Substance Abuse - What Drives Alcohol Addiction

From Visions, Spring 2006

Howard has a “drinking problem.” His story of substance abuse may be familiar.

Howard’s dad gave him his first beer when he was in the eighth grade. Dad thought it was a good idea for the boy to drink at home, so he wouldn’t have to go somewhere else to do it. Howard also had a few beers when his parents didn’t know about it.

By senior year of high school, Howard was having more than a few a couple times a month, sometimes passing out at a friend’s house so his folks wouldn’t know.

In college, his main sport was a drinking game called beer pong. He dabbled with marijuana and cocaine, but his ol’ faithful was alcohol.

After a binge weekend, Howard could always stay sober for a while, especially when he had a lot of school work to do. Because he could go for days without drinking, he was convinced that he had no problem with alcohol substance abuse.

He got his first DWI in college. Despite stiff penalties, even losing his license for a year, it happened again. He totaled his car while driving drunk a few years after graduation.

Now on his third job out of college, Howard says he has cut back on his drinking. Still, a weekend binge is not unusual, and week-nighters over poker are a staple. Sometimes it’s tough to get to work and accomplish anything, but he manages to avert suspicion. And he almost never drinks during the workday.

He has gotten better at doing some things he used to have trouble with when he was high — putting on a good face at the office, mowing the yard, playing with the kids, driving …. He has developed a tolerance for alcohol that lets him perform physical tasks better after drinking the same amount he did before — and that encourages him to drink more and deepen his substance abuse problem.

Howard says alcohol still takes the edge off, but he never has that same “flyin’ high” feeling he got from drinking when he was younger.

And there is a problem with sleeping. When he drinks, he can’t seem to get a good night’s sleep, but if he goes too long without a drink, he can’t get to sleep at all — that is, until the next afternoon at the office, when he can’t seem to stay awake.

Howard may be getting by, but without some kind of help, he can expect eventually to lose his job, his health, maybe his family. He may seriously hurt himself or someone else. He’s definitely going to be a tremendous burden to society for the costs of his health care and lost productivity.

Alcohol Dependence To Alcohol Substance Abuse

Howard is what the National Institute on Alcohol Abuse and Alcoholism calls “alcohol dependent,” or what most people call an “alcoholic.” “Alcohol dependence,” according to the NIAAA, “is a condition characterized by impaired control over drinking, compulsive drinking, preoccupation with drinking, tolerance to alcohol, and/or withdrawal symptoms.” One step away from alcohol dependence is another level of problem drinking that the NIAAA calls “alcohol abuse ... characterized by failure to fulfill major role obligations at work, school or home, interpersonal social and legal problems, and/or drinking in hazardous situations.”

Howard has lots of company. The number of American adults 18 and older who fall into either substance abuse category rose from 13.8 million in 1991–92 to 17.6 million in 2001–2002, according to an epidemiological survey directed by NIAAA. You would expect the number to go up, because the population increased; however, the percentage of problem-drinkers in the population also increased, from 7.41 percent to 8.46 percent.

Not surprisingly, young adults 18–29 are the heaviest drinkers. Overall, more than 10 percent of those young adults in the 2002 survey were either alcoholics or substance abusers, and that percentage had not changed much over the previous 10 years. However, the percentage of some young minority adults abusing alcohol had increased dramatically, specifically among black males, Asian females and Hispanic males. Alcohol dependence significantly increased among young black females and Asian males.

When those findings were announced in 2004, NIAAA director Ting-Kai Li, MD, said, “The fact that alcohol disorder rates are highest among young adults underscores the need for concerted research on drinking patterns that initiate in adolescence.” 

Which is exactly what is going on — among other alcohol research — at Wake Forest Baptist Medical Center.

Substance Abuse Developmental Disorders

“NIAAA and NIDA (National Institute on Drug Abuse) are both concluding that alcohol dependence and substance abuse are developmental disorders, so they tend to emerge early in life, in adolescence or even before,” said Allyson J. Bennett, PhD, assistant professor in the Department of Physiology and Pharmacology and the Department of Pediatrics.

“If you want to understand how adults became alcoholics, you want to begin studying them early in life,” said Bennett, who is part of an NIAAA Center of Excellence grant, first awarded in 2003.

That’s not possible with human research subjects. Once it has been established that an adult subject is alcohol dependent, researchers cannot then turn back the hands of time to look at them as children or adolescents, to try to identify factors that might have sent them along what Bennett called the “risk pathway” toward drinking problems.

