit combinations contribute to the different degrees of alcohol sensitivity in different neurons. A more recent hypothesis suggests that post-translational modifications, such as the phosphorylation status of a target protein, can determine sensitivity to alcohol.

Direct molecular Action Sites (8 grants) The majority of research projects within this category are attempting to identify the sites of alcohol action on target molecules, including voltage-gated CA⁺⁺ and K⁺ channels and ACh, GABA_A, NMDA, and glycine receptors. One working hypothesis is that alcohol alters channel kinetics, such as channel open time, channel closing time, and desensitization status of molecular targets. Other investigators study protein targets in their native environments. The vast majority use a combination of electrophysiological and molecular biological approaches to test alcohol effects on recombinant proteins expressed in Xenopus oocytes or transfected mammalian cell lines. Two research groups introduced a state-of-the-art approach - the chimeric receptor technique - to alcohol research. Chimeric receptors consist of complementary parts of two target proteins that give opposite responses to alcohol. By using a well-designed set of chimeras, the process of locating the sites of action can be significantly accelerated.

There has been a long debate over the question of whether lipid, protein, or the interface between them is the site of action of alcohol. Although increasing evidence suggests that membrane proteins are the direct targets, the role of the lipid environment in mediating effects of alcohol is likely to be important. Two projects are attempting to further clarify this challenging and confusing issue. Both projects use preparations that incorporate well-characterized protein candidates into a lipid bilayer. In this environment, each lipid component is known and can be individually manipulated.

Subunit Composition (8 grants) Both voltage-fated and ligand-gated channel proteins are composed of multiple subunits. The putative molecular structure of the superfamily of ligand-gated channels/neurotransmitter receptors is a pentamer consisting of five either identical or distinct subunits. It is evident that the number of possible combinations of subunits is quite large. In addition, an individual neuron can express multiple types of a given receptor, based on the combination of different subunits. When considering the many different regions in the brain, the patterns of expression of those subunit compositions can be exceedingly complex.

Currently, eight research groups supported by this program are testing the "subunit composition" hypothesis. The two major approaches that are investigating the structure-function relationship use either a) recombinant proteins produced in various expression systems or b) natural proteins expressed in intact neurons. Several research groups are taking advantage of some of the newest pharmacological tools. The binding selectivity to subunits of these agonists or antagonists appears to correlate with alcohol specificity of certain subunits. Other investigators are using different approaches, such as specific antibodies against the candidate subunits. A novel technique - the single cell RT-PCR method - has recently been introduced to alcohol research. This sophisticated method, when properly used, can identify the profile of the subunits at the mRNA level in an identified cell.

Protein Modifications (2 grants) Previous observations suggest that phosphorylation/dephosphorylation status of some target proteins, such as GABA_A, NMDA, and 5-HT₃ receptors, might be important for understanding the interactions between alcohol and these targets. Two research projects are exploring this hypothesis by applying a combination of electrophysiological, biochemical, and molecular biological techniques on recombinant receptors.

Cellular Level (7 grants)

Two projects are examining the effects of alcohol at the single cell level. One project is using the brain slice preparation and electrophysiological recording techniques to study the acute effects of alcohol. A second study is using both brain slice and in vivo preparations to explore the chronic effects of alcohol on the spontaneous activity of dopaminergic cells in the ventral tegmental area (VTA).

Most projects are focused at the synaptic level. For example, one investigator is using an in vitro NMDA synapse model to identify cellular mechanisms underlying the development of acute tolerance to alcohol. Another investigator is using both traditional and organotypic slice preparations to explore the alteration of voltage-gated Ca⁺⁺ channels following acute and chronic alcohol exposure.

Several projects are investigating the effects of alcohol on synaptic plasticity. One project is testing the hypothesis that subcortical inputs to the dentate gyrus mediate the acute actions of alcohol on both short- and long-term plasticity in hippocampus. Another project is exploring a possible role for the amygdala in mediating the acute effects of alcohol on synaptic plasticity. One study uses hippocampal activity-related spatial memory as a model system to test the effects of alcohol on different age groups of animals.

 Neural Circuitry Level (3 grants)

Research at the neural circuitry level has not yet been intensively studied. Investigators supported by this program have recently developed several novel methods that are further extensions of the traditional extracellular single-unit recording techniques. One uses a multi-electrode, single-unit recording apparatus that can perform simultaneous recordings of neuronal activities from different areas of a defined neural circuit during a specific behavioral paradigm. This allows the analysis of spatial/temporal pattern changes of neuronal firing related to alcohol-induced behaviors. Another new method combines in vivo microdialysis with electro-physiological and behavioral techniques. This provides a means of locally delivering alcohol and other pharmacological agents to individual neurons, simultaneously recording neuronal activity, and collecting neurotransmitters released from the same neuron in real-time, during ongoing behaviors.

• Emphasize less-studied molecular targets (e.g., serotonin receptors, peptide neurotransmitters, neurotransmitter transporters);
• Identify action sites of alcohol at the level of single amino acids;
• Examine channel kinetics of target proteins at the single-channel level;
• Study well-characterized protein targets in a known lipid environment.

• Emphasize studies of natural receptors in intact neurons, rather than focusing specifically upon recombinant receptors;
• Identify subunit composition profiles by

• Characterize role of subunit composition as mediators of alcohol's effects by

• Examine a larger variety of protein kinase pathways;
• Investigate the role of protein phosphorylation and alcohol interactions, using phosphorylation, state-specific antibodies and genetically engineered animals;
• Explore mechanisms other than phosphorylation modifications.

• Investigate mechanisms of alcohol's actions on neuronal firing rate at molecular and cellular levels;
• Determine the effects of alcohol on synaptic transmission (e.g., neurotransmitter release statistics and quantal efficiency, presynaptic modification, postsynaptic regulation);
• Characterize the effects of alcohol at integrated levels (e.g., interactions between excitatory and inhibitory receptors at single cell and pathway levels);
• Study the effects of alcohol on synaptic plasticity, using methods such as minimal stimulation, stimulation-induced miniature potential, and quantal analysis;
• Identify effects of alcohol on synaptic plasticity at locations other than hippocampal NMDA-dependent LTP (e.g., non-NMDA-dependent hippocampal LTP, cerebellar LTD and LTP, and synaptic plasticity in other areas of the brain, including the mesolimbic system, basal ganglia, thalamic relays, neocortex).

