Researchers have identified a novel strategy to reduce cocaine-seeking behavior. The approach uses a neurochemical normalization strategy that simultaneously releases two neurotransmitters deficient in the brains of those addicted to cocaine.

Background: Biogenic amine transporters (BATs) are proteins that transport dopamine and other neurotransmitters across cell membranes. As a result, they are principal sites of action for psychotropic drugs, including cocaine and
methamphetamine. Previous studies have suggested that withdrawal from long-term cocaine abuse produces a dual deficit of dopamine and another neurotransmitter known as serotonin. Researchers wanted to know if normalizing those deficits would reduce cocaine-seeking behavior.

Study Design: Researchers reviewed preclinical and clinical data suggesting that developing compounds that release both dopamine and serotonin, the two neurotransmitters most affected by chronic cocaine abuse, is a promising strategy for the treatment of cocaine addiction.

What They Found: Previous studies have shown that administration of dopamine and serotonin releasing agents alone or together reduces drug-seeking behavior in animals. However, a major limitation with the use of dopamine releasers (such as amphetamines) has been their stimulant and reinforcing properties. The studies reviewed here show that combining dopamine and serotonin releasers may reduce this abuse potential. Finally, the authors identified a compound, PAL287, which potently releases both dopamine and serotonin and found that it reduces cocaine self-administration in animal models without being reinforcing itself.

Comments from the Authors: Although additional work must be done to refine PAL287, it represents the prototype for a new generation of medications that target BATs. Medications like these may also be useful for treating depression, obsessive-compulsive disorder, attention-deficit disorder, and obesity.

What’s Next: Further work must be done on PAL287 to increase its selectivity and evaluate any potential adverse effects. However, it should be possible to test dopamine-serotonin releasers in humans using clinically available compounds.

Publication: The review’s lead author was Dr. Richard B. Rothman of the Clinical Psychopharmacology Section at the National Institutes of Health Intramural Research Program at NIDA in Baltimore. It was published in volume 27, number 12, pages 612-618 (2006) of TRENDS in Pharmacological Sciences.

NIDA NewScan, August 22, 2007

After repeatedly injecting mice with an amount of cocaine equivalent to a typical human dose, NIDA-supported researchers found in adult and fetal models that nerve cells in a region of the brain called the substantia nigra were more susceptible to MPTP. MPTP is an environmental agent that functions as a neurotoxin and is known to cause symptoms of Parkinson's disease (PD), such as tremor, stiffness, and slowness of movement.

Chronic cocaine administration interferes with the body’s ability to regulate the release and reabsorption of dopamine (a brain chemical that helps control movement and also is involved in feelings of pleasure/reward). It may cause sustained increases in extracellular dopamine, which over time sets off a molecular cascade that can mimic that seen following the administration of parkinsonian toxins. While the researchers found that exposure to cocaine alone or MPTP alone caused comparable neuronal loss in the substantia nigra, exposure to cocaine and MPTP together led to a greater decline in cell numbers than for either agent alone.

The scientists say the study provides additional evidence for a multihit hypothesis for PD development by suggesting that multiple environmental exposures in this region of the brain—including cocaine, and by analogy, other psychostimulants—can work together to increase cell susceptibility to toxins that contribute to PD etiology. However, because the underlying switch in vulnerability is unclear, further research is warranted.

What it means: Current estimates are that there are 2.7 million chronic, adult abusers of cocaine, and that 1 percent of pregnant women abuse the drug. The findings of this study suggest that exposure to cocaine and other psychostimulants together with other environmental agents may act synergistically to increase susceptibility to PD..

Dr. Richard Smeyne and his colleagues at St. Jude Children’s Research Hospital in Memphis published these results in December 2005 in the journal Neuroscience.

NIDA NewScan, May 19, 2006

Scientists at the Medical College of Wisconsin have developed a new form of functional magnetic resonance imaging (fMRI) that has helped them determine that cocaine activates a midbrain pathway involving dopamine and that the drug also stimulates frontal brain networks associated with learning, motivation, and memory.

The new technology, developed by Dr. Shing-Jiang Li and his colleagues, enhances visibility of neural activity in regions of the brain previously distorted by imaging artifacts. A total of 15 nontreatment-seeking cocaine abusers were recruited to complete two 15-minute brain scan sessions—1 with a single dose of cocaine and 1 with saline substitution.

The team of scientists observed that an acute dose of cocaine, a dose with the ability to induce a significant high and craving (20mg/70kg), triggered activity in both mesolimbic and mesocortical dopaminergic pathways - regions of the brain associated with reward, motivation, learning, and memory. These study findings support the involvement of dopaminergic pathways in cocaine addiction and suggest that hierarchical networks involved in reinforcement and cognitive functions, such as planning and task management, may also mediate cocaine addiction in the human brain.

What it means: Although the compulsive nature of drug abuse is generally attributed to a powerful desire for the drug, understanding the neurobiological process of addiction remains a central challenge in addiction research. These research findings suggest that acute cocaine abuse may activate pathways and networks in the brain that are responsible for reward, motivation, learning, memory, and reinforcement. Thus, these processes may play a significant role in the compulsive nature of drug abuse. Additional research is needed to better understand the neural pathways and systems involved in cocaine addiction in the human brain.

