Addiction

The results of this study suggest that many drug abusers may experience similar changes in the patterns of global gene expression in their brains, irrespective of their drug of choice. Whether longtime drug abusers favor cocaine, marijuana,
or PCP, their autopsied brains showed a number of common gene changes consistent with diminished brain plasticity--i.e., the ability to learn from new experiences and adapt to new situations. Therefore, brain functions may be similarly impaired as the result of chronically abusing different drugs.

Background: Chronic drug abuse can change the structure and function of several brain regions. Recent advances in genomic technologies allow us to monitor the expression level of thousands of genes simultaneously in specific parts of the
brain, including the anterior prefrontal cortex (aPFC), a region that plays an important role in decisionmaking. A dysfunctional aPFC appears to be a characteristic feature of the brains of drug abusers. Researchers wanted to know if different drugs of abuse can compromise the normal patterns of gene expression that converge in common pathways, resulting in similar changes in the brains of drug abusers.

Study Design: NIDA scientists compiled clinical case histories and toxicology reports to establish the primary drug of abuse of 42 deceased drug abusers. The drugs examined included cocaine, marijuana, and PCP. The researchers then measured the level of expression of more than 9000 individual genes in small brain tissue samples obtained from the aPFC.

What They Found: Although many effects were specific to each drug, the scientists also found that nearly 80 percent of the drug abuse cases displayed similar alterations in genetic output compared to the controls. For example, genes involved in calcium signaling were turned down, while genes involved in lipid- and cholesterol-related pathways were turned up.

Comments from the Authors: The aPFC is characterized by a particularly dense and complex network of neural connections. Our results show that cocaine, marijuana, and PCP can alter the function of this critical brain area in similar ways, which could threaten the drug abuser’s ability to make sound decisions.

What’s Next: Many of the gene families identified here point to common downstream pathways that should be studied further in order to understand their specific contributions to the long-term effects of abused drugs on the human brain.

Publication: The study, led by Dr. Elin Lehrmann of the Cellular Neurobiology Research Branch in NIDA’s Intramural Research Program in Baltimore, was published in the open access journal PLoS ONE on December 27, 2006 (PLoS ONE 1:e114).

NIDA NewsScan, August 22, 2007

Researchers report they have new evidence suggesting that the cerebellar vermis, a worm-shaped structure that plays a role in concentration that was once thought to have modest involvement in addiction, may be a key factor in modulating the brain’s dopamine and reward systems. Dopamine is a brain chemical that plays a significant role in drug abuse and addiction through its effects on reward and motivation.

Dr. Carl Anderson, of McLean Hospital and Harvard Medical School, and his colleagues took a closer look at data from a previous study in which 10 crack cocaine abusers viewed two videos (one of butterflies, one of people using the drug) while undergoing brain scans. Their analysis showed that the cerebellar vermis was particularly active when the participants watched the cocaine video.

The researchers also determined that the cerebellar vermis may contain dopamine transporters, so it may be a target for cocaine and other stimulants. The dopamine transporter is a protein that assists in the movement of dopamine from the intercellular space back into the nerve cell. When the dopamine transporter is blocked by drugs like cocaine, dopamine remains in the synapse for prolonged periods and can produce intense pleasurable sensations when it occurs in parts of the brain associated with reward. Prolonged activation in other areas may have different outcomes, but still represents a failure of the exquisitely regulated neuronal communication system.

What it means: Scientists have not focused much attention on the cerebellum as a brain region involved in drug-associated behaviors due to its low concentration of dopamine and dopamine receptors, although its importance in certain types of learning is well known. These findings offer new insights into how brain regions may interact in addiction

The scientists published their study in the October 12, 2005 issue of Neuropsychopharmacology.

NIDA NewsScan, February 1, 2006

Researchers studying the molecular machinery that underlies short-term gratification from drug abuse and the brain changes that fuel addiction have honed in on a key process that involves the activation of specific genes.

