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Volume 18, Number 4, December 2007

Director's Column

Dr. Fulton T. Crews Director, Bowles Center for Alcohol Studies

Science progresses on many levels with some of the most elegant discoveries relating molecular mechanisms to human behaviors.  Studies of humans have linked low sensitivity to the sedative and hormone increasing actions of ethanol to risk of developing alcohol dependence.  Dr. Mark Schuckit states this is the largest known risk factor for developing alcoholism, making an understanding of what regulates alcohol sensitivity central to understanding aspects of risk for dependence.  This association has been found in animal models of heavy drinking, sons and daughters of alcoholics and several ethnic populations. 

Dr. Hugh Criswell of the Bowles Ctr is making progress understanding the molecular basis of alcohol sensitivity.  His studies target the effects of alcohol on GABAergic transmission since intoxicating effects of ethanol are blocked by antagonists and inverse agonists at GABA-A receptors.  Further, the anxiolytic, anti-convulsant, muscle relaxant and hypnotic-sedative effects of ethanol overlap with drugs like valium as well as neurosteroids and barbiturates, that directly bind to and potentiate GABA-A receptor chloride currents.  These studies strongly suggested that ethanol too, must act directly on synaptic receptors, however, great numbers of studies have not found evidence for this. Results of these studies were often conflicting likely due to different experimental systems, brain regions, end points, temperature and other factors that make science a wonderful place for “Murphy’s Law – if anything can go wrong it will go wrong.”

Criswell has shown that alcohol can increase GABA release in the cerebellum and increase the concentration of neuroactive steroids in the synapse of cerebellar slices.  These effects likely contribute to behavioral effects of ethanol including ataxia and motor in- coordination as well as disruptions in spatial memories.  This novel mechanism could underlie ethanol potentiation of GABA-A receptors, previously thought to occur only directly at the receptor.  Since the neurosteroid can be increased in the preparation by ethanol this could be interpreted as a direct action of ethanol on the receptor if one was not aware of or checking for a neurosteroid effect.  This knowledge could change how one envisions differential sedative responses of ethanol, a key risk factor for dependence.  Criswell’s group is also exploring the mechanism of ethanol regulation of alcohol enhancement of GABA release including release of intracellular calcium and the synaptic presence of neurosteroid biosynthetic enzymes.   These studies could lead to an understanding of the genetic mechanisms that regulate sensitivity to alcohol and risk for alcohol dependence.     

The 2007 Thurman Lectureship Awardee, Dr. Cindy Ehlers, is also studying factors that regulate alcohol sensitivity among various ethnic groups.  We honor Ron Thurman with this lectureship and he devoted much of his career to understanding aspects of alcohol metabolism and hepatotoxicity.  Dr. Ehlers is well known for a number of important scientific discoveries, but perhaps her most significant seminal accomplishment is a systematic series of studies that have elucidated the factors that influence alcoholism in Native Americans.  Some Native Americans have rates of alcoholism 5-6 times that of the general population, the subject of “fire water myths”.  She studied multiple ethnic populations with variations in risk using genetic epidemiology, pharmacology, electrophysiology, psychiatry and molecular biology to better understand risk of dependence.  Again, relating basic molecular mechanisms to aspects of risk for alcoholism.  Through careful study she systematically eliminated the long held myth that social factors and poverty drive alcoholism risk in Native Americans.  Her studies suggest that genes that regulate sensitivity to alcohol, alcohol metabolism, externalizing behaviors and other metabolic factors join together to greatly increase risk for alcoholism.  Dr. Ehlers efforts build upon the discoveries on alcohol metabolism by Dr. Ron Thurman and she pointed out his influence on her work to honor his memory.  Further studies of both metabolic and brain specific mechanisms of alcohol sensitivity will likely lead to new approaches to prevention and treatment for alcoholism.