This article was published in the December 2005 issue of NeuroImage.

NIDA NewScan, February 1, 2006

Using functional magnetic resonance imaging (fMRI)—a neuroimaging technique that shows which brain structures are active during particular mental operations—scientists have shown that the same brain regions associated with animal models of cocaine reinforcement also are engaged in human drug-taking behavior. In addition, they observed that craving and the drug-induced “high” involve the same areas of the brain but in different ways.

The researchers analyzed brain scans on a minute-to-minute basis from six adult male cocaine addicts who self-administered the drug during a 1-hour session. The participants, who did not abuse other drugs, rated their levels of high, rush, craving, and anxiety once per minute. This allowed the scientists to track the developing relationship between the drug’s subjective effects and changes in brain activity.

Not surprisingly, the participants’ “high” ratings reached peak levels soon after cocaine administration, while craving ratings decreased to minimal levels about 2–3 minutes after giving themselves a dose of the drug. The scientists observed that the drug-induced highs correlated with reduced activity in the limbic, paralimbic, and mesocortical regions of the brain, while craving was associated with increased activity in these same regions.

The pathway between these brain regions is a major highway for transport of the chemical dopamine, associated with pleasure and reward. The limbic system also is involved in emotional behavior.

What it means: Understanding the neurochemical mechanisms that drive drug-seeking behavior is central to developing effective therapies for drug abuse and addiction. Information derived from this and future studies may lead to the development of pharmaceuticals targeting specific brain regions that show enhanced activity during drug craving.

Dr. Robert Risinger and his colleagues at the Medical College of Wisconsin and NIDA’s Neuroimaging Research Branch published their study in the July 15, 2005 issue of the journal NeuroImage.

NIDA NewScan, February 1, 2006

Scientists at the University of California, Irvine have been able to block learned associations between environmental cues and cocaine-seeking behavior in rats via an experimental drug that acts on a specific signaling pathway in the brain.

Dr. John Marshall and Courtney Miller trained rats, to associate a particular location with the rewarding effects of cocaine. The scientists then administered an experimental compound called U0126 that blocked the extracellular signal-regulated kinase (ERK) pathway, which has been implicated in the central nervous system effects of drugs of abuse.

They found that inhibiting this pathway interfered with the ability of the animals to maintain the environment–drug association, and the rats lost their preference for the drug-associated site.

What it means: Memories associated with drug-related stimuli are responsible for much of the relapse seen in drug abuse and addiction. These findings suggest there is a way to disrupt and “unlearn” these memories, breaking the bond between environmental cues and drug-seeking behavior. This opens the possibility of developing new therapies to treat cocaine abuse and addiction.

This NIDA-supported study was published in the September 15, 2005 issue of the journal Neuron.

NIDA NewScan, February 1, 2006

A new study by Dr. Therese Kosten and colleagues at Yale University indicates that early life stress of isolation during infancy has immediate and long-term effects in rats. The team of researchers examined neurochemical and behavioral effects of early life stress in 164 adult male rats exposed to isolation or non-handled during infancy.

The scientists found that isolated rats had higher dopamine levels after cocaine administration, when compared to controls. Although isolated and non-handled rats ate less food when cocaine doses were increased, the researchers observed that isolated rats were less responsive to food.

Similarly, isolation rats pretreated with eticlopride, a compound that binds to specific dopamine receptors (D2), were less likely to respond to scheduled food cues than when treated with a similar compound that binds to D1 receptors. Dopamine is a brain chemical involved in pleasure and reward. These study findings suggest that isolation decreases the number of available D2 receptors. Because cocaine addicts typically have lower D2 levels, this indicates a link between the D2 receptor and the likelihood of developing an addiction.

What it means: Isolation during infancy has immediate and long-term effects on behavior and chemical levels in the brain. The stress of isolation during infancy may increase one's risk for developing an addiction. Consequently, these findings suggest that prevention and treatment strategies should be tailored to address the presence or absence of early life stress.

These findings were published online in April 2005 in the Journal of Pharmacology and Experimental Therapeutics. It appeared in print in the August 2005 issue of the journal.

NIDA NewScan, September 7, 2005

NIDA scientists have shown that JHW007, a chemical structurally similar to benztropine - a drug used to treat people with Parkinson's disease - can block the behavioral stimulant effects of cocaine in mice, and may one day serve as a treatment for cocaine abuse.

The researchers showed that JHW007 actively and effectively competes with cocaine for binding sites on the dopamine transporter, a protein that removes and therefore terminates the actions of dopamine, a brain chemical associated with pleasure and reward. The scientists also found that while occupying these binding sites, JHW007 produced little of the hallmark stimulant effects produced by cocaine.

The prevailing thought among researchers has been that all substances that bind to the dopamine transporter will have effects similar to those of cocaine. But this study shows that binding to the dopamine transporter does not invariably result in cocaine-like effects, and that some drugs that act at that site may block the effects of cocaine.