In rat studies, the scientists investigated a process called chromatin remodeling, in which histones (proteins that bind to DNA, help give chromosomes their shape, and help control gene activity) enfolding certain genes are modified in an effort to activate the genes. They found that the acute effects of cocaine at this level differ from the chronic effects of the drug—acute cocaine activated a gene called cFos (an important regulator of other genes) while chronic administration of cocaine desensitized that gene. Acute administration of cocaine was defined as a single injection of the drug, while chronic cocaine was an injection given once daily for 7 days.

The researchers also observed that chronic cocaine administration activated two other genes, BDNF and Cdk5. Previous research has implicated the Cdk5 gene in the rewiring of brain circuitry in a region of the brain called the striatum, which is known to be important in cocaine’s behavioral effects. In humans, the striatum becomes active in the presence of dopamine, a brain chemical associated with pleasure and reward; involved in coordinating movement, it also becomes engaged in decision-making processes.

In behavioral experiments, the scientists found that enhancing histone modification increased the cocaine reward response. In contrast, when the animals received drugs that reduce histone modification, they showed diminished reward effects.

What it means: Long-term changes in chromatin remodeling might be a crucial mechanism driving brain changes that occur in response to drug abuse and lead to addiction. This line of research suggests that drugs designed to short-circuit these processes hold promise as addiction therapies.

Dr. Arvid Kumar, Dr. Eric Nestler, and their colleagues at the University of Texas Southwestern Medical Center published their findings in the October 20, 2005 issue of Neuron.

NIDA NewsScan, February 1, 2006

Researchers from the Johns Hopkins University Bloomberg School of Public Health and the Ben-Gurion University of the Negev in Beer-Sheva, Israel, who followed but did not treat 1,339 injection drug users for 12 years, showed that fewer than 20 percent were able to completely cease injection drug use.

Perhaps the most important finding from this study is that so few injection drug users were able to resolve their addiction. While 71 percent did experience some period of abstinence, most took up the practice of injecting drugs again. Only 19.6 percent succeeded in ceasing injection drug use completely during the study.

A younger age at enrollment, especially being younger than 30 years, was significantly associated with cessation of drug use or with cessation followed by relapse. Women were more likely than men to stop using injected drugs.

A total of 29 percent of the study population remained persistent drug users, the authors report. Fourteen percent relapsed once during the study period, and 37 percent relapsed at least twice.

The scientists say their data show that the average time to first relapse is 10–18 months. They suggest that intervention efforts should continue throughout this critical period to support injection drug users who try to overcome their addiction.

Study participants in all four groups—persistent drug users, those who ceased drug use completely,

those who relapsed once and continued using drugs, and those who had multiple relapses—could not be differentiated by educational level, marital status, and the presence of dependent children, the authors report. Only a history of incarceration differentiated people who successfully stopped using injection drugs from those who continued to use them. However, the scientists also report that daily use of alcohol was strongly associated with persistent injection drug use.

Participants who relapsed once were younger than persistent drug users. These male participants also were 4 times more likely to report engaging in homosexual sex.

The highest mortality rates were seen in the persistent drug users. The principal causes of death were overdose, violence, AIDS, and other infections.

What it means: Patterns noted in the study are consistent with the view of drug addiction as a chronic disease, the researchers say. The data presented emphasize the need to develop and make available effective cessation programs for people who use injection drugs to prevent adverse health and social outcomes.

The NIDA-funded study by Dr. Noya Galai and colleagues was published in the October 1 issue of the American Journal of Epidemiology.

NIDA NewsScan, December 12, 2003

A naturally occurring lipid called oleylethanolamide (OEA) is known to curb appetite and regulate body weight. Although it is structurally related to a neurotransmitter similar to marijuana’s active ingredient, it does not bind to cannabinoid receptors. Now, NIDA-funded researchers have found that in mice, OEA controls hunger and contributes to weight maintenance by binding to peroxisome proliferator-activating receptors (PPAR-alpha), which regulate several aspects of lipid metabolism.

