Category: Cocaine

Drug dependency is a recurrent but treatable kind of addiction. However, not all people who are drug dependent progress in the same way once they stop taking drugs. A new study shows that, in the case of cocaine, a high score on the so-called 'scale of craving', an antisocial personality type and previous heroin abuse are the factors most commonly involved in people falling back into the habit.

Ana López, lead author of the study and a researcher at the University of Santiago de Compostela (USC), says that the objectives of the new study were: "To understand the factors linked to treatment outcomes, in order to help people get the right kind of treatment, reduce their chances of abandoning the treatment, ensure they stop using drugs and don't fall back into the habit."

The study, published in the Spanish journal Psicología Conductual, analyses the significant factors (sociodemographic, psychopathological and patterns of drug and other substance abuse) involved in patients continuing to use cocaine two years after having requested treatment.

A high score on the 'scale of craving' (which measures the level of anxiety or desire to take drugs) at the start of the treatment, an antisocial personality type, and having previously taken heroin at some point previously in life are the main factors involved in falling back into cocaine abuse. For this reason, "it is crucial to first evaluate the person's consumption history and personality type," explains the researcher.

The researchers analysed a sample of 38 people (35 men and 3 women, with an average age of 31), who sought treatment for problems related to abuse of this substance in drug treatment centres in Galicia, in northern Spain, studying them at the start of their therapy and then two years later.

The study shows that impulsiveness and the desire for new sensations are also factors involved with substance abuse. "It's no surprise that people who have tried substances such as heroin, which is broadly rejected by society, score highly for impulsiveness and sensation-seeking, and these are also features that are characteristic of an antisocial personality type," adds the researcher.

The authors also highlight that, contrary to what had been believed up until now, a patient being depressed or anxious at the start of the treatment does not necessarily mean they will have worse long-term results. "These symptoms are often actually a consequence of cocaine use, and once they stop using the drug their symptoms start to improve," says López.

Although demand for treatment because of problems related to cocaine abuse has risen in drug dependency centres in Spain, there are as yet only a few studies analysing how the users progress throughout the course of the treatment, which is why this kind of research is so important.

A new study in rats has found that N-acetylcysteine (NAC), a commonly available and generally nontoxic amino acid derivative, reverses changes in the brain's circuitry associated with cocaine addiction. The reversal appears to lessen the cravings associated with cocaine, thus providing protection against relapse.

The findings were presented at Neuroscience 2009, the annual meeting of the Society for Neuroscience and the world's largest source of emerging news about brain science and health.

"Our finding suggests a promising therapeutic strategy for cocaine addiction, for which there is no approved treatment," said lead author Khaled Moussawi of the Medical University of South Carolina in Charleston.

Cocaine is a highly addictive drug characterized by frequent relapses. Recent advances in brain imaging are helping scientists uncover what happens in the brain when an addicted person is exposed to the drug-associated "cues" that trigger craving — and lead to relapse. They've found that repeated exposure to psychoactive drugs such as cocaine causes an imbalance in the brain circuits regulating reward and cognitive control.

One of these circuits is a pathway involving the neurotransmitter glutamate. In the current study, Moussawi and his colleagues found that NAC restored normal functioning to this circuit in rats that had been previously addicted to cocaine. In addition, after receiving NAC, the previously cocaine-addicted rats did not reengage in drug-seeking behavior, even in the presence of drug-associated cues.

"Clinical trials involving people addicted to cocaine and nicotine have already suggested that N-acetylcysteine may be useful in decreasing cravings for those drugs," said Moussawi. "Our research adds support to that suggestion." A phase III clinical trial using NAC to treat cocaine addiction is currently underway.

Research was supported by the National Institute of Drug Abuse.

New animal studies suggest that memory and other cognitive problems experienced by cocaine-addicted people can result directly from the cocaine abuse in addition to pre-existing traits or lifestyle factors.

The findings were presented at Neuroscience 2009, the annual meeting of the Society for Neuroscience and the world's largest source of emerging news about brain science and health.

"Our results clearly demonstrate the negative impact that even limited access to cocaine can have on cognitive function," said senior author Charles W. Bradberry, PhD, of the University of Pittsburgh. "These findings may lead to the development of therapies for cognitive impairments as a way to improve addiction treatment."

Cocaine users display a range of cognitive deficits, including problems with decision-making, planning, and memory. The greater these deficits, the more likely treatment will fail. The current finding is part of a multi-year longitudinal study of cognitive assessment in cocaine-exposed rhesus monkeys, which offer an ideal model for study because their brain structure and function are similar to that of humans.

