Increased connections among brain cells caused by excessive drug use may represent the body’s defense mechanism to combat addiction and related behaviors, scientists at UT Southwestern Medical Center have concluded.

Previous studies have shown that repeated use of drugs such as cocaine, amphetamines and nicotine increase the number of anatomical structures called dendritic spines in brain regions associated with pleasure and reward. These dendritic spines represent sites where brain cells communicate with one another. Many scientists believe that this long-lasting brain rewiring underlies the similarly persistent behaviors of drug-taking and drug-seeking associated with addiction and relapse. The mechanism that controls this brain rewiring, however, and its relationship to addiction-related behaviors were previously unknown.

In a study appearing in the Aug. 28 issue of Neuron, researchers found that cocaine suppresses the activity of the protein MEF2 in mice. Because MEF2 normally reduces the number of brain connections, suppressing MEF2 leads to an increase in dendritic spine density. The researchers also found that when they enhanced MEF2 activity in the brain this blocked the drug-induced increase in dendritic spine density and increased addiction-related behavioral responses to cocaine.

“Our findings suggest that increased brain connections during chronic drug use may actually limit behavioral changes associated with drug addiction, rather than support them,” said Dr. Christopher Cowan, assistant professor of psychiatry at UT Southwestern and senior author of the study.

Researchers said they hope this finding could lead to a pharmaceutical treatment for addiction.

“Relapse, or the resumption of active drug-taking and drug-seeking, is very common in drug addicts,” Dr. Cowan said. “Addiction-related brain changes and behaviors seem to be hardwired and semipermanent, and there are limited treatment options. Our data suggest that rather than trying to block the process of increasing dendritic spine density, we may actually want to look at treatments that try to enhance this process.”

MEF2 is activated in response to brain activity. It provides negative feedback to eliminate the potential growth of too many communication sites between nerve cells. Repeated exposure to cocaine disrupts this function of MEF2, resulting in new brain connections.

To investigate the relationship between MEF2 and spine-density changes, the researchers varied the level of the protein in an area of the brain called the nucleus accumbens. This region is associated with the feelings of reward that drug addicts seek. Brain imaging done after mice were given cocaine showed that cocaine stopped MEF2 from limiting dendritic spine increases.

To test MEF2’s relationship to behavior, researchers monitored the movement of mice after repeated daily exposure to the same amount of cocaine. This same dose of cocaine produced a larger behavioral response after repeated days of drug injections, resulting in a “sensitized” response. This sensitized behavioral response to the drug is very stable, lasting for many months after the drug is discontinued.

When the researchers manipulated animals so that their MEF2 levels remained high in the presence of cocaine, the animals were more sensitive to the drug. This suggested that increased communication sites might help combat the addiction process.

“This suggests the exciting possibility that MEF2 proteins may control expression of key genes that modulate drug-related brain changes and behavior,” Dr. Cowan said. “If we understand which genes are influenced by MEF2, we can intervene and try to help the system resist or reverse these sensitization processes.”

In 2006, 23.6 million people ages 12 and older needed treatment for drug or alcohol abuse, according to a Substance Abuse and Mental Health Services Administration survey. Substance abuse costs the U.S. more than half a trillion dollars annually, according to the National Institute on Drug Abuse.

Future research will focus on determining MEF2 target genes and exploring drug-related density changes in other regions of the brain associated with addiction, Dr. Cowan said.

Other UT Southwestern researchers involved in the study were Dr. Suprabha Pulipparacharuvil, instructor of psychiatry; William Renthal, graduate student in psychiatry and neuroscience; Carly Hale, research technician in psychiatry; Dr. Makoto Taniguchi, postdoctoral researcher in psychiatry; Colleen Dewey, graduate student in neuroscience; Dr. Scott Russo, assistant instructor of psychiatry; Dr. Devanjan Sikder, instructor of internal medicine; and Dr. Guanghua Xiao, assistant professor of clinical sciences. Dr. Eric Nestler, former chairman of psychiatry, and former instructor Dr. Arvind Kumar were also involved. Researchers from Yale and Rockefeller University also participated.

The work was funded by the Whitehall Foundation, the National Institute on Drug Abuse and the National Institute of Mental Health.

Alcohol Consumption Can Cause Cell Death Leading To Abnormalities

New insight has been obtained regarding how alcohol during pregnancy might affect fetal development, according to research performed at the Medical College of Georgia Schools of Medicine and Graduate Studies, funded by the March of Dimes.

Fetal alcohol syndrome (FAS) according to the Centers for Disease Control and Prevention, affects 1 in 1,000 babies. Pregnant and sexually active women who are not using effective birth control are recommended to refrain from drinking. Most notably, babies who are the victims of this deases have classic facial malformations, including a flat and high upper lip, small eye openings, and a short nose. These facial clues could provide insight into the mechanism of this process, as well as how much alcohol imposed at what point in development might cause these changes.