• Use single or multiple single-unit recordings in behaving animals to associate effects of alcohol directly to behavior;
• Use combinations of neurochemical (e.g., iontophoresis, microdialysis, and voltammetry) and electrophysiological recordings in behaving animals to associate neurochemical and neurophysiological events with alcohol-induced behaviors;
• Encourage utilization of sophisticated optical recording techniques and voltage-sensitive and CA⁺⁺ sensitive dyes in brain slice preparations to study the activity of large neural networks under the influence of alcohol, as well as studies of intrinsic optical activity using the newest computer algorithms coupled with modern photorecording techniques;
• Use computational modeling methods in combination with physiological and behavioral empirical studies to explore how neural circuitry synchronizes functions during alcohol-induced behaviors.

EFFECTS OF ALCOHOL ON THE NEUROENDOCRINE SYSTEM

Gaps in Knowledge and Research Opportunities (Catherine Rivier, Ph.D.)

• Despite the involvement of CRF in many alcohol-related disorders, and the fact that this peptide appears to be a reinforcer of drug abuse, the number of studies supported by NIAAA that investigate its synthesis, release, and effects on endocrine function in general, and the HPA axis in particular, is quite low.
• A greater emphasis should be placed on studies investigating the functional interactions between CRF and neurotransmitters involved in drug-seeking behavior, reinforcement, and relapse.
• Exposure of adult mice with a conditional null mutation for the CRF or CRF receptor gene to alcohol would provide valuable information.
• Exposure of pregnant dams lacking the CRF or CRF-R1 gene to alcohol could provide useful information on the endocrine, behavioral, autonomic, and immune pathologies observed in FAS.
• Studies of the functional interactions between alcohol and nitric oxide/carbon monoxide, and with NF-_KB are important.
• A good model of isolated cells (either primary culture or immortalized cells) that produce CRF is needed.
• The development of potent CRF antagonists that are long-lasting and receptor specific should be encouraged.
• NIH-distributed reagents for the measurement of plasma ACTH and corticosterone levels in rodents are urgently needed.
• It would be useful to have access to different strains of alcohol-preferring rats and mice.

ALCOHOL AND THE NEUROENDOCRINE SYSTEM
(Sam Zakhari, Ph.D.)

In FY97, the neuroendocrine portfolio consisted of 14 grants totaling $2.1 million. With the exception of one human study, all remaining 13 grants study alcohol effects on the endocrine system using experimental animals. Of the 14 grants, five focus on the Hypothalamic-Pituitary-Adrenal (HPA) axis, five on the Hypothalamic-Pituitary-Gonadal (HPG) axis, two on the endocrine regulation of immune function, one on hormonal regulation of alcohol metabolism, and one on enkephalin gene expression.

Twelve of the 14 grants are categorized as basic research while the remaining two are considered applied research. Two grants focus on response to stress, and all 14 grants study alcohol at the cellular and molecular level.

Studies on the HPA Axis (5 grants)

Studies on the HPG Axis (5 grants)

Studies on Endocrine Regulation of Immune Function (2 grants)

Studies on Endocrine Regulation of Ethanol Metabolism (1 grant)

Dihydrotestosterone (DHT) suppresses ADH transcription in hepatocytes, possibly explaining the higher ethanol elimination rates in women. The suppression of rat liver ADH activity by DHT was associated with a decrease in ADH protein.

Studies on the Effects of Ethanol on Enkephalin Gene Expression (1 grant)

The ultimate goal of this grant is to study the role of enkephalins in alcohol-seeking behavior. The immediate focus is on the mechanism by which members of the steroid-retinoid receptor superfamily modulate expression of the preproenkephalin gene.

More research is encouraged in the following areas:

• alcohol and neuroimmunomodulation;
• role of peptides in alcohol intake;
• alcohol and the Hypothalamic-Pituitary-Thyroid axis;
• alcohol and growth hormone.

Gaps in Knowledge and Research Opportunities (Paula L. Hoffman, Ph.D., A. Leslie Morrow, Ph.D., Tamara Phillips, Ph.D., and George R. Siggins, Ph.D.)

• It is important to establish the relationship between observed and neurochemical/ molecular changes after chronic ethanol treatment and the occurrence of neuroadaptive events, i.e., tolerance, dependence. Studies are needed that are interdisciplinary and translational - studies at the molecular/cellular, brain slice and whole animal levels, as well as human studies.

  Examples: Studies of synaptic neurophysiology and neural circuitry

  • after chronic ethanol exposure, using techniques to separate pre- and postsynaptic changes. Use of models such as slices and explants, with intact neurophysiology; use of animal models to observe neuronal ensemble activity.
  • Molecular mechanisms of changes in receptors/ion channels after chronic ethanol treatment; subunit composition, post-translational modification, receptor localization.
  • Functional importance of changes in gene expression for neuroadaptation; focus on gene expression in neural circuits that affect pharmacological responses to ethanol.
  • Studies of the interconnections among various signal transduction systems that influence cell survival, differentiation and responses to stress and other external stimuli, and the importance of these systems for neuroadaptation to ethanol.

• It is necessary to determine the relationship between tolerance or sensitization to the reinforcing/aversive effects of ethanol and ethanol intake. A corollary is whether tolerance or sensitization to the reinforcing effects of ethanol do, in fact, develop.
• Increased emphasis should be placed on the application of simple (e.g., invertebrate) models, that have been used to study learning and memory, to the study of ethanol-induced neuroadaptation (tolerance and dependence).
• Neuroadaptation after moderate drinking (events taking place in the brain during the transition from moderate to abusive drinking) should be explored. Biochemical and behavioral studies of the effects of the full range of alcohol-doses/concentrations should be carried out, to determine thresholds for neuroadaptive effects of ethanol, and J- or U- shaped dose-response curves.
• Tools are needed to study neuroadaptation, including genetic models such as transgenics, knockouts, selected lines, recombinant inbreds and congenics, in order to test hypotheses of mechanisms of neuroadaptation and identify genes involved in these processes. Animal models should also include non-human primates for behavioral studies.
• Emphasis should be placed on application of discoveries regarding molecular and neurochemical mechanisms of neuroadaptation to ethanol to the treatment/intervention arena.

Gaps in Knowledge and Research Opportunities (Fulton T. Crews, Ph.D.)

• It is important to determine the region-specific neurotoxic effects accompanying extended alcohol exposure as well as those accompanying withdrawal.
• Although the loss of white matter has been documented to accompany chronic alcohol exposure, there has been relatively little research into mechanisms.
• It is recommended that a human alcoholic brain bank be established in the United States.
• Although women represent approximately 25% of alcoholics and may suffer greater pathology, they have been understudied. Moreover, data regarding the role of gender might provide important fundamental insights into mechanisms of brain damage.
• A significant gap in knowledge is the relationship between acute excessive stimulation of neurons by glutamate and delayed neuronal death.
• Why specific brain regions are particularly sensitive to chronic alcohol exposure is an important question that needs to be answered.
• Oxidative stress is increased in brain by alcohol and is often postulated to contribute to brain damage. There are, however, relatively little data for or against this hypothesis.
• An important area of research is to determine the role alcoholic brain damage plays in the progression to alcoholism, recovery from alcoholism, and other behaviors associated with alcoholism. Understanding the relationship of neuropathology to behavioral pathology is essential and fundamental to improving prevention and treatment. 

