Center Line Newsletter

Volume 19, Number 1, March 2008

CAS Awarded Five-Year, Multimillion Dollar Center Grant:

Molecular and Cellular Pathogenesis in Alcoholism

A holiday surprise arrived early last December for researchers at the University of North Carolina’s Bowles Center for Alcohol Studies. The Center received official word from the National Institute of Alcohol Abuse and Alcoholism (NIAAA) that its Center grant renewal application – that will provide $10 million dollars of research support over 5 years—was to be funded. Only a handful of Alcohol Center grants are awarded, and competition for these prestigious and lucrative awards is fierce. The December 2007 renewal is the Bowles Center’s second renewal and its third consecutive five-year award; an exceptional run of success for alcohol research centers. This renewal was the culmination of a 14-month process during which laboratories contributing to the Center grant application evaluated their progress, generated and refined new hypotheses, and identified areas of synergy. The investigators will apply multidisciplinary approaches to elucidate the causes, consequences and potential treatments for alcohol abuse and alcoholism.

“Thorough preparation was crucial,” says Dr. Fulton Crews, Director of the Bowles Center for Alcohol Studies and Program Director for the Center Grant. “We began our work for this renewal in October 2005 with a retreat at which all of the Bowles Center laboratories and several external advisors met to review current research initiatives and generate ideas for new projects. Based on discussions at the retreat, we formed several research teams that met monthly to discuss progress and new ideas. Our goal was to identify unifying hypotheses and common areas of study where we expected our collaborative efforts to yield more progress than could be gained from individual laboratories working in isolation.”

For Center Grants, the integrated and synergistic aspects of the research are key. Center Grants differ from grants awarded to individual laboratories in their requirement for coordinated research initiatives involving several laboratories. Center Grants are built on the premise that discoveries are facilitated by cooperation among laboratories, each contributing its particular scientific expertise and technological strengths. As Center researchers worked to prepare the grant renewal application, they came to realize that much of the potential for research integration and synergy lay in their collective ability to investigate the full spectrum of the progressive pathology of alcoholism.

Center Grant Faculty (left to right): Shao-yu Chen, Ph.D., Jian Zou, M.D., Ph.D., A. Leslie Morrow, Ph.D., David Overstreet, Ph.D., Michael Chua, Ph.D., Liya Qin, Ph.D., Kirk Wilhelmsen, M.D., Ph.D., Clyde Hodge, Ph.D., Joyce Besheer, Ph.D., Darin Knapp, Ph.D., George Breese, Ph.D.,
Robert Gwyther, M.D., Kathy Sulik, Ph.D., Fulton Crews, Ph.D. and Donita Robinson, Ph.D.

The progressive pathology of alcoholism is defined behaviorally by increases in both the amount of alcohol consumed and the frequency of bouts of alcohol drinking. The path to alcoholism begins with initial experimentation with alcohol, followed by increasing alcohol consumption, and the development of alcohol dependence with behavioral and physiological manifestations of addiction. With time and sufficient doses, alcohol consumption is associated with chronic inflammation and damage to the brain and other organs. Bowles Center researchers are particularly interested in the cellular and molecular mechanisms that underlie the stages in this progression. The various laboratories in the Bowles Center use animal models that address different phases of pathology on the road to development of alcoholism and alcohol-induced tissue damage. In fact, the research of the collective laboratories encompasses the full spectrum of alcoholic progression from experimentation through dependence and drinking-induced tissue damage.

A scientific core of the Center Grant links all research components through support for studies of gene expression, cellular biology and sophisticated microscopy. The core sponsors informal science meetings that stimulate hypothesis among faculty, post-doctoral fellows and graduate students. The research ranges from the human genetics of alcohol response, a known factor regulating risk for alcohol dependence, to alcohol-induced brain cell damage in adults and fetuses that occur with the high alcohol consumption or alcohol dependence.