For the study, 14 animals were trained to perform two tasks on a touch screen. One test first assessed how well the animals learned to associate pictures with rewards and then measured cognitive flexibility by reversing high- and low-reward pictures. The other task was a visual working memory task, in which animals had to remember an abstract stimulus for varying periods of delay. After initial training they were separated into two groups, with one group self-administering cocaine on Tuesdays through Fridays. Cognitive testing for both groups was conducted on Mondays, after the cocaine-administering animals had been drug-free for about 72 hours.

The animals showed impairments in learning, cognitive flexibility, and, to a lesser degree, working memory. "The types of errors suggest that poor attention and distractibility were significant contributors to the deficits, for they were similar to those made on cognitive tasks by people with attentional deficit disorders," Bradberry said. His lab plans to investigate whether the brain mechanisms that lead to impaired attention in people with attention deficit disorders may be causing similar problems in people chronically addicted to cocaine.

Research was supported by the Veteran's Administration Medical Research Service and the National Institute on Drug Abuse.

Adult male monkeys exposed to cocaine while in the womb have poor impulse control and may be more vulnerable to drug abuse than female monkeys, even a decade or more after the exposure, according to a new study by researchers at Wake Forest University School of Medicine. The findings could lead to a better understanding of human drug abuse.

The study was presented at the annual Society for Neuroscience meeting in Chicago.

"This is the first time that so many different measures of impulsivity, which is considered a risk factor for drug abuse, have been looked at in the same group of animals," said Lindsey Hamilton, lead investigator and a graduate student working in the laboratory of Michael Nader, Ph.D., a professor of physiology and pharmacology. "We're looking for ways to predict which individuals are going to take drugs during their lives. It was very surprising to see that, even more than a decade after the prenatal cocaine exposure, the monkeys ended up being more impulsive and possibly more susceptible to drug use. It was particularly interesting, however, that this effect was only seen in the males. Something is either protecting the females from the effects of the cocaine exposure in the womb or making the males more susceptible to the lasting effects."

For the study, researchers compared adult monkeys — both male and female — prenatally exposed to cocaine more than 15 years ago, to monkeys who were raised under similar conditions, but not exposed to cocaine during gestation. To determine if the animals differed in impulse control, they performed four tests. For one of the tests, the researchers gave the animals the choice between pushing a lever that delivered a single banana pellet reward immediately or a lever that delivered several banana pellets, but required the animals to wait up to five minutes before the reward was delivered.

"That's where we saw very large differences between the groups," Hamilton said. "The males who were exposed to cocaine in-utero had no patience or impulse control whatsoever."

Those monkeys were less willing to wait for a larger food reward and preferred the immediately available, though much smaller, reward, indicating they were more impulsive than the adult male monkeys who had never been exposed to cocaine. There was, however, no difference in the preference of female monkeys prenatally exposed to cocaine and those never exposed to the drug.

After all of the impulsivity tests were administered, the researchers ranked each monkey from least to most impulsive and compared their average impulsivity score across the four tests. They found that the male, but not female, monkeys prenatally exposed to cocaine were more impulsive overall compared to control monkeys who weren't exposed.

"A lot of the differences we saw were subtle," Hamilton said. "We've done several different kinds of impulsivity tests and, on their own, each task resulted in only slight differences. But together, they paint a really clear picture of the effects of this early cocaine exposure. The more challenging the test, the more obvious the difference between the groups was.

"The fact that we are seeing differences at all is particularly striking because this is 15 years after the monkeys were exposed in the womb to cocaine," she added. "Fifteen years is the equivalent of middle age for monkeys. The fact that fairly large differences are still turning up is fascinating."

Hamilton described the findings further, explaining that dopamine is a chemical in the brain that has been associated with drug abuse. When dopamine is released, it is broken down into homovanillic acid (HVA), which can be readily measured from a sample of cerebrospinal fluid (CSF). The researchers found that the less HVA present in a monkey's CSF, the less impulse control that monkey demonstrated. This finding is the first time a relationship between this dopamine metabolite and impulsivity has been documented, and indicates that there is a biological correlation associated with the alterations in impulse control observed in the monkeys exposed to cocaine in the womb.

Since decreased impulse control is a defining characteristic of cocaine addicts, Hamilton and her colleagues are currently working on an ongoing study to assess whether the monkeys that were prenatally exposed to cocaine will be more likely to self-administer drugs in adulthood.

So far, Hamilton said, it appears that the male monkeys exposed to cocaine in utero are more likely to self-administer the drug, even in low doses, than controls. Again, the difference is not being observed in the female monkeys.