Dr. Erhard Bieberich, biochemist in the Medical College of Georgia Schools of Medicine and Graduate Studies, has focused work on the mechanism that cause problems for children with FAS. Strong evidence has shown that, in just the first few weeks of fetal development, usually a period before a woman knows that she is pregnant at all, a few glasses of wine in an hour could increase cell death. Death of cells that might further develop to form the face, brain, or spinal cord could lead to developmental problems in these areas. "It's well known that when you drink, you get a buzz. But a couple of hours later, that initial impact, at least, is gone," states Bieberich. "But, your fetus may have experienced irreversible damage."

In development, there is always a set of cells that die once they have served their purpose, and a set of cells that move on to form other types of cells. "There is always a very delicate balance between newly formed cells and dying cells," says Bieberich. "It's a very active period of that balance, because usually you develop a surplus of tissue then later melt it back down to acquire a specific shape." The classic example of this phenomenon is the absense of webbed fingers in newborns, while the fetus maintains skin between the fingers for some time. "The digits form because the inter-digital tissue dies. If it did not die, we would have paddles instead of hands with fingers," Bieberich says. 

According to the team, damage may result from the accelerated death of neural crest cells, which help form various types of connective tissue, including bone, cartilage, and parts of the cardiovascular system. At the same time, neural tube cells form the brain and spinal cord. This means that the visible damage shown in facial abnormalities may be a signal that future problems could be present in learning, memory, vision, hearing, or other areas. The cell death can result from disruption of the metabolism of the lipids that help control the initially undifferentiated cells, due to alcohol.

The team compares cell loss in mice following various levels of alcohol consumption to the usual birth and death of cells in normal development. The focus lies in the neural crest cells, which among their other functions form the upper part of the skull. Some of these cells will remain in the brain, and are often controlled by the same factors as the neural tube cells, which might lead to the cognitive and memory problems. While this type of damage may be difficult to identify in mice of this age, it has been shown that damage to the neural crest gene can cause problems in both skull and brain development.

These measurements will help women understand the true risks of alcohol consumption during pregnancy, and help develop a method to reduce the damage. Dr. Bierberich hopes for better education: "You have to make people aware of the science behind the risk," he says. "We are not saying that every pregnant woman who drinks three or four glasses of wine in a short period will have a baby with birth defects, but it elevates the risk."

For more information about the Medical College of Georgia and the Bieberich Group, please see http://www.mcg.edu/ .

Researchers Study Relationship Between Injecting Drug Use And HIV

Estonia, Ukraine, Burma, Indonesia, Thailand, Nepal, Argentina, Brazil, and Kenya all have one disturbing fact in common: an HIV positive rate of over 40% for injecting drug users (IDUs). An article published early online and in an upcoming edition of The Lancet estimates that worldwide there are some 15.9 million IDUs - 3 million of whom are HIV positive. In the last ten years, the number of countries that report injecting drugs use has increased. However, Dr Bradley Mathers (National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia) and colleagues from the 2007 Reference Group to the UN on HIV and Injecting Drug Use maintain that HIV transmission in many regions is bolstered by IDUs, and the research community needs better data from around the world in order to address the problem.

The authors conducted a systematic review of HIV use among IDUs and found some interesting differences around the world. In the United Kingdom, 0.39% of 15-64 year-olds are IDUs and 2.3% are estimated to be HIV positive. These data contrast with Spain, where 0.31% of the same age group are IDUs, but the percentage of IDUs with HIV is 39.7% - several times higher. The table below summarizes these figures for other countries:

Italy and Switzerland had the highest proportion of IDUs among 15-64 year-olds in western Europe, with 0.83% and 0.65%, respectively. However, Spain and Portugal had the highest proportions of IDUs that are HIV positive with 39.7% and 15.6%, respectively.

In Africa, where a "constellation of risk factors exists for the development of injecting drug use," there is not as much information compared to European countries - a serious concern for the authors. The researchers note that for regions with data, "Areas of particular concern are countries in southeast Asia, eastern Europe, and Latin America, where the prevalence of HIV infection among some subpopulations of people who inject drugs has been reported to be over 40%." Although a 1998 review identified 129 countries with injecting drug use, only 103 reported HIV use among the IDUs. This new research from Mathers and colleagues expands the knowledge base to 148 countries with IDU and 120 of reporting HIV among this population. "There is a pressing need to understand injecting drug use in all countries," emphasize the authors.

"Injecting drug use occurs in most countries and HIV infection is prevalent among many populations of IDUs, representing a major challenge to global public health. People who inject drugs have the right to enjoy the highest standard of health attainable," conclude the researchers. "There is a clear mandate to invest in HIV prevention activities such as needle and syringe programmes and opioid substitution treatments and to provide treatment and care for those living with HIV/AIDS. The magnitude of this risk has not been met with an equally concerted investment in research to accurately quantify the problem."