PROGRAM IN MOLECULAR NEUROPHARMACOLOGY
(Robert W. Karp, Ph.D.)

In order to identify the primary effects of chronic alcohol exposure, investigators studying neuroadaptation and neurotoxicity have examined alcohol-induced molecular changes in cellular components. Some of these studies can be performed in intact animals, thereby permitting correlation with alcohol-induced changes in systemic neural function and behavior. Other studies can be performed only in cultured cells. While studies in cultured cells provide information about some molecular processes that can't be assayed in intact animals, it is often difficult to evaluate their behavioral significance. Moreover, for some measures that can be made both in cultured cells and whole animals, different changes are observed in these two experimental systems. For this reason, many investigators try to confirm cellular observations in intact animals whenever possible.

NIAAA supports a number of studies, most of them in intact animals, of molecular changes associated with withdrawal from chronic alcohol exposure. The largest group of these studies is directed at GABA_A receptors, focusing on changes in brain-regional distribution and pharmacological properties (including interactions with neurosteroids), and the underlying causes of such changes. The second largest group of studies focuses on similar issues related to NMDA receptors. Other studies examine 5-HT receptors and their downstream signaling (especially their relationship to anxiety during withdrawal), non-NMDA glutamate receptors, fos-like immunoreactivity, mechanism of upregulation of voltage-gated Ca⁺⁺ channels, and free radical accumulation due to oxidative stress. Of the 11 projects in this category, four include studies on cultured cells.

NIAAA supports studies of a variety of molecular changes induced by chronic alcohol exposure in various types of neuronal cell lines. While the precise relationships of these changes to alcohol-induced physiological changes in animals are not yet understood, they could potentially be related to tolerance or dependence. These studies include heterologous desensitization of signaling from purine receptors, intracellular translocation of protein kinase A, global changes in gene expression, and the normal physiological role of a phosducin-like protein, whose levels are raised in response to chronic alcohol exposure.

Most of the studies of molecular changes associated with neurotoxicity involve a combination of experiments on both intact animals and culture cells. The largest group of such studies focuses on alcohol-induced changes in brain-regional distribution of neurotrophic factors and their receptors, the role of neurotrophic factors in protection from alcohol-induced disruption of calcium homeostasis, and the mechanism of enhancement of neurotrophin-induced neurite outgrowth by alcohol. The second largest group of studies is directed at NMDA receptors, focusing on changes in brain-regional distribution and pharmacological properties, underlying causes of such changes, and changes in downstream signaling (especially induction of nitric oxide synthase). A small group of studies is concerned with alcohol's enhancement of pro-oxidant-induced membrane lipid peroxidation and changes in gene expression. Finally, individual projects study, variously, the mechanisms of alcohol-induced changes in the levels and/or activities of the Na-Ca exchanger and metabotropic glutamate receptors.

Recommendations

The projects described above study molecular changes induced by alcohol in intact animals and/or cultured cells. Alcohol-induced molecular changes can be correlated with behavioral and physiological changes in animals, whereas molecular changes in cultured cells cannot be directly correlated. Investigators typically hypothesize that the molecular changes they observe actually mediate particular behavioral and physiological changes. Since chronic alcohol exposure induces a multitude of molecular, physiological, and behavioral changes, correlative evidence is insufficient to prove that a particular molecular changes mediates a particular physiological or behavioral change. Emphasis should be placed on experiments in which an investigator specifically blocks either the alcohol-induced molecular change under study, or the function of the molecule whose disposition is changed by alcohol, and then observes whether this intervention also blocks the behavioral change under study. Alternatively, the investigator can induce the molecular change by some means other than alcohol treatment, and observe whether the behavioral or physiological change still occurs. Only about one fifth of the projects described above attempt to perform such an intervention.

ADDICTION AND OTHER BEHAVIORS IN ANIMAL MODELS

Gaps in Knowledge and Research Opportunities (Kathleen A. Grant, Ph.D.)

• The initiation of alcohol seeking needs additional exploration with new paradigms using animals models. There is also a lack of studies investigating the possibility of protecting the individual from the development of alcohol-seeking behavior.
• Additional studies are needed to characterize the interrelationships among oral self-administration of alcohol and preference conditioning studies.
• Studies are needed to understand the apparent differences between rats and mice in sensitivity to alcohol's rewarding effects in the place-conditioning paradigm.
• Combine sophisticated neuroscientific procedures with sophisticated behavioral procedures.
• As candidate genes become identified and gene products known, there will be a need to have ligand development to target potential sites of action in rats, monkeys, and humans.
• Increase the use of monkey models for noninvasive imaging procedures related to alcohol abuse. Monkeys are important models because of their compliance in drinking excessive quantities of alcohol, neuroanatomy, brain size, complex behavior, neuroendocrine system, and longevity.
• Cloning techniques of nuclear transplantation from adult monkey cells should at least be given thoughtful consideration. Such approaches could be used to address the genetic basis of complex behavioral responses associated with the development of alcohol abuse and alcoholism.
• Gender differences in the behavioral neuroscience of alcohol using animal models is understudied.
• The role of stress in alcohol's behavioral effects requires more sophisticated approaches.
• Depression is a risk factor that animal models in alcohol abuse have not addressed extensively.
• The age at which individuals start regular, heavy use of alcohol has recently been reported to predict the occurrence of alcohol dependence. The macaque monkey has at least a 12-month adolescent phase, which allows a window of opportunity to design appropriate experimental manipulations.
• The concurrent use of alcohol and other drugs of abuse has received limited attention.

Gaps in Knowledge and Research Opportunities (Friedbert Weiss, Ph.D.)