What it means: These findings suggest that chemical analogs of cocaine that attach to the same binding site can block the cascade of effects that ultimately result in addiction and compulsive drug-seeking behavior. Some of these compounds prevent the effects of cocaine and therefore show promise for development as treatments for cocaine abuse.

The study, led by Dr. Jonathan Katz of NIDA's Intramural Research Program, was published in the February 23, 2005 issue of the Journal of Neuroscience.

NIDA NewScan, August 23, 2005

People who continue to abuse cocaine while undergoing methadone therapy for opiate addiction may benefit from long-term abstinence reinforcement that incorporates the use of vouchers, new research reports.

A total of 78 methadone patients who used cocaine during their methadone treatment were randomly assigned to either an abstinence reinforcement group that included take-home doses of methadone, an abstinence reinforcement group that included take-home doses of methadone and monetary vouchers, or a usual care control group that included daily methadone in a clinic setting. All participants also received individual and group counseling.

When the scientists analyzed the results of the 52-week intervention, they found that the take-home plus voucher group had significantly longer durations of sustained abstinence from cocaine and opiates than either of the other groups. Members of this group sustained about 19 weeks of continuous abstinence compared to 6.3 weeks for the take-home only group and 2.3 weeks for the usual care group.

What it means: Persistent cocaine use has been a serious problem in individuals receiving methadone treatment for opiate addiction. However, no drug treatment and few psychosocial therapies have proven effective in reducing cocaine use. These results point to the potential efficacy of long-term, voucher-based reinforcement to achieve and maintain drug abstinence in this population, and suggest the need to develop practical vehicles to deliver such interventions on a wide scale.

Dr. Kenneth Silverman, of the Johns Hopkins University School of Medicine, and his colleagues published the study in the October 2004 issue of the Journal of Consulting and Clinical Psychology.

NIDA NewScan, March 9, 2005

Medication for Multiple Sclerosis May Help in Treating Cocaine Addiction

Results of a NIDA-funded study show that a combination of substance abuse counseling and baclofen—a medication often used to treat muscle spasms in people with multiple sclerosis—can reduce cocaine use.

The study involved 70 people who participated in a 16-week treatment program for cocaine addiction. Thirty-five received counseling and baclofen, and 35 received counseling and a placebo. Cocaine use was monitored by thriceweekly urine tests.

Analyses showed that people who received the counseling/baclofen combination had lower levels of drug use during the treatment period than the individuals in the counseling/placebo group, as indicated by urine testing. The response was most apparent among people who were chronic, heavy users of crack cocaine.

The researchers say baclofen may help by inhibiting the release of the brain chemical dopamine, thus reducing the desire for cocaine.

What it means: The combined effect of drug abuse counseling and a medication that targets dopamine release in the brain may offer hope to the many people struggling with cocaine dependence. There are currently no Food and Drug Administration-approved medications to treat cocaine addiction.

Dr. Steven Shoptaw and his colleagues at the University of California–Los Angeles published these results in the December 15, 2003 issue of the Journal of Clinical Psychiatry.

NIDA NewsScan, April 30, 2004

Cocaine Use May Cause Alterations in Brain Regions Involved in Decisionmaking

Scientists may have uncovered a biological mechanism that could help explain why cocaine users continue to use the drug despite their inability to relive the powerful, pleasurable feelings that they experienced at first use. The researchers found that cocaine use may cause changes in an area of the brain involved in decisionmaking called the orbitofrontal cortex (OFC).

In humans, the OFC shares neural connections with many brain regions that affect decisionmaking, compulsive behaviors, and feelings of reward. Damage to the OFC may result in personality changes that include irresponsibility and persistence in self-destructive behaviors, such as drug use.

For the study, the research team led by Dr. Karen I. Bolla at the Johns Hopkins University School of Medicine recruited cocaine users who reported using the drug regularly for at least 2 years and nonusers. Participants were admitted to the Clinical Inpatient Research Unit at the NIDA Intramural Research Program. They were asked to remain abstinent from drug use during their stay, and random drug testing verified abstinence. On day 3 of the residential stay for nonusers and day 25 for cocaine users, changes in cerebral blood flow were measured during a rest period, during a control task, and while engaged in a decisionmaking task known as the Iowa Gambling Task. The task measures the ability to choose between high gains with high risk and low gains with low risk.

The researchers found that while performing the Iowa Gambling Task, the abstinent cocaine users had increased blood flow—an indicator of increased brain activity—in the OFC compared to nonusers. This finding suggests that during the task, the cocaine users may have had an abnormally intense focus on winning and its rewarding aspects, which may have suppressed thoughts of losing. This may mean that the cocaine users may be more likely to focus on the rewarding effects of the drug, while ignoring its destructive consequences.

In a related study by lead author Dr. John Matochik at the NIDA Intramural Research Program, the same core team of researchers found structural differences in the brains of the cocaine users and nonusers who had participated in the previous study. Cocaine abusers had less gray matter tissue than nonabusers in the same brain regions that showed increased blood flow during the Iowa Gambling Task. Gray matter is primarily composed of neuron cell bodies and is considered to play a role in thought processes. Some researchers believe that a reduction in gray matter may indicate damage to or a loss of neurons.