So Bennett and other researchers turn to animal models — in her case, monkeys.

“There is no single gene or combination of genes and environmental influences that pull individuals along that risk pathway,” she said. Only a handful of genes have been identified that tend to have been associated with alcohol substance abuse in humans, and monkeys have similar genetic risk factors. That allows researchers to control environmental variables such as parental attention and stress levels to see what will increase vulnerability to alcohol substance abuse, or promote what Bennett calls “resilience” from negative genetic factors.

“There could be a genetic variation or a gene that puts one at risk for changes in neurochemistry that are associated with alcoholism. But there may be early-childhood environments that promote resilience,” she explained, “so that under the right conditions the individual with that genetic vulnerability does not go on to become an alcoholic.

“It goes the other way too. You might have a very bad environment, but something about your genes protects you from its adverse effects.”

Genes, Bennett hastens to add, contribute only part of the risk for alcohol or drug problems. There are many genes that contribute, and the vast majority of them have yet to be discovered.

Serotonin, Stress And Binge Drinking

A monkey model that has proven very useful for the childhood and adolescent research is one in which the animals are taken away from their mothers soon after birth and are nursery- reared, creating a certain level of “stress,” compared to a maternally raised monkey. And the nursery-reared monkeys tend to drink more than the maternally raised animals.

The genetic risk factors for alcoholism, binge drinking, depression and other substance abuse problems have been linked to the neurotransmitter serotonin. In their monkey models, the Medical Center researchers can follow the animals’ development behaviorally and neurochemically to try to discern each twist and turn of the risk pathway.

Binge drinking is a particular problem among human adolescents. The latest statistics from NIAAA indicate that more than 12 percent of 8th-graders and nearly 30 percent of 12th-graders report drinking five or more drinks in a row in the past two weeks. Bennett’s research focuses on how starting to drink in adolescence might increase risk of excessive drinking in adulthood and also on how binge drinking in adolescence affects physiology, maturation and behavior.

Work by Bennett and others has already shown that kids who start drinking early and binge drink as adolescents, like Howard, are at greater risk for alcoholism as adults. But exactly why is that? And now that they know the early drinkers will have problems later, is it possible to know who those early binge drinkers will be? That pursuit has led the Wake Forest researchers to one of their biggest findings of the past year.

"What we’ve found is that monkeys that are high in response to novelty — they’re quick to impulsively touch new things — are those that go on to binge drink or drink very quickly when they first begin to drink, and then eventually become the heaviest drinkers,” Bennett said.

“What’s interesting about that is we also know that low serotonin is associated with that impulsivity or that high-risk kind of behavior. We know that in adolescence serotonin drops, in both humans and monkeys, and that makes sense because the role of adolescents in most species is to go out and try new things. So it’s logical that the neurochemistry would support that.”

Risk-taking

Risk-taking is a focus of the human alcohol research of Anthony Liguori, PhD, associate professor of physiology and pharmacology. Liguori is director of the Human Performance Lab, which can simulate driving and other motor tasks under the influence of alcohol and other drugs.

In one recent study, Liguori gave male social drinkers varying amounts of alcohol then put them in the driving simulator. They could earn points by making a risky lane change, but would lose points if they hit a cone. Liguori found that only a mid-range dose of alcohol, below the legal limit, “significantly increased risk-taking” in the face of the greatest penalty.

“This finding suggests that breath alcohol concentrations within current legal standards can alter a driver’s decision-making such that the willingness to enter a high-risk situation is increased,” he reported.

Stress Response

Interestingly, the NIAAA center’s young nursery-reared monkeys also have low serotonin levels even before adolescence, said David Friedman, PhD, professor of physiology and pharmacology and director of the NIAAA center.

Friedman has been closely examining the stress-response system of the nursery-reared monkeys and comparing their “endocrine profile” with that of maternally raised monkeys. The stress response is a cascade of neuroendocrine events that ultimately leads to the release of cortisol, which prepares the body to deal with stress.

“We’ve been able to show that in some ways at least, their stress response is blunted,” Friedman said. “Because their internal chemical environment is different, they may for some reason be more vulnerable to the effects of alcohol. It’s certainly reasonable to suggest that those chemical differences may be in part responsible for the increased drinking.”

Now, he said, “what we’re trying to do is look further into the brain at neurotransmitter systems, especially serotonin, that also modulate the stress response, because we know that serotonin is affected by alcohol. We also know that these nursery-reared monkeys when they’re infants have lower amounts of serotonin in their brains. So what I’m looking at is this link between alcohol, serotonin and stress response.”