• A systematic research effort at the behavioral, neurochemical, cellular, and molecular levels will be needed to identify and characterize neuroadaptive changes and homeostatic disturbances during protracted withdrawal, and to determine their motivational significance in appropriate models of alcohol-seeking behavior and relapse.
• It is essential to develop new, or modify existing animal models of self-administration suitable for the longitudinal monitoring of neuroadaptive or homeostatic changes during the development of chronic alcohol drinking and over the course of withdrawal and intervening periods of abstinenc
• Effective procedures or models are needed that permit investigation of behavioral plasticity such as the development of associations between alcohol's subjective rewarding effects and relevant environmental stimuli that may trigger relapse during abstinence.
• It is important to examine the role of stressful stimuli on the reinstatement of alcohol-seeking behavior at different stages of the protracted abstinence phase and to determine whether vulnerability to relapse becomes exacerbated with repeated withdrawal and abstinence episodes.
• Research strategies need to be developed to identify neural or molecular mechanisms mediating the switch or transition from nondependent social drinking to a state of dependence.
• There is a need to better model various aspects of alcoholism in laboratory animals. This includes, in particular, voluntary drinking models that promote spontaneous and persistent intake of high alcohol concentrations or volumes without prior need to induce dependence. Such models will represent an important step toward the need for studying critical issues such as the mechanisms underlying the switch from nondependence to dependence, and the reinforcement contingencies that maintain alcohol consumption in dependent individuals.
• There is a need to study neurotransmitter circuitries and interactions mediating ethanol reward in the dependent and post-dependent state. While there is increasing evidence that the acute reinforcing actions of ethanol depend on multiple neurochemical systems and their interactions, little, if anything is known about these mechanisms in dependent individuals. In this context, it will also be beneficial to incorporate multiple systems approaches in medication development efforts and to examine the therapeutic efficacy of combinations of relevant pharmacological agents.
• It is important to clarify the role of dopamine in alcohol reinforcement. This need involves both a better understanding of mechanistic questions such as, for example, how ethanol activates mesolimbic dopamine transmission, and a better understanding of the precise role of dopamine in various aspects of ethanol-seeking behavior.
• An important emerging issue is the role of sensitization in ethanol reinforcement, genetic preference, and dependence. In particular, the following questions will require clarification: (1) does ethanol sensitization augment the reinforcing efficacy or potency of ethanol; (2) does ethanol sensitization promote a heightened motivational state with increased ethanol-seeking behavior ("craving") without necessarily altering the reinforcing efficacy of ethanol; (3) is ethanol sensitization a correlate of aversive or side effects of repeated ethanol intoxication; and (4) if so, is ethanol sensitization negatively linked with ethanol preference or vulnerability to abuse?
• It is important to better understand the mechanisms of kindling or sensitization of withdrawal seizures at the molecular, cellular, and biochemical levels. This includes efforts to define sensitization of psychological components of withdrawal (e.g., anxiety, affective changes), to characterize possible changes in the subjective perception of ethanol's intoxicating actions (i.e., ethanol's discriminative stimulus effects), to determine whether multiple ethanol withdrawal experiences alter the reinforcing properties of ethanol, and to examine potential changes in susceptibility to ethanol neurotoxicity and associated cognitive impairments. Finally, it is important to examine whether conditioning factors contribute to the kindling phenomenon.
• The field would benefit from the development of genetic models of alcohol-seeking behavior selected on the basis of motivational measures such as operant responding or even progressive ratio performance during dependence.

• Further research is needed to examine how sensitivity to various effects of alcohol differs in adolescents from other aged organisms, and to explore the neural mechanisms underlying these ontogenetic effects.
• Research to examine the reinforcing efficacy of alcohol and other reinforcers during adolescence is particularly critical, given evidence for alterations during adolescence in forebrain regions modulating the reward efficacy of reinforcing drugs.
• Stress effects on alcohol self-administration during adolescence should be examined, along with fundamental research examining the relationships among hormonal, behavioral, and neural responses to stressors throughout ontogeny.
• In addition to further research examining normal brain function in adolescence, research is also needed to determine factors that trigger ontogenetic changes in brain function, alcohol sensitivity, and responsivity to stressors during the adolescent period.
• It is critical to determine whether early exposure to alcohol increases the likelihood for later alcohol problems, and if so, why such early exposure should be so predictive.

STUDIES OF THE ADDICTION PROCESS AND OTHER BEHAVIORS IN ANIMAL MODELS(Ellen D. Witt, Ph.D.)

Animal studies, representing about $6 million, are focussed largely on neural mechanisms of sensitization, tolerance, dependence, withdrawal, relapse, and more recently the reinforcing and hedonic effects of alcohol that can lead to alcohol-seeking behavior and excessive drinking. Animal models have also been constructed to study innate neural and behavioral traits as well as the acute and chronic effects of alcohol on behaviors such as learning, memory, and aggression.

The animal portfolio has been divided conceptually into five broad scientific categories.

1. Alcohol-Seeking Behavior/Hedonic Effects, Neural Circuitry, Neurotransmitters

Behavioral Paradigms/Phenotypes: More studies are needed in the areas of tolerance and
acute withdrawal and development of temperament phenotypes.

Gaps in Knowledge and Research Opportunities (Peter R. Finn, Ph.D.)

• Research should be undertaken on the effects of early exposure to alcohol (pre-adolescent/adolescent) and the development of disinhibited traits using longitudinal designs.
• It is important to conduct cross-sectional studies of the effects of alcohol challenge on disinhibited/impulsive behavior (and factors associated with such behavior), using multimethod measurements to capture the multidimensional nature of behavioral disinhibition and controlling for important sources of individual differences such as pre-existing disinhibited traits, family history of alcoholism (and antisocial behavior), drinking history, and level and limb of the blood alcohol curve.

Gaps in Knowledge and Research Opportunities (John H. Krystal, M.D.)

• More emphasis should be placed on developing drugs that block the euphoric effects of alcohol.
• NIAAA should assist investigators in gaining access to alcohol-related investigational new drugs.
• Increased emphasis should be placed on studying the neurobiology of triggers for relapse to alcohol use, particularly alcohol-related cues; priming effects of alcohol consumption on subsequent drinking; and the interactive effects of stress (negative mood induction) and alcohol cues.
• Alcohol research should more fully integrate functional neuroimaging techniques in order to facilitate the study of neural circuitry underlying craving and factors related to alcohol consumption.

Gaps in Knowledge and Research Opportunities (Gary Wand, M.D.)

• It is important to better understand the relationships between specific neurotransmitter input to hypothalamic CRH neurons as a function of family history of alcoholism and to estimate their relevance to vulnerability for alcoholism. More specifically, dose-response neuropharmacologic studies are needed that activate or block 5HT, GABA, and opioid input. It is important that physiological and behavioral responses be examined in these studies.
• Relationships between HPA and alcohol-seeking behavior should be investigated. In rodent models, emphasis should be on relationships among CRH/cortisol states, mesolimbic neurochemistry, and alcohol-seeking behavior. In humans, there should be comparisons of the entire HPA axis between alcohol- and nonalcohol-dependent individuals as a function of family history of alcoholism.
• It would be useful to determine (1) whether the magnitude of HPA axis activity during acute withdrawal predicts relapse rates; (2) if supplements with CRH, ACTH, and/or glucocorticoids during early abstinence decreases mood disturbances and attenuates relapse; and (3) whether effectiveness of opioid receptor antagonists in treating alcoholism relates to ability to stimulate HPA axis?
• It is important to determine if individuals at increased risk for the future development of alcoholism have enhanced opioidergic sensitivity to alcohol exposure.
• The effects of stress dampening by alcohol should be studied in a family-history design using the HPA axis as end-point measures.
• Future studies should more clearly define the relationships between alcohol-associated alterations to HPA axis function and immune system function.