What it means: These findings suggest that cocaine users have structural and functional abnormalities in the areas of the brain involved in decisionmaking and that these effects are related to cocaine use. Impairments in the ability to make decisions may play a role in the development of addiction and undermine attempts to stop abusing drugs. Therefore, understanding how these abnormalities are related and their role in drug abuse could contribute to the development of more appropriately targeted treatment and prevention interventions.

These studies, funded by the National Institute on Drug Abuse, were published in the July issue of Neuroimage.

NIDA NewsScan, December 12, 2003

Behavioral Treatment May Reverse Brain Changes that Occur with Cocaine Use and Help Prevent Relapse

Brain changes that occur with cocaine use and the tendency toward relapse may be reduced by a behavioral treatment using extinction training—a form of conditioning that removes the reward associated with a learned behavior. NIDA-funded researchers found that extinction training during cocaine withdrawal produces changes in brain receptors for glutamate, a brain chemical found in the nucleus accumbens, the reward center of the brain. A reduction in glutamate input from cortical brain regions by chronic cocaine use is thought to contribute to persistent cravings for the drug.

The researchers trained rats to self-administer cocaine by pressing a lever and to associate the availability of cocaine with certain environmental cues (lights and noise). Once the rats had learned to expect cocaine when they pressed the lever, cocaine and the cues were removed so that the rats did not receive the cocaine that they were anticipating. One group of rats received this extinction training during cocaine withdrawal while another group did not receive the training. After extinction training was over, the researchers exposed the rats to the cocaine-associated cues and administered cocaine to induce relapse.

The researchers found that the rats given extinction training during withdrawal had more than a 30 percent increase in glutamate receptors in the outer regions of their nucleus accumbens. The number of glutamate receptors did not increase in rats that did not receive the training during withdrawal. When cocaine-related cues were reinstated, rats showing relatively no response to these stimuli had a greater increase in receptors than rats that responded to the cues.

What it means: These findings indicate that behavioral-based treatment approaches have the potential to reverse or lessen the harmful neurobiological and behavioral consequences of chronic drug use. Increasing the number of glutamate receptors may help ease cravings for cocaine during abstinence and also help prevent relapse.

This study was published by lead investigator Dr. David Self at the University of Texas Southwestern Medical Center in the January issue of Nature.

NIDA NewsScan, May 23, 2003

Study Finds Link between Inflammatory Protein and Heart Disease Among Cocaine Users

Cocaine use has been associated with a number of cardiovascular complications, including artery blockages and heart attacks. In a recent study, NIDA-funded scientists have helped to identify the effects of cocaine use that may lead to heart problems. They found that in cocaine abusers, elevated levels of serum C-reactive protein (CRP)—a protein associated with inflammation—were associated with endothelial abnormalities and coronary artery calcification, which are factors known to contribute to heart disease.

Fifty-three African-American adults from Baltimore, Maryland, between 25 and 45 years of age with a history of cocaine use were recruited to participate in the study. The researchers conducted a variety of tests, including an echocardiographic examination, spiral computed tomography (CT) scans to look for coronary calcification, analysis of blood for serum cholesterol and CRP, and an evaluation of endothelial function.

The researchers found that 45 percent of the participants had serum CRP levels above the normal range of the general population. Those with elevated CRP had greater endothelial abnormalities and more coronary calcification than those with normal CRP levels.

What it means: CRP may be a marker of future cardiovascular events. The findings in this study suggest that many chronic cocaine users have elevated levels of serum CRP, which are associated with subclinical coronary atherosclerosis and cardiac abnormalities.This study provides more evidence that cocaine use may contribute to the development of coronary artery disease.

This study was published by lead investigator Dr. Shenghan Lai at Johns Hopkins University in the April 2003 issue of the International Journal of Cardiology.

NIDA NewsScan, May 23, 2003

Treatment for Cocaine Addiction May Reduce HIV Risk

Cocaine addiction has previously been linked to an increased risk of contracting HIV, mainly as a result of sharing contaminated injection equipment, unprotected sex, exchange of sex for drugs, increased sexual drive from the stimulatory effects of cocaine, and impaired judgement. Although research has indicated that patients receiving treatment for heroin addiction have a decreased risk of HIV infection, few studies have focused on changes in HIV risk following treatment for cocaine addiction. Now, NIDA-funded researchers have found more evidence that participation in cocaine treatment may reduce the risk of HIV infection.

The researchers evaluated HIV risk among 487 cocaine-dependent patients that were recruited from five treatment programs participating in the NIDA Cocaine Collaborative Treatment Study. The multi-site trial examined the efficacy of four outpatient-based psychosocial treatments for cocaine dependence consisting of group drug counseling (GDC) alone and GDC in combination with individual drug counseling (IDC), cognitive therapy (CT), or supportive-expressive therapy (SE). Patients attended GDC weekly and individual therapy sessions for IDC, CT, or SE twice per week. At the end of screening and after 6 months of treatment, patients completed the Risk Assessment Battery, a standardized questionnaire that measures behaviors associated with HIV risk, such as drug use and high-risk sexual behaviors.

