their blood levels were now much higher, approximating 300 mg percent. Since the blood alcohol level tells us the concentration of alcohol in the brain, this improvement in behavior cannot be due to less alcohol in the nervous system. Instead, something happened in the brain to accommodate and adapt to the presence of ethanol. This is a short-term or acute tolerance. We also encounter more striking long-term tolerance to alcohol in every emergency department across the country. Here I illustrate a study of patients who came to an emergency department for medical care. They were asked the question, "Have you had a drink in the last 6 hours?" If the answer was yes, blood alcohol levels were measured. The results show that the average was 270 mg percent, and a few people had blood ethanol levels greater than 500 mg percent, concentrations that can cause coma or death. What I didn't tell you is that all of these people were considered to be "sober" on crude physical examination. Clearly, these patients were chronic alcoholics with remarkable tolerance to the intoxicating effects of ethanol. If you are interested in the world's record for blood alcohol levels, it was measured at UCLA in a woman who walked into the emergency department after having discontinued drinking 3 days earlier. She had symptoms of withdrawal and her blood level was about 1,500 mg percent. Clearly, some alcoholics exhibit a remarkable ability to tolerate tremendous amounts of alcohol.

Alcoholics begin to experience symptoms and signs of alcohol withdrawal when more than 6 hours elapses after the last drink. That is why alcoholics tend to have a drink first thing in the morning. Alcohol suppresses these symptoms. Perhaps the craving for a drink during alcohol withdrawal is the same craving responsible for alcohol addiction. Alcohol withdrawal is characterized by hyperexcitability, and the most dangerous problem is alcohol withdrawal seizures; these occur in the first 24 to 48 hours. Later, of course, withdrawing alcoholics may develop delirium tremens, a well-known hyperexcitable syndrome with dramatic symptoms and signs.

We begin to wonder how we could approach such clinical phenomena at a cellular and molecular level. We thought it would be possible to identify cellular tolerance as a reduced response to repeated doses of ethanol, or cellular dependence by an abnormal cellular response during ethanol withdrawal that would be corrected by returning alcohol to the cells. We succeeded in both instances.

Robert Messing at the Gallo Center was interested in the molecular basis of hyperexcitability, particularly alcohol withdrawal seizures. He discovered that neural cells in culture adapt to ethanol by increasing the concentration and activity of voltage-dependent calcium channels. Ordinarily, ethanol inhibited calcium flux through these channels, but when ethanol was removed from the cells, the increased concentration of channels mediated a tremendous increase in calcium flux during alcohol withdrawal. This could contribute to neuronal hyperexcitability. The advantage of working with a cellular system is that it is possible to identify the molecular mechanisms that underlie these functional adaptations. For example, Bob Messing discovered that protein kinase C was required for ethanol to induce up-regulation of the voltage-dependent calcium channel.



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