"Our studies indicate that males may be more vulnerable to the long-lasting behavioral and neurobiological consequences of cocaine exposure during gestation than females, suggesting male children who were exposed to cocaine during their mothers' pregnancies may be predisposed to abuse drugs in adulthood," Hamilton said.

It has been estimated that there are about 7.5 million children in the United States that were exposed to cocaine during gestation and between 30,000 and 160,000 infants born each year who have been prenatally exposed to cocaine, according to the National Pregnancy and Health Survey, the Department of Health and Human Services and previous research. The effects of cocaine use during pregnancy on children's development are not well established.

"Whether or not these children who were exposed to cocaine in the womb may be more vulnerable to drug use is a timely question," Hamilton said, "both because these children are now young adults, a time when a lot of drug experimentation occurs, and because cocaine abuse among young women of childbearing age is a growing problem in this country."

It is challenging to study children exposed to cocaine in utero because there are many other factors that could affect their behavior, such as less-than-optimal prenatal care, inadequate nutrition, and exposure to multiple types and doses of drugs during their mothers' pregnancies, Hamilton explained. By using a monkey model, researchers are able to control these variables and determine the long-term effects of prenatal cocaine exposure.

"We know that drug abusers are more impulsive than non drug users," Hamilton said. "But what is not as clear is whether people become drug abusers because they are impulsive or if people become impulsive because they're drug abusers. It's a bit of the chicken or the egg puzzle. We'll probably find that it's a little bit of both. The more we learn about the causes of drug abuse, the more likely that, one day, we'll be able to prevent it."

Co-researchers on the study, funded by the National Institute on Drug Abuse, were Paul Czoty, Ph.D. and Michael Nader, both in the Department of Physiology and Pharmacology.

A vaccine to treat cocaine dependence appears to reduce use of the drug in a subgroup of individuals who attain high anticocaine antibody levels in response, according to a report in the October issue of Archives of General Psychiatry, one of the JAMA/Archives journals. However, only 38 percent of vaccinated individuals produced high enough antibody levels and those who did maintained them for only two months.

About 2.5 million Americans are dependent on cocaine, but only 809,000 receive treatment, according to background information in the article. One of every three drug-related emergency department visits can be attributed to cocaine dependence, which also has substantial social and economic effects. The U.S. Food and Drug Administration has not approved any pharmacological therapies for cocaine abuse, and behavioral therapies have a wide range of effectiveness. Animal and human studies have suggested that high levels of anticocaine antibodies in the blood can sequester and inactivate cocaine before it enters the brain, reducing feelings of euphoria from the drug without causing any psychoactive effects or harmful interactions.

Bridget A. Martell, M.D., M.A., of Yale University School of Medicine, New Haven, and Veterans Affairs Connecticut Healthcare System, West Haven, and colleagues conducted a 24-week phase 2b trial of a vaccine designed to increase levels of cocaine antibodies in the blood. A total of 115 cocaine-dependent individuals enrolled and 58 were randomly assigned to receive five vaccinations of the active vaccine. The other 57 received placebo injections over 12 weeks. In both groups combined, 94 (82 percent) completed the trial. Three times per week for 24 weeks, participants' urine was tested for metabolized cocaine.

Of the 55 participants who completed five active vaccinations, 21 (38 percent) attained blood cocaine antibody levels of 43 micrograms per milliliter or higher; those who did had significantly more cocaine-free urine samples between weeks nine and 16 of the study than individuals who did not attain those antibody levels or who received placebo injections (45 percent vs. 35 percent cocaine-free urine samples). The proportion of participants who reduced their cocaine by half was also greater in the group with high antibody levels than in those with a low antibody level (53 percent vs. 23 percent).

Adverse events associated with the vaccine were mild or moderate, with the most frequent being hardening and tenderness at the injection site. No treatment-related serious adverse events, withdrawals or deaths occurred.

"Optimal treatment will likely require repeated booster vaccinations to maintain appropriate antibody levels. Furthermore, efforts will be needed to retain subjects during the initial series of injections since antibody levels increased slowly over the first three months when patients were immunized according to the protocol used in these studies," the authors write. "Other treatments need to be used during this early treatment period to encourage abstinence. As an example, to retain subjects in this study during the initial slow increase in antibody responses, we enlisted cocaine-dependent subjects who were enrolled in a methadone maintenance program."

"Thus, the goals for future vaccine development will be to increase the proportion of subjects who can attain the desired antibody levels and to extend these periods of abstinence through long-term maintenance of these adequate antibody levels," they conclude. "We look forward to extending our promising findings in a broader population of cocaine abusers as we also reach for these future vaccine development goals."