Bennett thinks serotonin adjustments might also hold promise for steering adolescents away from early alcohol use and substance abuse. And it could begin with something as relatively simple as diet. She notes that serotonin comes from dietary tryptophan, which is abundant in breast milk, but much less so in formula like that fed to the nursery-reared monkeys. She theorizes that this could cause long-lasting changes in serotonin levels.

“We don’t know if we can reverse it, but we’re learning how we might treat it, with pharmaceuticals or nutriceuticals or altered diet,” Bennett said.

Generally, she said, the substance abuse research is showing that a youth’s environment is a major part of the risk — or resilience — pathway to alcohol, and parents can be an influential part of the environment. “They need to know that alcohol use may have unique effects on adolescents, and that encouraging them not to engage in it, or to at least postpone it until their twenties, is a good idea.”

Rodent Models Show Drinking Behaviors

What exactly happens at the cellular or even molecular level when someone abuses or becomes dependent on alcohol? To try to answer those questions, Medical Center researchers turn to rodents, which have been shown to be excellent models for many other human diseases and conditions.

“We’re working on developing a very sophisticated rodent model of alcohol drinking and substance abuse where we can measure a whole variety of drinking behaviors of rats that are voluntarily drinking enough alcohol to get drunk,” explained Jeff Weiner, PhD, professor of physiology and pharmacology and scientific director of the Wake Forest NIAAA center.

“We can study how hard they want to work to get drunk, how much they drink, how impaired they get, and then sacrifice them and look at the synapses in the brain and study how they’ve changed, how they responded to alcohol. With this model we can begin to look at synaptic correlates of alcohol-related behaviors.”

Weiner explained that much is already known about how alcohol generally operates in the brain, by shifting the balance between excitatory and inhibitory communication between neurons in favor of inhibition — thus the reason that alcohol is considered a depressant.

“What we don’t really know,” he said, “is which synaptic mechanisms are most important for any alcohol-related behavior.” That, however, is changing as a result of work at the NIAAA center.

Weiner’s lab uses very sophisticated electrophysiology techniques that can isolate just an inhibitory synaptic connection or just an excitatory connection between two brain cells, and determine if the properties or the alcohol sensitivity of that synapse has changed.

“The history of alcohol drinking obviously is changing some of the properties of these synapses, and we think that’s important in contributing to addiction,” Weiner said.

“But what’s more exciting is that we’re finding that there are things that don’t change with the alcohol drinking. Some of those properties may actually correlate with the drinking patterns of the animal, so what we’re finding are probably synaptic traits that may actually contribute to the drinking patterns that we were studying.”

When something does change in the brain as a result of chronic drinking, it’s called “tolerance.” It typically happens with motor-impairing effects, so that over time an alcoholic can drink more and more before it begins to affect his speech or his movement.

Weiner has discovered that one important mechanism of acute alcohol consumption does not show tolerance — an increase in synaptic inhibition caused by the neurotransmitter known as GABA (gamma-aminobutyric acid). Alcohol increases this synaptic inhibition, and “whether it’s your first drink or your thousandth drink, that acute effect doesn’t seem to show tolerance, to go away,” he said.

And whatever the actual feeling is that results from this synaptic effect, it apparently encourages animals to drink. “That alcohol sensitivity (of the synapse) correlates with alcohol-seeking behavior. So the animals that are the most motivated to drink alcohol are actually the ones whose synapses are the most inhibited by alcohol.”

So, what is the feeling? Weiner and others theorize that this synaptic effect may contribute to the anxiety-relieving effects of alcohol. “It’s well established that GABA is very important in anxiety, and when you increase GABA you decrease anxiety. What’s interesting is that the anxiolytic (anxiety-relieving) effects of alcohol are some of the few effects that don’t show much tolerance. So even long-time alcoholics still feel those anxiolytic effects of alcohol, and that could be a major reason that they drink.”

Alcohol And Anxiety

The link between alcoholism and substance abuse and anxiety — at both the behavioral and genetic levels — is under study in rodents by Brian A. McCool, PhD, professor of physiology and pharmacology.

“It has been known for a long time that anxiety and alcohol abuse tend to go hand-in-hand. Alcoholics who withdraw often relapse when they’re stressed, when they report high levels of anxiety,” McCool explained. “So most of the research we’ve done has utilized these animal models to understand neurobiological mechanisms, the proteins, the genetic basis in the brain that is responsible for those interactions.”