In the study, a team of researchers led by Dr. Daniele Piomelli at the University of California, Irvine, fed a high-fat diet to mice that were either normal or had their PPAR-alpha receptors genetically removed. After the mice became obese, the researchers administered OEA for 4 weeks.

The researchers found that the normal mice ate less and lost weight while OEA feeding had no effect on mice that lacked PPAR-alpha receptors. They also found that in normal mice, OEA lowered blood cholesterol levels.

What it means: This study suggests that OEA plays a role in weight maintenance and satiety by activating PPARalpha. Identifying the receptors that contribute to the compound’s weight maintenance properties may lead to the development of a new class of medications that target obesity and other eating disorders. The researchers also say that because neural mechanisms underlying reward for drugs and food can overlap, these findings may contribute to the development of medications for the treatment of other compulsive behaviors such as drug addiction.

This study, funded by the National Institute on Drug Abuse, was published in the September 4, 2003 issue of Nature.

NIDA NewsScan, December 12, 2003

Building on previous research using microarrays that identified more than 400 human genes affected by long-term cocaine abuse, researchers at the Yerkes Regional Primate Research Center at Emory University have shown for the first time that long-term use of cocaine induces significant changes in gene expression in the human brain.

The scientists compared gene and protein expression patterns in specific brain areas—the ventral tegmental area (VTA) and the substantia nigra—in 10 cocaine overdose victims and 11 age-matched, drug-free control subjects.

They found significant increases in glutamate receptor subunits in the VTA of the cocaine abusers. Glutamate is a neurotransmitter, a class of compounds involved in regulating cell–cell communication. It is involved in neuronal excitability and is associated with learning, memory, and synaptic plasticity.

In addition, the scientists found significant increases in CREB (cyclic AMP responsive element binding protein), a molecule that regulates gene expression and is associated with addiction and memory, in the abusers’ brains.

The scientists say this study marks the first attempt to identify molecular neuropathological markers that may be associated with cocaine addiction.

What it means: These results show that cocaine abuse can lead to significant alterations in the expression of specific genes in defined brain areas associated with addictive behavior. Identifying such molecular markers in human drug abusers broadens our understanding of the neuropathology associated with drug abuse and may help identify new biological targets for developing medications to treat addictive disorders.

The study, published by Dr. Scott Hemby and colleagues and supported by the National Institute on Drug Abuse, appeared in the May issue of the Journal of Neurochemistry.

NIDA NewsScan, December 12, 2003

Nonmedical use of prescription opioids is increasing in the United States. In a new position statement, a task force of the College on Problems of Drug Dependence says programs to control and reduce such abuse must be balanced against the need for access to these drugs for legitimate medical purposes.

Opioids are drugs that include morphine, codeine, hydrocodone (Vicodin®), and oxycodone (Percodan®, OxyContin®), to name a few. Prescription opioids often are prescribed to treat pain that is not alleviated by such nonopioid medications as acetaminophen.

Results of surveys and other data collection sources show that use of prescription opioids appears to have risen in recent years.

Data from the Monitoring the Future survey show that usage of prescription opioids over a 30-day period by high school students who reported taking these drugs without a physician telling them to do so increased by 173 percent between 1991 and 2001. The Monitoring the Future survey is conducted annually by the University of Michigan for the National Institute on Drug Abuse.

The National Household Survey on Drug Abuse tracks incidence and prevalence of drugs of abuse in Americans aged 12 and older. Survey results showed that the number of people using prescription opioids for nonmedical purposes for the first time increased by 400 percent between the mid-1980s and 2000 (from 400 thousand to 2 million). Prevalence of opioid abuse was higher in people aged 12–25 than in people aged 26 and over. The survey also showed that the prevalence of opioid abuse is similar to that of cocaine and heroin.

The Drug Abuse Warning Network collects information on drug-related visits to emergency departments. It shows that the number of ED visits related to opioid analgesics and opioid analgesic combinations increased by 123 percent between 1994 and 2001.

The task force emphasized that prescribed opioids are an effective means for treating pain. It also expressed the concern that an undue focus on opioid abuse, and the addiction that may result because of misuse of opioids, may unwittingly lead to less use of opioids for treating pain.