Dr. Kirk Wilhelmsen investigates genetic determinants of human alcohol sensitivity and relates them to variants in CYP2E1, an enzyme that is induced by alcohol in brain and other tissues, metabolizes alcohol and increases oxidative stress.

Drs. Clyde Hodge and Joyce Besheer model alcohol drinking and motivation to drink in mice that voluntarily drink alcohol, progressively increase drinking, and show relapse heavy drinking after abstinence. Molecular signals in specific brain regions, particularly a kinase called ERK, change in association with motivation to drink, and drugs that block these signals can block relapse drinking.

Dr. Donita Robinson studies motivation to drink using multi-electrode arrays that follow the firing patterns of neurons with special electrochemical detectors for dopamine that measure synaptic release while rats respond to a light cue letting them known they can press a lever and get alcohol. This approach allows an investigation of the brain circuitry that drives motivation to drink and compulsive uncontrolled drinking.

Drs. George Breese, Darin Knapp, David Overstreet and Todd Thiele follow persistent changes in anxiety-like behaviors that occur with repeated drinking and abstinence cycles. Brain region specific changes in various signaling proteins, including inflammatory cytokines, lead to a progressively increasing withdrawal anxiety that can be blocked with selective drugs providing mechanistic insights as well as potential new therapies.

Drs. Leslie Morrow and Sandeep Kumar investigate the mechanisms of alcohol dependence-induced changes in inhibitory transmission mediated by GABA-A receptors including the role of specific subtypes of protein kinase C. These studies relate alcohol dependence to alterations in phosphorylation and cell surface expression of GABA-A receptor subtypes that determine how brain cells respond to alcohol, GABA and other endogenous modulators.

Drs. Fulton Crews, Liya Qin, and Jian Zou identify mechanisms of neuroinflammation and brain damage that result from exposure to binge drinking of alcohol. Studies investigate how cytokines, oxidative gene induction and other processes alter brain structure and function in brain regions that contribute to self-control, impulse inhibition and goal setting, brain areas important in protecting against dependence.

Similarly, Drs. Kathy Sulik and Shao-Yu Chen work on brain damage in the fetal brain following high alcohol exposure. Innovative methods in brain imaging coupled with molecular studies of oxidative cell damage are hoped to allow better understanding of the molecular mechanisms and the course of fetal pathology. These studies could lead to new forms of diagnosis and specialized therapy for fetal alcohol-exposed babies.

Together the Center has overlapping themes of alcohol-induced changes in genes, signaling and pathology that range from the behavioral pathology of initial drinking, to tolerance and physical dependence, to marked brain damage that occurs with binge and alcoholic drinking. The mechanisms that underlie this spectrum of pathology overlap substantially and this overlap stimulates discovery among all the research components.
The Center Grant includes an educational core that complements the scientific core. The educational core includes several initiatives targeting health professionals (including clinicians, counselors, and policymakers) and legal professionals with information on alcohol abuse and its prevention and treatment (see article, page 3).

Reflecting on the wide-ranging research and educational activities made possible by the Center Grant, Crews likens the potential for advancing prevention and treatment of alcoholism to progress in the prevention and treatment of tobacco dependence. In the past two decades, tobacco research has elucidated the harmful effects of tobacco and led to new therapeutic approaches for nicotine dependence. This research has led to improvements in public health and significant changes in public policy. “The Center Grant positions us to begin to do the same for alcohol dependence,” says Crews.
“Our research reveals how alcohol changes the brain and how alcohol dependence develops over time. By educating the public, particularly young people, about these effects, we arm them with information that can prevent them from becoming alcoholics.”

“By defining therapeutic targets for alcohol dependence, we can hope to treat alcoholism in those who have become addicted to alcohol. Although alcohol is different from tobacco and can be beneficial in moderation, alcohol also has more immediate negative consequences than the delayed illnesses (cancer and heart disease) related to tobacco use. We look forward to successful education-prevention, intervention and treatment coming out of our research efforts.”