Prior to treatment, the average patient had used cocaine for 7 years and reported 10 days of cocaine use in the previous month. Crack smoking was the most common form of use. Seventy-nine percent of patients smoked crack, 19 percent snorted cocaine, and 2 percent injected the drug. HIV risk was mainly associated with high-risk sexual behaviors.

At the 6-month follow-up, cocaine use had decreased to an average of once per month. Patients receiving a combination of IDC and GDC showed the best improvements in reducing cocaine use compared to patients receiving CT and SE. Overall, the decrease in cocaine use was associated with a 40 percent reduction in HIV risk across all treatment, gender, and ethnic groups, mainly due to fewer sexual partners and less unprotected sex.

What it means: These findings indicate that treatment for cocaine addiction, including HIV-risk-reduction counseling, may be an effective strategy for preventing HIV infection.

Dr. George E. Woody and colleagues from the University of Pennsylvania and the Department of Veterans Affairs Medical Center in Philadelphia published the study in the May issue of the Journal of Acquired Immune Deficiency Syndromes.

NIDA NewsScan, May 23, 2003

Sigma Receptors Play Role in Cocaine-Induced Suppression of Immune System

Cocaine use is known to have negative effects on the immune system but how the drug exerts this effect is poorly understood. Now a research team, led by Dr. Steven Dubinett from the University of California Los Angeles Lung Cancer Research Program, has demonstrated that some of cocaine's effects on the immune system may be mediated by sigma receptors. These receptors are unique proteins found in the brain and other areas of the body and have been shown to play a role in some of the toxic and behavioral effects of the drug.

The researchers administered cocaine or saline to male mice five times per week. Another group of mice were given the sigma receptor antagonist BD1047—a substance that blocks the sigma receptors and does not stimulate them—in addition to cocaine or saline. After 2 weeks, tumor cells were implanted in the mice. Tumor growth and interleukin (IL)-10 concentrations were measured. IL-10 is a chemical messenger that suppresses the production of several substances that inhibit tumor growth. Tumors in cocaine-exposed mice were significantly larger and contained higher levels of IL-10 than those in saline-treated mice. However, tumor growth was less enhanced in mice who received both cocaine and treatment with the sigma receptor antagonist BD1047. In addition, administration of anti-IL- 10 antibody reversed the tumor growth-promoting effects of sigma ligand agonists—substances that bind to and stimulate the receptors—such as cocaine.

In a separate study, the researchers administered cocaine or saline and the sigma receptor antagonist BD1047 to male mice. Two weeks later, the mice were administered staphylococcal entertoxin, which promotes IL-10 production by immune cells. The researchers found that the level of IL-10 in the blood of cocaine-exposed mice was significantly higher than those receiving saline but IL-10 production was inhibited in mice who received the sigma receptor antagonists.

What it means: These finding suggest that cocaine and other drugs that stimulate sigma receptors may promote tumor growth by increasing the production of immunosuppressive chemical messengers.

This study, cofunded by the National Institute on Drug Abuse, was published in the April 1 issue of The Journal of Immunology.

NIDA NewsScan, May 2, 2003

Real-Time Monitoring of Dopamine Activity in Brain Helps Explain
How Environmental Cues Contribute to Cocaine Relapse

Real-time monitoring of dopamine activity in the brain shows that in rats the mere anticipation of receiving cocaine may cause significant increases in dopamine levels. This finding may help explain why, in humans recovering from cocaine addiction, cocaine paraphernalia, surroundings, and other factors associated with drug use can elicit an intense craving for the drug, often resulting in relapse to use. Dopamine is a brain chemical associated with feelings of pleasure (reward); increases in dopamine levels in an area of the brain called the nucleus accumbens have been associated with drug use. Measuring dopamine level changes in real time enable researchers to carefully and accurately correlate drug-related behaviors in rats with changes in brain chemistry.

The researchers trained male rats to self-administer cocaine by pressing a lever and to associate the availability of cocaine with certain cues such as changes in lighting and an auditory tone. During daily sessions, the rats had access to cocaine and their behavior was recorded. Using fast-scan cyclic voltammetry, the researchers monitored changes in dopamine levels in the nucleus accumbens of the rats every 100 milliseconds while the rats had access to cocaine or were exposed to drug-related cues. Voltammetry allows subsecond measurements of dopamine release by monitoring changes in electrochemical currents that occur when brain cells release dopamine.

In the seconds following the cues, but before rats pressed the lever to receive cocaine, researchers observed an increase in dopamine in rats’ brains. After each lever press, an additional increase in dopamine was measured.

In another experiment, the researchers found that they could initiate drug-seeking behaviors in rats by stimulating the release of dopamine in the nucleus accumbens.

What it means: These findings reveal for the first time that rapid dopamine transmission occurs during key components of cocaine-seeking behavior and during presentation of cocaine-associated stimuli.

This study, published by Dr. Regina Carelli and colleagues from the University of North Carolina at Chapel Hill and funded by the National Institute on Drug Abuse, appeared in the April 10 issue of Nature.