Gaps in Knowledge and Research Opportunities (Cindy L. Ehlers, Ph.D.)

• There is a clear need to increase funding in the area of alcohol and sleep.
• It is important to determine if chronic alcohol intake produces prolonged sleep disturbances and increased risk for relapse.
• It is not known what brain mechanisms underlie alcohol-induced sleep disturbances.
• It would be valuable to determine the risk factors for sleep disturbance and excessive alcohol consumption.
• It would be useful to investigate gender-related, alcohol-associated sleep disturbances.
• It is important to determine if new therapies that target sleep disturbances can be effective in preventing relapse.

STUDIES OF ACUTE AND CHRONIC EFFECTS OF ALCOHOL IN HUMANS (Ellen D. Witt, Ph.D.)

Human studies, representing about $4.4 million, investigate the consequences of acute and chronic alcohol on cognitive and other behaviors, as well as the underlying structural changes associated with the behavioral deficits using state-of-art imaging technologies. The neural mechanisms of alcohol-motivated behaviors such as craving, have also been studied in humans, but to a lesser extent.

Grants for studies of acute and chronic effects of alcohol in humans are detailed below.

Category	No. of Grants	FY97
Acute Cognitive and Behavioral Effects	3	$348,967
Mechanisms of Alcoholic Behavior	4	550,772
Sleep	1	202,466
	8	$2,024,466

Acute Cognitive and Behavioral Studies

1. Acute Effects of Alcohol on Stress Dampening Response/Aggressive Behavior (2 grants)

Two grants are studying the acute behavioral effects of alcohol. One grant is examining the effects of alcohol on aggressive responding in women in a laboratory setting. The second grant is examining the ability of alcohol to reduce stress/anxiety using "stress dampening" techniques (i.e., alcohol's effects on the magnitude of physiological responses) and a "cognitive appraisal" model of stress and emotion.

2. Innate Behaviors Antisocial Personality, Behavioral Activation/inhibition/Aggression

(2 grants)

Two grants are investigating the relationship between innate characteristics, such as antisocial personality and/or temperament (behavioral activation and inhibition), and alcohol-related behaviors (i.e, consumption and/or alcohol-induced aggression). One grant investigates the relationship between antisocial personality, alcohol induced-aggression, and serotonin function. The second grant is investigating the biobehavioral mechanisms (i.e., strength of the behavioral inhibition and activation systems) mediating the relationship between impulsive personality, disinhibited/antisocial personality, and alcohol abuse.

Recommendations

There is a long history of research on the acute effects of alcohol on cognitive processes, but these studies have largely focussed on memory, divided attention, reaction time, and visuomotor skills. The currently funded research is investigating how alcohol's effects on cognitive processes may have a role in increasing drinking or other alcohol-related behaviors, such as aggression. More research is needed in other areas, such as alcohol's effects on executive functioning, a cognitive construct involving the cognitive regulation of behavior, and how that may increase drinking. More research is also needed on the role of temperament and/or personality characteristics in contributing to excessive drinking and/or other alcohol-related behaviors.

Mechanisms of Alcoholic Behaviors

1. Neurotransmitter and Neurohormonal Mechanisms: Behavioral Psychopharmacology

(3 grants)

Three grants are examining the role of neurotransmitters and neuropeptides in alcohol reinforcement and craving in alcoholics. One grant is studying the interactive contributions of noradrenergic and serotonergic systems to alcohol craving in detoxified alcoholics using cue reactivity paradigms. A second grant is evaluating the role of a glutamate antagonist (ketamine) at the NMDA receptor in producing subjective effects similar to alcohol. The third grant is studying opioidergic mechanisms of reinforcement for coexisting alcohol and nicotine use.

2. Neurotransmitter Mechanisms: Imaging Studies (1 grant)

One grant is studying whether the DA system is abnormal in alcoholics, functional consequences of abnormalities, and effects of detoxification. Using PET imaging and multiple tracer methods, this grant is evaluating the DA system in alcoholics in two phases: the DA system at rest and during pharmacological activation.

Recommendations

While many animal studies are investigating neural circuitry and neurochemical mechanisms of alcohol-motivated behaviors, such as reinforcement, few studies are exploring neurochemical mechanisms in humans. With the advent of new imaging technologies such as PET, and the discovery of ligands/and receptor agonists and antagonists, more studies are needed to investigate neural mechanisms of alcohol-motivated behaviors in humans.

Effects of Alcohol on Sleep (1 grant)

One grant is investigating whether disruption of sleep continuity and/or loss of slow-wave sleep leads to greater elevations in sympathetic nervous system activity in African American alcoholics, which in turn results in impaired immune function and increased risk for disease.

Recommendations

Sleep disturbance is a common problem during withdrawal and abstinence which could contribute to relapse to drinking. More research is needed to understand the underlying neural mechanisms of sleep disturbances in abstinent alcoholics, and whether potential medications will ameliorate these sleep disorders.

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COGNITIVE/BEHAVIORAL/STRUCTURAL DEFICITS

NEUROPSYCHOLOGICAL SEQUELAE OF CHRONIC ALCOHOLISM

Gaps in Knowledge and Research Opportunities (Marlene Oscar-Berman, Ph.D.)

• Additional research is needed to clarify the separate and combined roles of malnutrition and alcohol neurotoxicity to brain damage and functional impairments.
• Additional studies would be useful on the enhanced susceptibility to alcoholism-associated deficits in women and the elderly.
• Future research should include longitudinal or retrospective methods to evaluate the likelihood of subgroup vulnerability.
• Specific evaluation of nonhuman animal models of alcohol-associated cognitive deficits should be encouraged.
• It is important to establish uniform positive diagnostic criteria for subtypes of brain-impaired alcoholics (e.g., Korsakoff's syndrome versus alcoholic dementia); this can be approached most effectively with the aid of sophisticated neurological and neurobehavioral techniques.
• Follow-up post mortem examination of brains of well-studied alcoholics should be encouraged for clues about neurotransmitter abnormalities, as well as analyses of injury at the cellular level.
• Particular problems in need of future research effort include the following: neurobehavioral and brain functional/structural recovery with abstinence; extent of multimodal sensory and perceptual deficits; nature of the loss of emotional and motivational functioning among subgroups of alcoholics; specific contributions of frontal system dysfunction to alcoholic symptomatology.

