Fact: Cocaine Use May Alter Brain Cells and Play a 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 deregulated 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.
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 neuro-biological 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 effect, thereby further aggravating the deregulation 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 neuro-biological 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.
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.
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).
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.
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 exposure interferes 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.”
Rhesus Monkeys as a Model for Cocaine Abuse in Pregnant Humans
To determine the dosage and route of cocaine administration for studies in pregnant monkeys that would be relevant to humans, Dr. Lidow and his colleagues looked at the absorption and elimination of cocaine administered by mouth (orally) and intravenously in pregnant monkeys and in their fetuses. Based on their results, they decided to use oral administration of cocaine, which closely resembles the snorting of cocaine in humans, at a dose of 20 milligrams per kilogram body weight per day, which produces maternal blood concentrations of cocaine in the range of those seen in people who are heavy users of cocaine. 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.
Prenatal Cocaine Exposure Interferes With New Cell Formation and Increases the Incidence of Cell Death in the Developing Cerebral Cortex
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. Lidow says, 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.
Chronic Prenatal Cocaine Exposure Leads to Long-term Changes in the Primate Brain
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 cerebral cortex. 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 cells in 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.
Long-Term Cognitive Impairment Found in Crack-Cocaine Abusers
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 makes developing 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 Neuro-behavioral 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.
Neuronal Differences in Brain Regions Involved in Decision-Making and Other Functions Observed for the First Time in Chronic Users of Cocaine
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. This decrease 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 future negative 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.