Our strategy was straightforward. First, we wanted to use simple, homogeneous cellular systems to identify the most important molecular mechanisms that mediate the response of neural cells to alcohol. Whenever we could, we would extend our findings to circulating blood cells taken from alcoholic subjects to confirm the relevance of our observations. Once we were able to measure important cellular and molecular events, I thought we would be in a much better position to apply this information to the brain with all its complexity and heterogeneity.

What about the problem of alcoholism in our society? Two-thirds of the adults over 14 years of age in the United States drink alcohol. If you calculate how much alcohol is produced in America and divide it by the number of people who drink, the quantity of alcohol consumed is roughly equivalent to 10 gallons of whisky per person per year. Now, this is clearly not the case for each American. Instead, about 10 percent of the drinking population, or perhaps 7 percent of the public, consume nearly 50 percent of the alcohol produced in this country. These are the alcoholics we encounter in hospitals and clinics; a conservative estimate is that about 25 percent of hospital beds in the United States are occupied by patients who have alcohol-related problems. In San Francisco, I estimate that as much as 75 percent of patients at San Francisco General Hospital have alcohol-related medical diagnoses. Medical complications involve the liver, heart, and just about every organ system in the body. When you add socioeconomic costs to the medical costs, the burden of alcoholism and alcohol abuse to American society is estimated to be more than $100 billion per year. Parenthetically, this enormous cost to society is much greater than the cost of other major medical problems, such as heart disease or stroke. Yet, the percentage of the National Institutes of Health's budget devoted to alcohol research is trivial when compared to the research budgets for other research areas.

What happens to people who drink excessively? Everyone is aware of the characteristic intoxicated behavior produced by alcohol. The degree of intoxication can be correlated with blood alcohol levels, because there is a very rapid equilibration between alcohol in the blood and in the brain. Therefore, blood alcohol levels accurately reflect brain alcohol concentrations. Alcohol is a sedating agent and, when blood levels reach 500 mg percent, naive individuals can become comatose and even die because of respiratory depression. This happens not because alcohol destroys neurons, but because alcohol depresses neuronal function in the respiratory center of the brain, so that breathing stops.

Yet, not everything is as simple as these correlations suggest. Many years ago, Mirsky found that blood levels can be misleading. Here, I reproduce some of his studies with volunteers given alcohol to drink. After volunteers were given a few drinks in about an hour, intoxication developed at blood levels approximating 170 mg percent. These subjects would be considered "drunk" by most conventional tests. And yet, if the same individuals were given more alcohol and examined 6 hours later, they were considered to be "sober" even though



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