McCool uses behavioral tests that indicate when a rodent is feeling stress or anxiety. He can then measure the effect of alcohol — and the removal of alcohol — on anxiety levels. Using a complementary approach, the McCool lab can target alcohol or drugs to specific brain regions using implanted “guide” cannulae to examine how neurotransmitter systems contribute to anxiety. He can then use electrophysiology to study the electrical signals that mediate communication between neurons, and try to understand how alcohol influences that communication.

“The main point is to understand how the animal is adapting at a cellular level,” he said, “how are the neurons themselves changing in response to the exposure to the drug? We look at a lot of different markers for that.” Those markers include gene expression (production of messenger RNA) and receptor function (identifying particular proteins in the brain that mediate communication between neurons).

Two or three genes have been identified as relevant for alcoholism, McCool said, and his lab has been sending out tissue to test for new genes. But he is quick to point out that most of what we know about genetic mechanisms in the brain are “global,” or affecting the whole brain generally.

“The brain is not a uniform tissue. It’s made up of many, many systems that interact with each other in very complicated ways,” he said. We are all born with the same complement of genes, but they may be acting — or at least reacting — quite differently in different brain regions.”

Eventually, McCool said, he hopes his work could have substance abuse treatment potential. “Right now we’re just understanding how those alcohol-related consequences are manifested in the cells. Ultimately I would like to see my lab evolve towards manipulating neurotransmitter systems that are altered by chronic alcohol use, in the hopes of diminishing some of the negative consequences.”

Weiner, too, hopes that his and the NIAAA center’s work can directly address the root causes of problem-drinking. “Self-medicating” to relieve anxiety may be one of those causes, and it doesn’t help that people — like the rodents — may not build up a tolerance to those anxiety-relieving effects. As with Howard, drinking “takes the edge off” time after time. But the problem is, alcohol withdrawal also creates anxiety, which leads to more drinking.

How can the research change that? “The goal would be,” Weiner speculated, “that if we find out that these GABA synapses in, let’s say, the hippocampus, are very important in alcohol drinking behavior, then obviously we would want to test pharmacotherapies that, as specifically as possible, target those hippocampal GABA synapses.

“We’re trying to figure out what exactly is responsible for the alcohol drinking behavior and the escalation in alcohol drinking behavior and alcoholism, and then try to find drugs that directly target those mechanisms.”

Seeking Pleasure

Anxiety relief is one cause for alcohol substance abuse. But another major substance abuse cause could also be, simply, pleasure. Is that possible? Can someone who starts drinking just because it makes them feel good go on to abuse or become dependent on alcohol?

Those are among the questions that Sara R. Jones, PhD, professor of physiology and pharmacology, is trying to answer in her rodent research.

The euphoric effects of alcohol and most other abused drugs are associated with the amount of the neurotransmitter dopamine in the brain synapses. Virtually all abused substances elevate “extracellular” dopamine levels in the nucleus accumbens and other brain regions, but they do it in different ways.

Alcohol increases dopamine levels by directly raising the firing rate of isolated dopamine neurons, Jones said. That is well established. Beyond that, she said, there is some controversy over other ways that alcohol might influence the dopamine system.

One theory, which Jones’s work has recently disproven, was that alcohol also blocked uptake by dopamine transporters, with the net effect of leaving more dopamine in the synapse. This is the mechanism cocaine uses to elevate dopamine.

“What we have published is that that’s wrong,” Jones said. She explained that her lab uses tiny electrodes that actually take measurements across individual synapses at intervals of 1/10 of a second. “This is really the best way to look at dopamine uptake, and we have shown that alcohol does not inhibit dopamine uptake.”

In fact, she said, after chronic alcohol use the brain actually increases the number of dopamine transporters, trying to carry away the increased amount of dopamine in the synapses. This bodes ill for the alcoholic.

When the alcohol stops, so does its increased dopamine production. But the extra number of transporters remains, clearing away what little dopamine there is. When this occurs in Jones’s mouse model, “they are the most depressed mice you’ve ever seen. They have almost no dopamine, and that has got to be a very anhedonic or dysphoric state.” In human terms, she said, “you feel very, very low, and you can’t feel any normal pleasure.”

And that, she said, could be a reason that alcoholics relapse. “These mice are probably going back to the alcohol because the alcohol brings their dopamine back up to a ‘normal’ level. Why wouldn’t you go back to the alcohol, to try to get back to a normal state?”