 HUMAN BRAIN DYSFUNCTION SECONDARY TO ALCOHOL ABUSE

• Gaps in Knowledge and Research Opportunities (George Fein, Ph.D.It is important to determine which brain systems are most vulnerable to the morbid effects of chronic alcohol abuse.
• What alcohol use-related factors influence brain morbidity secondary to alcohol abuse, including nutritional deficiency, number of episodes of withdrawal, development of tolerance, and role of pattern of drinking?
• Other factors influencing brain morbidity secondary to alcohol abuse should also be studied, including, genetically transmitted vulnerabilities, gender, age, variability in brain functional reserve as measured by intracranial volume, adolescence, and comorbidity.
• What are the mechanisms involved in recovery of the brain from the effects of chronic alcohol abuse?
• Electrophysiological methods should continue to be used because of the advantages over other neuroimaging techniques in terms of temporal resolution, ease and cost-effectiveness of data acquisition, and the ability to collect data during the performance of complex cognitive tasks.
• It is important to combine behavioral, structural, and functional measures of brain function.

 NEUROIMAGING STUDIES OF BRAIN VULNERABILITY TO ALCOHOLISM

Gaps in Knowledge and Research Opportunities (Edith V. Sullivan, Ph.D.)

• Even though alcohol abuse and dependence is prevalent in adolescents as well as older individuals, alcohol's adverse effects on the adolescent brain is unknown.
• It is unknown whether adequate nutritional supplements improve the structural condition of the brain of alcoholics.
• There is a paucity of data on the effects of alcoholism on the brains of women.
• The mechanisms underlying morphological recovery are still unknown.
• Increased emphasis should be place on in vivo metabolite imaging because of its possible utility in helping to define disease progress, assess efficacy of treatment, and track alcohol-related changes across the life span.
• To examine the extent that tolerance may be genetically determine, it should be possible to use MRS to compare estimates of non-absorbed alcohol in nonalcoholics, low alcohol-consuming individuals who have a positive family history for alcoholism versus those with a negative family history.
• Although the functional significance of brain volume loss in terms of the commonly observed alcoholism-associated cognitive behavioral deficits has been difficult to demonstrated, functional MRI (fMRI) has the potential to identify areas throughout the brain that are activated during performance of specific components of cognitive operations.
• Diffusion anisotropy offers a potential metric for assessing the integrity of white matter throughout the course of alcoholism.
• It would be useful to examine brain function and psychiatric comorbidity in alcoholics in a systematic manner.
• It is important to determine whether, with abstinence, alcoholics whose brains show recovery of tissue volume are the individuals who also show improvement in their cognitive and motor abilities.
• It needs to be established whether alcoholism-associated, brain-volume deficits are accompanied by predictable neuropsychological performance.
• The question of gene-environment interaction with respect to apolipoprotein genotype and alcohol on the development of dementia and accelerated brain volume loss in alcoholics has yet to be addressed.
• The extent to which the frontal lobes and cerebellum recover in structure or function remains unknown despite their importance to problem solving, contextual memory, and execution and learning of procedures.
• Controlled studies of alcoholics who remain abstinent for years in comparison to those who drink for years are needed.
• No quantitative in vivo studies have been conducted to examine, even cross-sectionally, potential alcohol-gene interactions on brain morphology. These studies are essential to determine the pattern and extent of potentially preexisting differences in individuals genetically predisposed to alcohol addiction compared with those not so disposed.

COGNITIVE/BEHAVIORAL/STRUCTURAL DEFICITS IN HUMANS
 (Ellen D. Witt, Ph.D.)

Human studies, representing about $4.4 million, investigate the consequences of acute and chronic alcohol on cognition and other behaviors, as well as the underlying structural changes associated with the behavioral deficits using state-of-art imaging technologies. The neural mechanisms of alcohol-motivated behaviors such as craving, have also been studied in humans, but to a lesser extent.

Grants for studies of cognitive/behavioral/structural deficits in humans are detailed below.

Category No. of Grants FY97

Brain Damage/ Cognitive/Motor Deficits	12	$3,173,813
Methodology Development	1	103,482

Brain Damage, Cognitive/Motor Dysfunction: Affected Brain Areas, Contributions of Malnutrition, Influences of Polysubstance Abuse, Aging, Gender

1. Neurobehavioral/Cognitive/motor Dysfunction (7 grants)

Seven grants are investigating cognitive/motor deficits and their underlying neural substrates in chronic alcoholics and Korsakoff patients using neuropsychological, neurocognitive, neurophysiological, and/or magnetic resonance imaging (MRI) techniques.

Motor Functioning (2 grants) Two grants are targeting alcohol's effects on the cerebellum. One grant uses Pavlovian techniques (delayed-classical conditioning tasks involving heart rate, GSR conditioning, eyeblink conditioning, and extinction) to dissociate structures in the medial temporal lobe (amygdala) and cerebellum in mediating associative learning deficits. The other is quantifying regional volumes of the cerebellar hemispheres and vermis with MRI, using a component-process approach to assess motor coordination and motor skill learning, and determining structure-function relationships between specific motor processes and regional cerebellar volumes.

Attention, Memory, Executive Processes (4 grants) Two grants study attention and/or memory processes using cognitive tests. One grant is studying deficits in explicit and implicit conceptual memory in chronic alcoholic and Korsakoff patients. The second grant is evaluating cognitive efficiency (principally attention and memory) in subtypes of alcoholics classified on the basis of other substance use/abuse (marijuana, stimulants). Two grants are studying attention, memory, and executive functioning in conjunction with ERP and/or functional MRI (fMRI) to understand the underlying neural mechanisms of these deficits in alcoholics. One of the grants uses fMRI to study localized brain activation during performance of auditory and visual working memory tasks. The fourth grant uses ERP and EEG techniques to study attention and memory processes in abstinent alcoholics classified along several variables including Type I and Type 2 alcoholism, family history of alcoholism, as well as the relationship between antisocial behavior and neurophysiological characteristics.

Affective (emotional) and Conative (intentional) Functions (2 grants) Two grants are investigating emotional and intentional abnormalities in chronic alcoholics (with and without Korsakoff's syndrome) and whether these changes are mediated by right frontal or bilateral frontal lobe pathology.

2. Brain Metabolic Changes and Tolerance and Long-Term Abstinence (2 grants) One grant is using magnetic resonance spectroscopy (MRS), which allows noninvasive quantification in vivo of brain metabolites, to investigate the mechanism of alcohol-induced tolerance in humans. A second grant is using MRS to characterize the longitudinal course of metabolic changes (i.e, the ratio of visible choline (Cho) to the neuronal marker n-acetylaspartate (NAA)) in the brains of abstinent alcoholics.