Members of the task force recommend several steps be taken to improve the ability to make informed policy decisions on prescription opioid abuse. These include: further epidemiological research, laboratory testing of prescription opioids to determine abuse liability, and clinical trials to determine the efficacy of different approaches to the prevention and treatment of prescription opioid abuse.

What it means: Overuse and abuse of prescription opioid drugs can have harmful ramifications for their legitimate and appropriate use. A balanced approach is needed so programs developed to reduce and prevent such abuse do not deter physicians from prescribing these drugs for appropriate patients.

Dr. James Zacny of the University of Chicago chaired the task force. The position paper was published in the April 2003 issue of Drug and Alcohol Dependence.

NIDA NewsScan, July 30, 2003

A long-term study has linked adolescent drug use with health problems in early adulthood. Subjects in their mid-to-late twenties who had used drugs as teens reported more health problems than those who had never used drugs. Health problems included: increased incidence of respiratory conditions, such as colds and sinus infections; cognitive problems, such as difficulty in concentrating, remembering, and learning; and headaches, dizziness, and vision problems.

The NIDA-funded study found also that rebelliousness, distrust of authority, and risk-taking
behavior in early adolescence and peer influences in middle adolescence were precursors to later drug use, which, in turn, led to increased health problems.

These findings are from a 22-year study that tracked the self-reported substance abuse and health histories of more than 600 youths through their early- and mid-teen years into early adulthood.

Scientists from the Mount Sinai School of Medicine and Columbia University started collecting data on the children in 1975, when the subjects were one through 10 years of age. Four follow-up interviews were conducted in 1983, 1986, 1992, and 1997. By the time of the last interview, the average subject was 27 years old.

What it means: This study adds to the body of research about the long- term
public health consequences of drug abuse and the importance of early intervention to
prevent adolescent drug abuse.

Lead investigator Dr. Judith S. Brook published the study in the June 2002 issue of the Journal of Adolescent Health.

NIDA NewsScan, July 31, 2002

Researchers from the Johns Hopkins University report on data from the National Comorbidity Survey which investigated the age at which individuals are at greater risk for starting to use marijuana, alcohol, and cocaine and when dependence on these drugs is likely to occur. More than 8,000 individuals ages 15 to 54 answered questionsregarding the age at which they first used these drugs, and at what age they became dependent. Of this sample, almost half (3,940) had used marijuana; the majority (7,485) had used alcohol; and fewer than 20 percent (1,337) had used cocaine. There were 354 cases of marijuana dependence, 220 cases of cocaine dependence, and 212 cases of alcohol dependence.

The survey indicated that the ages at which individuals are more at risk for starting to use alcohol and marijuana are 17 to18 years, about 2 years earlier than for cocaine. However, once use of cocaine begins, cocaine dependence occurs earlier and more rapidly, with more than 5 percent of cocaine users becoming dependent on the drug during thefirst year of use. Within 10 years of their first use, more than 15 percent of those who used cocaine were dependent, versus 8 percent of marijuana users and approximately 12 percent of individuals who used alcohol.

The data also indicated that the risk of developing alcohol dependence extends through middle age, whereas for marijuana and cocaine users, the period of developing dependence generally has ended by ages 30 and 35 years, respectively.

What it means: The periods of risk for developing dependence on alcohol, marijuana, and cocaine are not the same. Cocaine dependence almost always develops within the first several years after initial use, while alcohol dependence develops more insidiously, often many years after starting to drink. Interventions seeking to prevent ordelay development of cocaine dependence among cocaine users should be timed to occur soon after the start of cocaine use, since cocaine dependence may occur within the first few years of use.

This study was authored by Dr. Fernado Wagner and Dr. James C. Anthony, and was published in the electronic online journal, Neuropsychopharmacology (the official journal of the American College of Neuropsychopharmacology), and is due to appear in a hard-copy issue of Neuropsychopharmacology early in 2002.

NIDA NewsScan, January 30, 2002