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.

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