NIDA NewsScan, May 2, 2003

Study of Twins Reveals That Changes in Attention and Motor Skills
Persist at Least a Year after Heavy Stimulant Abuse

In a study supported by the National Institute on Drug Abuse (NIDA), researchers found that heavy stimulant abuse can result in changes in attention and motor skills that can persist for at least a year.

The investigators studied 50 pairs of twins; in each pair, one twin had a history of abusing cocaine and/or methamphetamine and the other had no history of drug abuse. Thirty-one monozygotic (identical) and 19 dizygotic (fraternal) adult male twin pairs were tested for attention and motor skills, executive functioning, intelligence, and memory at least one year after the drug-using twin’s last-reported use of stimulants.

The researchers, led by Dr. Rosemary Toomey from Massachusetts General Hospital, found that the twin with a history of stimulant abuse performed significantly worse on several tests of attention and motor skills than did the sibling who had never used drugs. However, abusers outperformed their non-drug-using twin on visual vigilance, a test measuring the ability to pay attention over time.

What it means: This study provides evidence that stimulant abuse can result in long-term residual neuropsychological effects.

The study was published in the March 2003 issue of the journal Archives of General Psychiatry.

NIDA NewsScan, April 9, 2003

Cocaine Use May Alter Brain Cells, Play Role in Depression

A study by researchers from the University of Michigan and the Ann Arbor Veterans Affairs Medical Center suggests that chronic cocaine use may cause damage to brain cells that help produce feelings of pleasure, which may contribute, in part, to the high rates of depression reported among cocaine abusers. It is well-known that cocaine increases levels of the brain chemical dopamine, resulting in the “high” that abusers feel. Prolonged use of the drug, however, may reduce dopamine levels, making it harder for abusers to experience positive feelings.

Dr. Karley Little, lead investigator, and colleagues studied samples of brain tissue obtained during autopsies of 35 long-term cocaine users and 35 non-users. They analyzed the tissue for dopamine and the protein VMAT2, which is found in dopamine transporters. Urine or serum samples were also analyzed for the presence of cocaine, opioids, antidepressants, and antipsychotic medications. A person close to each individual was interviewed about the individual’s substance abuse, alcoholism, and symptoms of personality and mood disorders.

Researchers found that cocaine users had lower concentrations of dopamine and VMAT2 in their brains than did non-users. Additionally, cocaine users suffering from depression had lower levels of VMAT2 than those who were not depressed. Dr. Little and colleagues were uncertain whether dopamine cells had been destroyed or just dysregulated by cocaine use, and if such changes could be reversed.

What it means: These findings suggest that chronic cocaine use may cause changes in the brain that could make it harder for a person to feel a sense of pleasure. Further efforts at clarifying the detrimental effects of cocaine on brain cells may help in the development of effective treatment interventions and pharmacotherapies.

This study, funded in part by the National Institute on Drug Abuse, was published in the January 2003 issue of the American Journal of Psychiatry.

NIDA NewsScan, March 5, 2002

Research Helps Explain Why Perception of Pleasure Decreases
With Chronic Cocaine Use

Investigators demonstrated in rats that repeated starting and stopping of cocaine use decreased the brain’s reward function and reduced the pleasurable effects of cocaine. This decrease in pleasure-perception was highly correlated with escalation of cocaine intake.

The persistence of this pleasure deficit after stopping prolonged cocaine use may be part of the neurobiological basis for the continued craving and increased vulnerability to relapse associated with drug addiction.

The study’s findings also show that tolerance does not result from a decreased effect of cocaine on basal reward thresholds, but results instead from the establishment of a new basal reward threshold, above the initial threshold. As a result, more doses are progressively needed to maintain the same hedonic effect, thereby further aggravating the dysregulation of brain reward function.

Changes in pleasure thresholds were only observed in animals that developed excessive levels of cocaine intake. Those that developed stable and moderate levels of cocaine intake did have altered pleasure perception. Thus, a chronic shift in pleasure thresholds appears to be one of the neurobiological signatures of the transition to addiction.

What it means: Based on this study, it appears that promising new therapies for addiction may be based on treatments that mute the desire to escalate cocaine intake by blocking the elevation of brain reward thresholds produced by chronic cocaine use.

Serge H. Ahmed, Paul J. Kenny, and colleagues from the University of Bordeaux, France and The Scripps Research Institute in LaJolla, California published the study in the July 2002 issue of the journal Nature Neuroscience.

NIDA NewsScan, July 31, 2002

Methamphetamine, Cocaine Abusers Have Different Patterns of Drug
Use, Suffer Different Cognitive Impairments

Studies supported by NIDA show that methamphetamine abusers typically use the drug 20 days per month, beginning early in the morning and using it at regular intervals throughout the day. In contrast, cocaine abusers are more likely to exhibit a “binge” pattern. They use the drug fewer days per month, typically in the evening rather than in the daytime, and use it continuously over several hours. Both drugs cause deficits in measures of reasoning and concentration, but methamphetamine abusers perform more poorly than cocaine abusers on tests measuring perceptual speed and the ability to manipulate information, according to Dr. Sara Simon of the University of California, Los Angeles.

