Former alcoholics have a tough time resisting the urge to drink in two particularly trying situations. Analysis of what is happening in their heads under these circumstances is greatly improving neurobiologists understanding of how chronic alcohol use changes the brain. And their findings suggest measures that could help people abstain.

The following case illustrates one of the most tempting situations. Hank had been dry for several weeks thanks to a radical withdrawal program, but a simple walk past Petes Tavern on any given night almost erased his will to abstain. During the daytime he did not feel a craving for alcohol, but when he passed the bar in the evening--when he saw the warm light through the windows and heard the glasses clinking--he would be sorely tempted to run inside for a beer. Addiction researchers call this phenomenon "conditioned desire." If a person had always consumed alcohol in the same situation, an encounter with the familiar stimuli will make the feeling of need for the substance almost irresistible. Then, even after years of abstinence, consuming a single drink can set off a powerful longing to imbibe more and more.

Kens story illustrates the other common temptation. Ken had given up alcohol and was doing fine, even after he had lost his job and had begun collecting unemployment. But on one visit to the unemployment office downtown, a bureaucrat refused to approve his benefits. After a fruitless argument, Ken left. While standing on the subway platform for a train home, he suddenly began to sweat, twitch and feel sick. What he really wanted was a bottle. Before he had given up drinking, he would have automatically taken a swig whenever he faced a tense situation. After the argument, his brain--shaped by experience--expected the calming effect of alcohol. When the drug did not come, he began to suffer what experts call "conditioned withdrawal" symptoms.

Conditioned desire and conditioned withdrawal are produced in the brain by different mechanisms. In recent years, neuroscientists have investigated both phenomena thoroughly. They now feel comfortable explaining how routine alcohol consumption changes circuitry in the brain in ways that lead to addiction, and they are beginning to develop new medications that could dramatically reduce the chances of falling off the wagon.

High Tolerance Is Bad
For centuries, societies have labeled alcoholics as self-indulgent people who lack willpower. Although the decision to drink in the first place does rest with each individual, traits inherent in a persons brain cells can strongly influence the slippery slope into addiction. Furthermore, once a person is addicted, simple willpower may be insufficient to break the grip; drugs that can reverse the brains alcohol-altered chemistry may be necessary.

An individuals sensitivity to alcohols effects on neurons significantly influences the chance that he or she can become addicted. According to Marc A. Schuckit, a psychiatry professor at the University of California, San Diego, and director of the VA San Diego Healthcare Systems Alcohol and Drug Treatment Program, one of the best protections against addiction is nausea; people who readily get sick as they drink are less likely to consume enough, consistently, to the point that they become addicted. The very people who can drink others under the table are the ones who are especially at risk. Inhibitory and excitatory messenger substances in the brain become unbalanced in response to excessive alcohol doses. The people who can handle more drinking send more alcohol to the brain, thereby increasing over time the chance that a permanent imbalance will develop.

This brain chemistry was partially worked out in rhesus monkeys that had to grow up without their mothers, some in the laboratory and some in the wild. James Dee Higley, a research psychologist at the National Institute on Alcohol Abuse and Alcoholism, learned that these monkeys reacted less to drinks of high-proof alcohol than normal monkeys did. The motherless monkeys were similarly insensitive to other substances that, like alcohol, increase the impact of the neurotransmitter GABA (gamma aminobutyric acid), which inhibits signals between neurons so the cells do not get overexcited.

As a result of this reduced sensitivity, the rhesus monkeys raised in isolation could drink an unusually large quantity of alcohol--and they sought to do so when researchers provided free access to the drug. Human studies have revealed similar changes in peoples brains.

Altered brain chemistry resulting from experience is just one factor that contributes to individual differences in susceptibility. Genes play a role, too. Schuckit maintains that up to half the causal factors for reduced sensitivity to alcohol are inherited. In a small-scale study that tracked people for 15 years, Schuckits research group found that a variation in the gene that codes for a part of the GABA receptor may be related to low sensitivity to alcohol.

Although high tolerance to alcohol from adjusted brain chemistry or genetics may seem like a protective trait, it is ultimately damning. If such an individual consumes quantities of alcohol regularly, his or her brain and body will gradually become accustomed to the poison, almost assuring the person will become addicted.