3. Effect of Aging and/or HIV on Cognitive Functioning in Alcoholics (5 grants)

Alcohol and Aging (4 grants) One grant is using structural MRI, electrophysiology, and neuropsychological assessments to critically evaluate two opposing models of central nervous system effects of chronic alcohol abuse as they interact with age and gender. Three grants are continuations of ongoing research on the interaction between alcohol and aging. Two of these are investigating emotional, attentional, and intentional processes in alcoholics and age-matched controls to evaluate the ways in which the behavioral consequences of aging and alcoholism are parallel, divergent, and/or interactive. The fourth grant is a continuation of an ongoing longitudinal study of alcoholic and control women using MRI, ERP, and neuropsychological tests to identify cross-sectional patterns of sparing and loss, their interaction with age, and comparability to findings in alcoholic men.

Alcohol and HIV (1 grant) One grant is examining the effect of alcohol consumption on neuropsychological function across stages of HIV infection.

Recommendations

More research is needed in relating cognitive deficits produced by chronic alcoholism to excessive drinking and the inability to benefit from treatment.

Methodology Development (1 grant)

This grant is developing a method to induce and maintain a steady-state concentration of alcohol in the brain and blood while multiple dependent measures are assessed.

Recommendations

Technologies which improve our understanding of the neural mechanisms alcoholism and improve treatment are encouraged.

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APPENDIX A

Subcommittee for Review of Neuroscience and Behavior Portfolio

Co-Chairs

Henri Begleiter, M.D., Ph.D.
Department of Psychiatry
Health Science Center at Brooklyn
450 Clarkson Avenue, Box 1203
Brooklyn, NY 11203-2098

Catherine Rivier, Ph.D.
The Salk Institute
10010 North Torrey Pines Road
La Jolla, CA 92037-1099

Experts in Alcohol-Related Areas

Ivan Diamond, M.D., Ph.D.
Department of Neurology/Gallo Center
UCSF
San Francisco General Hospital
Bldg. 1, Room 101
1001 Potrero Avenue
San Francisco, CA 94110-3594

Adron Harris, Ph.D.
Department of Pharmacology, C-236
University of Colorado HSC
4200 East Ninth Avenue
Denver, CO 80262-0236

Harold Kalant, M.D., Ph.D.
Department of Pharmacology
University of Toronto
Medical Science Building
Toronto, Ontario
CANADA M5S 1A8

George Koob, Ph.D.
Department of Neuropharmacology
The Scripps Research Institute - CVN-7
10550 North Torrey Pines Road
La Jolla, CA 92037 

Ting-Kai Li, M.D.
Indiana University
School of Medicine
Emerson Hall 421
545 Barnhill Drive
Indianapolis, IN 46202-5124

Elias Michaelis, M.D., Ph.D.
Department of Pharmacology and Toxicology
Malott Hall
University of Kansas
Lawrence, KS 66045-2505

Oscar Parsons, Ph.D.
University of Oklahoma HSC
Rogers Building, Suite 410
800 N.E. 15th Street
Oklahoma City, OK 73104-4602

Adolf Pfefferbaum, M.D.
SRI International
333 Ravenswood Avenue
Menlo Park, CA 94025

Bernice Porjesz, Ph.D.
Department of Psychiatry
Health Science Center at Brooklyn
450 Clarkson Avenue, Box 1203
Brooklyn, NY 11203-2098

Herman Samson, Ph.D.
Department of Physiology/Pharmacology
Wake Forest University School of Medicine
Medical Center Blvd.
Winston-Salem, NC 27157-1083

Boris Tabakoff, Ph.D.
Department of Pharmacology, C-236
University of Colorado HSC
4200 East Ninth Avenue
Denver, CO 80262-0236

Maharaj Ticku, Ph.D.
Department of Pharmacology
University of Texas HSC
7703 Floyd Curl Drive
San Antonio, TX 78284-7764

Nora Volkow, M.D.
Department of Medicine
Brookhaven National Laboratory
Upton, NY 11973

Gary Wand, M.D.
Division of Endocrinology
The Johns Hopkins University
School of Medicine, Ross 850
702 Rutland Road
Baltimore, MD 21205

Experts in Non-Alcohol-Related Areas

Robert Freedman, M.D.
Department of Psychiatry
University of Colorado HSC
Box C-268-71
4200 East Ninth Avenue
Denver, CO 80262

ALIGPeter Kalivas, Ph.D.
Department of VCAPP
Washington State University
Pullman, WA 99154

Steven Paul, M.D.
Lily Research Laboratory
Lily Corporation Center
893 Delaware Avenue
Indianapolis, IN 46285

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APPENDIX B

Experts in Neuroscience and Behavior

Marlene Oscar Berman, Ph.D.
Boston University School of Medicine
80 E. Concord Street, M-902
Boston, MA 02118-2394

Fulton Crews, Ph.D.
UNC School of Medicine
Center of Alcohol Studies, CB# 7178
Thurston-Bowles Building
Chapel Hill, NC 27599-7178

Cindy Ehlers, Ph.D.
The Scripps Research Institute - CVN-14
10550 North Torrey Pines Road
La Jolla, CA 92037

George Fein, Ph.D.
Department of Psychiatry
University of California
4150 Clement Street, 116R
San Francisco, CA 94121

Peter Finn, Ph.D.
Department of Psychology
Indiana University
Bloomington, IN 47405

Kathy Grant, Ph.D.
Department of Physiology/Pharmacology
Wake Forest University School of Medicine
Medical Center Blvd.
Winston-Salem, NC 27157-1083

Paula Hoffman, Ph.D.
Department of Pharmacology, C-236
University of Colorado HSC
4200 East Ninth Avenue
Denver, CO 80262-0236

John H. Krystal, M.D.
Yale-VA Alcoholism Research Center
Psychiatry Service (116A)
West Haven VAMC
950 Campbell Avenue
West Haven, CT 06516

David Lovinger, Ph.D.
Department of Molecular Physiology
and Physiology
Vanderbilt University School of Medicine
702 Light Hall
Nashville, TN 37232-0615

Leslie Morrow, Ph.D.
UNC School of Medicine
Center of Alcohol Studies, CB# 7178
Thurston-Bowles Building
Chapel Hill, NC 27599-7178

Catherine Rivier, Ph.D.
The Salk Institute
10010 North Torrey Pines Road
La Jolla, CA 92037-1099

George Siggins, Ph.D.
The Scripps Research Institute - CVN-12
10550 North Torrey Pines Road
La Jolla, CA 92037

Linda Spear, Ph.D.
Department of Psychology
Center for Developmental Psychobiology
SUNY - Binghamton
Box 6000
Binghamton, NY 13902-6000