The typical methamphetamine abuser reported using the drug when he or she first got up in the morning and then using it approximately every two to four hours during the waking day. Most of the descriptions of use more closely resembled taking a medication than using a drug for pleasure. Cocaine abusers, however, reported patterns of use that began in the evening and continued until all the cocaine had been used.

Both drugs are associated with similar cognitive deficits, although some types of impairment differ. The most striking difference is that methamphetamine abusers had more trouble than cocaine abusers with tasks requiring attention, organizing information, and switching points of view.

What it means: These studies add important details to our understanding of the real-world characteristics of methamphetamine and cocaine use. This understanding can be incorporated into the development of treatment strategies that help abusers avoid or cope with situations that put them at risk for relapse and give them behavioral tools they can learn, understand, and apply in those situations.

Dr. Simon and her colleagues described their findings in a special methamphetamine issue of Journal of Addictive Diseases (Vol. 21, Number 1, 2002).

NIDA NewsScan, July 31, 2002

Cocaine Use Linked to Poor Adherence To Antiretroviral Therapy in HIV Patients

Researchers from the Montefiore Medical Center in New York City measured adherence to antiretroviral drug regimens in 85 HIV-infected current and former cocaine users.

The study’s lead investigator, Dr. Julia H. Arnsten, says that active cocaine use was the strongest predictor of poor adherence and, in turn, failure to maintain viral suppression. Overall adherence among cocaine users was 27 percent, compared with 68 percent among subjects who reported no cocaine use during the 6-month study period. Thirteen percent of active cocaine users maintained

viral suppression, compared with 46 percent of nonusers. The study was funded by NIDA.

What it means: The findings from this study indicate that interventions to improve adherence to drug regimens to treat HIV infection should include assessing and treating cocaine use by patients.

The study was published in a special issue on substance abuse by the Journal of General Internal Medicine.

NIDA NewsScan, June 24, 2002

Studies Show Effects of Cocaine Use During Pregnancy on Infants' Brains

Babies born to mothers who abuse cocaine during pregnancy often are delivered prematurely, have low birth weights, smaller head circumferences, and tend to be shorter. However, the full consequences of prenatal cocaine exposure on children are still unclear and are difficult to study.

In a series of recently published studies, a team of NIDA-supported researchers at the University of Maryland, Baltimore, led by Dr. Michael S. Lidow, examined the effects of prenatal cocaine exposure in rhesus monkeys. The researchers found that such exposureinterferes with the production of nerve cells and leads to a significant increase in cell death in the developing cerebral cortex. They also found that, as a result of these actions of cocaine, the number and density of nerve cells (neurons) in the cerebral cortex of monkeys

born from cocaine-exposed mothers is reduced, their positioning is abnormal, and the cortex lacks its usual layered structure.

"The results of these studies provide important information on the effects of prenatal cocaine exposure on the developing brain," says NIDA Director Dr. Alan I. Leshner. "Particularly noteworthy is the finding that a mother's use of cocaine during pregnancy can lead to long-lasting abnormalities in her infant's cerebral cortex, the part of the brain that is largely responsible for our higher brain functions, including visual perception, social behavior, and learning, memory and attention."

More detailed information about these studies follows.

What it means: Studying the effects of fetal exposure to cocaine in humans is difficult. This study provides evidence that rhesus monkeys given 20 milligrams of cocaine per kilogram body weight daily by mouth can serve as a model for studying the effects ofcocaine abuse by pregnant women.

The study appears in the May 2001 issue of the Journal of Pharmacology and Experimental Therapeutics. An abstract of the article is available online at jpet.aspetjournals.org.

NIDA NewsScan, August 29, 2001

The University of Maryland researchers looked first at the ability of prenatal cocaine exposure to interfere with the generation of neurons destined for the cerebral cortex in the developing fetal brain. They injected pregnant rhesus monkeys either 1.5 hours or 10 hours after cocaine administration with a radioactive compound that marks dividing cells. Cocaine levels in the fetal circulation peak at 1.5 hours after oral administration and are undetectable 10 hours after the drug is given.

The researchers found that when cocaine levels are highest, formation of new neurons in the developing cortex is cut roughly in half. However, when fetal cocaine levels are undetectable, new neuron formation is nearly doubled. These fluctuations in cell division suggest that the initial suppression of new nerve cell formation caused by a single dose of cocaine is followed by a significant compensatory burst of cell division when the drug level drops. Therefore, the net amount of new neuron formation may not change. Nevertheless, Dr. Lidowsays, the abnormal fluctuations in the production of cortical neurons caused by cocaine may ultimately affect these cells" survival.

The researchers also used chemical markers of cell death to determine whether cocaine exposure of fetuses increases neuronal death in the developing cerebral cortex. They treated pregnant animals with cocaine for 10 days at the beginning of the second trimester and then looked at the number of dying cells in the fetal brain. They found that the number of such cells in the developing cortex nearly triples in cocaine-exposed fetuses, suggesting that cocaine kills fetal cortical neurons.