Dangerous Accommodation
Tinkering with the GABA system could perhaps offer a fix, but alcohols effects on brain chemistry depend on more than just GABA uptake. The drug does not merely boost the inhibitory function of GABA on neurons; it also blocks the excitatory effects of their NMDA (N-methyl-d-aspartate) receptors. These receptors bind glutamate, which comes from neighboring neurons and enables the receiving neuron to forward signals on to others in the network. Guochuan Tsai, now at the University of California, Los Angeles, and Joseph T. Coyle of Harvard Medical School have discovered that the brain, when exposed to chronic alcohol consumption, creates additional NMDA receptors to compensate for the blocking effect [see box on preceding page]. The brain is trying to find a new balance between the underexcitatory action of glutamate and the overinhibitory action of GABA.

The repercussions come, however, when alcohol is withdrawn for a few days or, for hard-core drinkers, even overnight. The NMDA receptors maintain their increased sensitivity, and the GABA receptors maintain their reduced sensitivity. Yet without the alcohol that this new balance is attempting to counter, the brains networks fire erratically, causing withdrawal symptoms. Anyone who wakes up with tremors, sweating or nausea and immediately needs alcohol is already critically dependent. The victims brain is so utterly adapted to the drug that even the few nighttime hours without it are enough to throw the new chemistry into a tailspin.

Such withdrawal symptoms can be combated with agents such as chlormethiazol or a benzodiazepine, which restore the sensitivity of GABA receptors and calm the patient. Acamprosate suppresses NMDA receptors and seems especially helpful for persons suffering from conditioned withdrawal. Clinical studies show that 30 to 40 percent of patients remain dry for the first year after detoxification while taking acamprosate. The drug is particularly effective during the first few hard months of abstinence, when relapse rates are the highest. The results still leave a high failure rate, however, necessitating additional therapeutic measures such as self-help groups and individual counseling.

One reason medication can be insufficient is that alcohol also works on dopamine, the neurotransmitter that runs the motivation and reward system. Normally, stimuli that are important to survival--related, for example, to feeding and sex--trigger the release of dopamine. The neurotransmitter increases our anticipation of happiness and makes us want these things. The pleasant reward feelings, in turn, make us seek the sensations again and again, and we engage more strongly in the behaviors that cause dopamine to be released. Addictive drugs such as heroin unleash the same mechanisms.

As it does for GABA and NMDA, brain chemistry related to the reward system also adapts to fit the constant presence of alcohol. The brain reduces the number of dopamine binding sites on neurons, called D2 receptors, to protect itself from a persistent oversupply of the neurotransmitter. Alcohol affects other aspects of the motivation system as well. When alcoholics look at photographs of beer or wine, the regions of their brain that control attention are aroused more than they are for nonalcoholics, according to MRI imaging studies done in my lab. The fewer the D2 receptors they have, the more activity is elicited in their attention centers by the sight of alcohol.

This predilection explains why it is so difficult for alcoholics to find other stimuli pleasant and rewarding. It seems almost impossible for them to become interested in anything new that might bring satisfaction--be it a relationship, a hobby or even good food. The more serious the damage to the dopamine system, the more fixated attention becomes on the familiar images of alcohol--even when the person is lying inside the narrow, noisy tube of an MRI machine, when the brain knows it is not about to receive beer or whiskey.

The extent to which the attention centers can be activated in this lab situation highlights the severe problems recovering alcoholics have ignoring the advertising all around them. About a third of the subjects in our studies complain about the powerful effects of television commercials, especially when they are broadcast in situations in which patients would previously have been drinking, such as while watching a football game.

Tainted Pleasure
Although dopamine directs desire, the actual feeling of pleasure comes from endorphins--the bodys own opiatelike substances. Once again, regular drug use changes the system. Alcoholics develop a higher number of binding sites for endorphins. When they drink, their neurons bind more endorphins, producing a greater feeling of pleasure.

Certain medications have been designed to alter this interchange. Naltrexone, for example, blocks the receptors and can reduce the risk of relapse considerably. Recovering alcoholics say that if they are taking naltrexone and have a drink, the taste is foreign, to the point of being terrible. Yet the drug alone, without psychosocial care, is not enough, because for some patients the second or third drink will start to taste good again. A patient must want to live abstinently; then, naltrexone will help him or her avoid that first sip.

With the expanding understanding of how alcohol alters the action of neurotransmitters, it is becoming clear that people addicted to alcohol are suffering from dramatic changes in brain activity. No particular personality type is prone to becoming dependent. The culprit is excessive alcohol consumption itself, which changes the brain so that victims can no longer free themselves from the bottle. It is time to destigmatize alcoholism and to develop better methods of breaking dependency and preventing relapse. The knowledge gained from research certainly opens avenues for creating new drugs. Still, alcoholics need one aid above all: people who will listen to and stand by them as they strive to recover.