Edith Sullivan, Ph.D.
Department of Psychiatry
Stanford University
333 Ravenswood Avenue
Menlo Park, CA 94025

Steven Treistman, Ph.D.
Department of Pharmacology
University of Massachusetts Medical Center
55 Lake Avenue, N.
Worcester, MA 01655

Gary Wand, M.D.
Division of Endocrinology
The Johns Hopkins University
School of Medicine, Ross 850
702 Rutland Road
Baltimore, MD 21205

Friedbert Weiss, Ph.D.
Department of Neuropharmacology
The Scripps Research Institute - CVN-15
10550 North Torrey Pines Road
La Jolla, CA 92037

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APPENDIX C

NIAAA Program Staff

Walter Hunt, Ph.D.
Neurosciences and Behavioral Research Branch
Division of Basic Research, NIAAA
6000 Executive Blvd., Suite 402
Bethesda, MD 20892-7003

Robert Karp, Ph.D.
Neurosciences and Behavioral Research Branch
Division of Basic Research, NIAAA
6000 Executive Blvd., Suite 402
Bethesda, MD 20892-7003

Yuan Liu, Ph.D.
Neurosciences and Behavioral Research Branch
Division of Basic Research, NIAAA
6000 Executive Blvd., Suite 402
Bethesda, MD 20892-7003

Ellen Witt, Ph.D.
Neurosciences and Behavioral Research Branch
Division of Basic Research, NIAAA
6000 Executive Blvd., Suite 402
Bethesda, MD 20892-7003

Samir Zakhari, Ph.D.
Division of Basic Research, NIAAA
6000 Executive Blvd., Suite 402
Bethesda, MD 20892-7003
Phone: (301) 443-0799

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 APPENDIX D

NIAAA Staff, Representatives from other NIH Institutes, and Guests

Megan Adamson, M.D.
Office of Collaborative Research, NIAAA
6000 Executive Blvd., Suite 400
Bethesda, MD 20892-7003
Phone: (301) 443-4354

Faye Calhoun, D.P.A.
Office of Collaborative Research, NIAAA
6000 Executive Blvd., Suite 400
Bethesda, MD 20892-7003
Phone: (301) 443-1269

Mary Dufour, M.D., M.P.H.
Deputy Director, NIAAA
6000 Executive Blvd., Suite 400
Bethesda, MD 20892-7003
Phone: (301) 443-3851

Michael J. Eckardt, Ph.D.
Office of Scientific Affairs, NIAAA
6000 Executive Blvd., Suite 409
Bethesda, MD 20892-7003
Phone: (301) 443-6107

Joanne Fertig, Ph.D.
Division of Clinical and Prevention Research, NIAAA
6000 Executive Blvd., Suite 505
Bethesda, MD 20892-7003
Phone: (301) 443-0635

Richard K. Fuller, M.D.
Division of Clinical and Prevention Research, NIAAA
6000 Executive Blvd., Suite 505
Bethesda, MD 20892-7003
Phone: (301) 443-1206

Klaus Gawrisch, Ph.D.
Laboratory of Membrane Biochemistry and Biophysics
NIAAA
12420 Parklawn Dr., Room 116
Bethesda, MD 20892-8115
Phone (301) 594-3750

Thomas Gentry, Ph.D.
Office of Collaborative Research, NIAAA
Bethesda, MD 20892-7003
Phone (301) 443-6009

Enoch Gordis, M.D.
Director, NIAAA
6000 Executive Blvd., Suite 400
Bethesda, MD 20892-7003
Phone: (301) 443-3885

Daniel Hommer, M.D.
Laboratory of Clinical Studies, NIAAA
Building 10, Room 3C114
Bethesda, MD 20892-1256
Phone: (301) 496-7874

Nancy Hondros
Planning and Financial Management Branch, NIAAA
6000 Executive Blvd., Suite 412
Bethesda, MD 20892-7003
Phone: (301) 443-5733

William M. Lands, Ph.D.
Office of the Director, NIAAA
6000 Executive Blvd., Suite 400
Bethesda, MD 20892-7003
Phone: (301) 443-0276

Ting -Kai, Li, M.D.
Indiana University School of Medicine
Emerson Hall 421
545 Barnhill Drive
Indianapolis, IN 46202-5124
Phone: (317) 274-8495

Burt Litman, Ph.D.
Laboratory of Membrane Biochemistry and Biophysics
NIAAA
12420 Parklawn Dr., Room 116
Bethesda, MD 20892-8115
Phone (301) 594-3608

Raye Litten, Ph.D.
Division of Clinical and Prevention Research, NIAAA
6000 Executive Blvd., Suite 505
Bethesda, MD 20892-7003
Phone: (301) 443-0636

Steve Long
Office of Policy Analysis, NIAAA
6000 Executive Blvd., Suite 405
Bethesda, MD 20892-7003
Phone: (301) 443-2435

Matthew McGue, Ph.D.
Department of Psychology
University of Minnesota
Elliot Hall, Room N-218
75 East River Road
Minneapolis, MN 55455
Phone: (612) 625-8305

Antonio Noronha, Ph.D.
Office of Scientific Affairs, NIAAA
6000 Executive Blvd., Suite 409
Bethesda, MD 20892-7003
Phone: (301) 443-7722

Carrie L. Randall, Ph.D.
Department of Psychiatry and behavioral Science
Medical University of South Carolina
171 Ashley Avenue
Charleston, SC 29425
Phone (803) 792-5200

Norman Salem, Jr., Ph.D.
Laboratory of Membrane Biochemistry and Biophysics
NIAAA
12420 Parklawn Dr., Room 116
Bethesda, MD 20892-8115
Phone (301) 443-2393

Jules Selden, D.V.M., Ph.D.
Division of Basic Research, NIAAA
6000 Executive Blvd., Suite 402
Bethesda, MD 20892-7003
Phone: (301) 443-2678

Martin K Trusty
Office of Planning and Resource Management, NIAAA
6000 Executive Blvd., Suite 412
Bethesda, MD 20892-7003
Phone: (301) 443-4373

Ernestine Vanderveen, Ph.D.
Division of Basic Research, NIAAA
6000 Executive Blvd., Suite 402
Bethesda, MD 20892-7003
Phone: (301) 443-1274

Kenneth Warren, Ph.D.
Office of Scientific Affairs, NIAAA
6000 Executive Blvd., Suite 409
Bethesda, MD 20892-7003
Phone: (301) 443-4375

Forrest Weight, M.D.
Laboratory of Molecular and Cellular Neurobiology
NIAAA
12420 Parklawn Dr., Room 118
Bethesda, MD 20892-8115
Phone (301) 443-1234

Herbert Weingartner, Ph.D.
NIDA
Building 31, Room 1B58
Phone: (301) 402-2996