What it means: Cocaine-induced increases in cell death in the fetal cerebral cortex are likely to play a role in the reduced number and density of cortical neurons in monkeys that were prenatally exposed to the drug. Prenatal cocaine exposure also interferes with new cell generation in the developing cortex, but how or whether this contributes to the decreased density and number of cortical neurons is still unclear.

These studies appear, respectively, in the June 2001 issue of Cerebral Cortex, and the December 1999 issue of Neuropathology and Applied Neurobiology.

NIDA NewsScan, August 29, 2001

To determine how the actions of cocaine on neurons affect the cerebral cortex, the researchers examined this brain region in adult monkeys born from cocaine-treated mothers. They gave pregnant rhesus monkeys cocaine during the second trimester of pregnancy and allowed the monkeys to deliver at the normal time (day 165 of pregnancy). When the offspring reached 3 years of age, the researchers examined the anatomy of the cerebral cortex.

They found that the cortex in the offspring lacked its normal multilayered, highly organized, structure. The cortex also contained nearly 50 percent fewer neuronal cells than the cortex of non-drug-treated monkeys. The researchers also found a significant increase in the number of cells below the cortex in the white matter of the brain, which normally contains few neurons. However, even counting these neurons, which did not assume their normal position in the cortex, the total number of neurons was lower than in normal animals.

Finally, the researchers determined the time during pregnancy when cocaine can produce all these abnormalities in the developing cerebralcortex. In this study, they examined the cerebral cortex in

monkeys exposed to cocaine during the first, second, or third trimester of pregnancy. They found that the cortex was affected only in monkeys exposed to cocaine during the second trimester. However, Dr. Lidow emphasizes, "while the abnormalities we detected seem to be caused by cocaine exposure in the second trimester, this does not mean that cocaine use in other trimesters is safe," because cocaine use at other times could and probably does have other effects.

What it means: Prenatal cocaine exposure in rhesus monkeys during the second trimester of pregnancy affects the organization of the cerebral cortex and the number and positioning of nerve cellsin this brain region. The abnormalities in cortical structure and neuronal positioning persist in 3-year-old monkeys, indicating that these effects are long-lasting and may be permanent.

The study on long-term effects of cocaine appears in the July 2001 issue of the Journal of Comparative Neurology. The article on the timing of cocaine administration appears in the May 2001 issue of Developmental Brain Research.

NIDA NewsScan, August 29, 2001

Impaired memory and motor skills were found in crack-cocaine users up to 6 months after their last use of the drug. Individuals with a history of heavy crack use had the most severe impairments. The researchers believe that these deficits are evidence of brain damage caused by substance abuse.

The researchers administered a battery of comprehensive neuropsychological tests to 20 crack-dependent subjects, 37 crack-and-alcohol-dependent subjects, and 29 individuals with no history of drug or alcohol abuse. The tests were given twice–the first time following 6 weeks of abstinence from drugs and again after 6 months of drug abstinence. The tests assessed the subjects’ attention span, decision-making, spatial processing, immediate and delayed memory, calculation ability, reaction time, verbal fluency, and psychomotor skills.

Both drug-abusing groups showed significant

cognitive impairments at both the 6-week and the 6-month time points. The largest effects were found in the executive function and spatial processing assessments.

What it means: With approximately 2 million cocaine abusers in the United States, the finding that brain damage resulting in long-term impaired mental and physical functioning can result from its use makesdeveloping and utilizing effective prevention and treatment methods an urgent public health priority.

The study was published in the February 2002 issue of Drug and Alcohol Dependence by a research team from Neurobehavioral Research, Inc., Corte Madera, CA; University of Illinois at Chicago; and the Herrick/Alta Bates Hospital, Berkeley, CA. Dr. George Fein was the lead author.

NIDA NewsScan, May 28, 2002

Researchers at the University of Pennsylvania have detected differences in areas of the brain in chronic cocaine users. These differences were detected in regions involved in decision making, behavioral inhibition, and emotional reaction to the environment.

Using magnetic resonance imaging (MRI) and other brain mapping techniques, the researchers, led by Dr. Teresa R. Franklin, examined 13 men who had used cocaine for an average of 13 years each. They found that, compared to controls who had never used cocaine, select regions of the brains of the cocaine users had less gray matter. Thisdecrease in critical working brain tissue ranged from 5 to 11 percent. This is the first time in either animal or human studies that differences in gray matter concentrations have been found in chronic cocaine users.

The investigators suggest that some of the behaviors observed in chronic cocaine use– such as choosing immediate gratification over long-term reward; engaging in risky behaviors, particularly when attempting to obtain cocaine; and succumbing to the overwhelming desire to seek and use drugs undeterred by the prospect of futurenegative consequences– may be a result of these gray matter deficiencies.

What it means: Understanding the long-term impact that cocaine can have on the brain and cognition will help scientists to develop strategies to reverse those effects and, and, ultimately, restore the brain to normal function.

The study was published in the January, 2002 issue of Biological Psychiatry.

NIDA NewsScan, May 28, 2002