So what began as a pleasurable experience, over time becomes a necessity, just to try to bring things back to something approaching normal. “And that takes weeks (of abstinence) to recover from, to reach a naturally normal dopamine state again, even in a mouse that’s only been exposed to alcohol for four days,” Jones said.

“You can imagine that after years of drinking, people may never recover. If you’re a motivated alcoholic, you can go without a drink for a week. But six months down the road, if you’re still not feeling good, it’ll wear you down.”

Reason For Hope?

So what hope is there through substance abuse research?

One possibility for prevention, Jones said, is that in the future we may be able to identify dopamine- or serotonin-related risk factors for alcoholism, which your doctor could inform you about, similar to the way we now understand risk factors for breast cancer.

There are also possibilities for treatment related to the dopamine system, to try to lessen the craving and the likelihood of relapse. Those include using L-dopa (which is enzymatically converted to dopamine) just enough to try to give people a motivation to stay off alcohol, analogous to methadone treatment for heroin addiction. Other possibilities, she said, are the new generation of antidepressants, and even the old “tricyclic” antidepressants that raised dopamine directly.

There is very good help now for alcoholics like Howard, through successful substance abuse treatment programs for adults and adolescents such as those offered through the Medical Center’s Department of Psychiatry and Behavioral Medicine.

Research at Wake Forest Baptist and other institutions shows great promise for better understanding and treating alcohol abuse and dependence.

Even if you don’t know someone like Howard who has broken your heart with his or her affliction, it is easy to justify the federal government’s spending for alcoholism research. We all pay, one way or another.

In 1998, the most recent NIAAA figures available, the total economic cost of alcohol substance abuse was $185 billion a year and rising. That included health care costs, lost productivity, auto accidents, crime and social welfare administration. At the same growth rate, the estimate would be over $230 billion this year.

The Medical Center’s alcohol researchers are enthusiastic and hopeful about making an impact on the mammoth problem. “It’s a pretty exciting time here at Wake because there’s a lot of interdisciplinary interaction between research that spans all the different levels of analysis,” Weiner said. “Over the last five years, we and others have made major advances in figuring out how alcohol acutely and chronically alters the brain.”

“Howard” was inspired by a recent interview with a long-time alcoholic, now undergoing treatment at Wake Forest Baptist Medical Center.

For information and resources about alcohol, go to www.niaaa.nih.gov.

Disrupting The Sleep Cycle

“It’s a case of a cat chasing its tail,” said Dwayne W. Godwin, PhD, professor of neurobiology and anatomy.

“While in the short term alcohol can make you fall asleep faster,” he said, “there are severe disruptions in the quality and pattern of sleep caused by alcohol.

“The brain is wired to operate on a 24-hour ‘circadian’ schedule,” Godwin explained. “Even moderate alcohol consumption disrupts that schedule, and it’s a significant source of sleep problems for alcoholics.”

Godwin said sleep is a reason many people turn to alcohol, and it becomes a major reason that many alcoholics can’t stop abusing alcohol — and wind up like those cats chasing their tails.

Sleep initiation, he explained, is controlled by the brain’s master clock, called the suprachiasmatic nucleus. Each day, the clock is reset by light signals from the environment, which helps the body to stay in sync with its surroundings. A key part of the resetting mechanism is a calcium ion channel “that we have found to be very sensitive to the effects of alcohol,” Godwin said.

“Moderate amounts of alcohol can cause a phenomenon where you get good sleep during the early part of the night, but at the cost of awakening during the later part of the night.

“Alcoholism can actually produce a neuroadaptation in this sleep circuitry that will cause long-term disruptions in sleep quality. Those sleep disruptions can last months or years after a person completely stops drinking. The changes in the brain that underlie this effect are poorly understood, and if we can determine how they are switched on and off by alcohol it will help in the design of therapies that would reduce their influence on the recovery process.”

An important part of this is to understand the basic circuit properties and neurotransmitter systems that are involved in sleep disruption. 

At the cellular level, the lab uses electrophysiology to precisely measure the calcium flow in brain cells from mice that are exposed to alcohol. In the suprachiasmatic nucleus, a number of “clock genes” are turned on and off on a daily schedule by the rise and fall of calcium levels. At the molecular level the lab is studying how disturbances in these calcium channels can disrupt the normal calcium signals that are important for the daily expression of these clock genes.

“Our operating hypothesis is that alcohol is actually blunting those normal circadian cues and causing the brain to cycle abnormally — like jet lag in a bottle.”

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