Dr Kamyar Arasteh and Dr Don C Des Jarlais (Beth Israel Medical Center, Baron Edmond de Rothschild Chemical Dependency Institute, New York, USA) write in an accompanying comment about various factors that could explain the rise in injecting drug use worldwide. "The one optimistic aspect of this rather gloomy situation is that, if HIV-prevention efforts are implemented on a large scale when prevalence is low in injecting drug users, it is possible to avert HIV epidemics in users. Thus it should be an imperative - for both resource-constrained countries and international donors - to implement large-scale evidence-based programmes for HIV-prevention whenever there is an indication of a developing injecting-drug-use problem."

Global epidemiology of injecting drug use and HIV among people who inject drugs: a systematic review
Bradley M Mathers, Louisa Degenhardt, Benjamin Phillips, Lucas Wiessing, Matthew Hickman, Steffanie A Strathdee, Alex Wodak, Samiran Panda, Mark Tyndall, Abdalla Toufik, Richard P Mattick, for the 2007 Reference Group to the UN on HIV and Injecting Drug Use

Experience, Science And The Drinking Age

Recently more than 100 college presidents surrendered their authority to do something meaningful about campus alcohol abuse by urging policymakers to lower the drinking age from 21 to 18. There has not been so great a "hand-washing" of a significant problem since Pontius Pilate! Thankfully, this group did not include University of Wyoming leadership.

I have a unique perspective on this issue. I was a member of the Wyoming Legislature when it lowered the drinking age to 18 in 1973. In fact I co-sponsored the bill. We argued then, as do these college presidents now, that if you were old enough to go to war (then it was Viet Nam) you were old enough to drink. We railed that the law was not enforced and argued that learning to drink earlier in life would teach responsibility. I was just as wrong then as these college presidents are now.

Two matters have changed my mind since we experimented with a lower drinking age in the 1970s. One is simply that we tried that route and it didn't work. The other is the science and research available today that was not available then.

Any informed discussion must be based in part on our knowledge as state leaders, the experience of local community coalitions, and the extensive literature dedicated to underage drinking. This knowledge, experience, and research all point to an important conclusion: the current 21 year-old drinking age is consistent with human brain development and is an essential component of a comprehensive strategy to advance healthy lifestyles and address the negative consequences of youth alcohol use.

When the U.S. Surgeon General visited Wyoming this spring he noted "adolescence is a time when the developing brain may be particularly susceptible to long-term negative effects from alcohol use." The Surgeon General's research establishes the use of alcohol is a significant health issue for youth as their brains are not fully developed until well into their 20s "creating a significant and extended period during its development of potential exposure to alcohol's harmful effects."

Underage drinking has a devastating impact in this country:

Mortality: It is estimated underage drinking is responsible for the deaths of approximately 5,000 people under the age of 21 each year - including 1,900 deaths from motor vehicle accidents. The National Highway Traffic Safety Administration found drinking drivers under the age of 21 are involved in fatal crashes at twice the rate of adult drivers.

Student violence: Every year, alcohol is the cause of more than 696,000 assaults and 97,000 instances of sexual assault or date rape among college students. According to the National Institute on Alcohol Abuse and Alcoholism, 11 percent of students damaged property while under the influence of alcohol.

Academic problems: According to the U.S .Department of Education, alcohol abuse creates academic problems among 25 percent of college students.

Science also proves the earlier a person begins drinking, the more likely he or she is to become a problem drinker.

Among Wyoming youth, binge drinking remains a huge challenge with almost 30 percent of our high school students engaging in this dangerous behavior. Lowering the drinking age to 18 would mean many high school students could legally drink. No doubt some would provide alcohol to their younger classmates, siblings and friends.

The relationship between being "old enough to fight for your country" and being "old enough to drink" is perverse at best. The military may recruit youth partially because of their risk-taking characteristics, but commercial insurance companies also charge them higher premiums for the same reason. The impulsiveness of youth may make a good soldier but it does not mix well with alcohol use.

Gladly, we have made progress in prevention. Studies examining the impact of the minimum legal drinking age reflect a number of positive changes. In 1984, before the drinking age was 21, approximately 8 percent of high school seniors never used alcohol in their lifetime. In 2007, approximately 28 percent of high school seniors never used alcohol in their lifetime. In 1982, when most states still had an 18 year-old drinking age, 60 percent of traffic fatalities were alcohol related. In 2005, that number had declined by more than a third.

Yes, prevention is hard work and continued progress requires college presidents to become engaged. Waving the white flag and returning to a time when young people were allowed to drink legally would be to ignore all we learned from that failed experiment and all that we know now because of science.

by Rodger McDaniel
Wyoming Department of Health deputy director for mental health and substance abuse services

Wyoming Department of Health