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Journal Reference:

1. Bridget A. Martell; Frank M. Orson; James Poling; Ellen Mitchell; Roger D. Rossen; Tracie Gardner; Thomas R. Kosten. Cocaine Vaccine for the Treatment of Cocaine Dependence in Methadone-Maintained Patients: A Randomized, Double-blind, Placebo-Controlled Efficacy Trial. Arch Gen Psychiatry., 2009; 66 (10): 1116-1123 [link]

About 2 million Americans currently use cocaine for its temporary side-effects of euphoria, which have contributed to making it one of the most dangerous and addictive drugs in the country. Cocaine addiction, which can cause severe biological and behavioral problems, is very difficult to overcome.

Now, University of Missouri researchers Ashwin Mohan and Sandeep Pendyam, doctoral students in the Department of Electrical and Computer Engineering, are utilizing computational models to study how the brain’s chemicals and synaptic mechanisms, or connections between neurons, react to cocaine addiction and what this could mean for future therapies.

“With cocaine addiction, addicts don’t feel an urge to revolt because there is a strong connection in the brain from the decision-making center to the pleasure center, which overwhelms other normal rewards and is why they keep seeking it,” Pendyam said. “By using computational models, we’re targeting the connection in the brain that latches onto the pleasure center and the parameters that maintain that process.”

Glutamate is the major chemical released in the synaptic connections in the brain; the right amount present determines the activity of those connections. Using the computational model, MU researchers found that in an addict’s brain excessive glutamate produced in the pleasure center makes the brain’s mechanisms unable to regulate themselves and creates permanent damage, making cocaine addiction a disease that is more than just a behavioral change.

“Our model showed that the glutamate transporters, a protein present around these connections that remove glutamate, are almost 40 percent less functional after chronic cocaine usage,” Mohan said. “This damage is long lasting, and there is no way for the brain to regulate itself. Thus, the brain structure in this context actually changes in cocaine addicts.”

Mohan and Pendyam, in collaboration with MU professor Satish Nair, professor of electrical and computer engineering, and Peter Kalivas, professor and chair of the neuroscience department at the Medical University of South Carolina, found that the parameters of the brain that activate the pleasure center’s connections beyond those that have been discovered must undergo alteration in order for addicts to recover. This novel prediction by the computer model was confirmed based on experimental studies done on animal models by Kalivas’ laboratory.

“The long-term objective of our research is to find out how some rehabilitative drugs work by devising a model of the fundamental workings of an addict’s brain,” said Mohan, who will attend Washington University in St. Louis for his postdoctoral fellowship. “Using a systems approach helped us to find key information about the addict’s brain that had been missed in the past two decades of cocaine addiction research.”

Moham and Pendyam’s research has been published in Neuroscience and as a book chapter in New Research on Neuronal Network from Nova Publishers.

A study by Queen’s University Belfast has confirmed that some Northern Ireland teenagers are experimenting with cocaine.

Research conducted by the Institute of Child Care Research at Queen’s School of Sociology, Social Policy and Social Work has found that 7.5% of young people who took part in the Belfast Youth Development Survey had tried cocaine at least once by the age of 16.

The survey involves 4,000 teenagers in 43 schools in Northern Ireland, who have taken part in the study each year since entering post-primary education. Funded by the Health and Social Care Research and Development, Public Health Agency, Northern Ireland, it is one of the largest schools-based surveys of its kind in the UK or Ireland.

Dr Patrick McCrystal, Senior Research Fellow at the Institute or Child Care Research, said: "A small number of those who took part in the survey told us they had tried cocaine at least once. Of those who had taken cocaine, only one in ten used it on a weekly basis. This indicates that while some teenagers have experimented with the drug, few continue to use it regularly.

“While cocaine has only recently emerged on to the Northern Ireland drug scene, this study suggests that it may be making its way into the adolescent drug scene quite quickly. It also indicates that the profile of cocaine users may be changing.

“In the 1990’s the typical cocaine user was single, in their twenties, well-educated, and in a well-paid professional job. In this study, however, more than half of those who had experimented with the drug were females, and one third had experienced social deprivation. They were more likely to live within a disrupted family with just one parent, have poor levels of communication with parents or guardians, and have low levels of motivation to do well at school. Most of those who had taken cocaine also regularly got drunk, smoked tobacco daily, and used cannabis on a weekly basis. Two thirds had also used inhalants.

“This study shows that young people are able to get hold of cocaine for their own personal use. Oder friends were the most popular source for obtaining the drug, followed by a dealer and friends of the same age. When we began this study, outside in the street or at a party were the most popular places for taking cocaine. By the end of the study period the most common place was at a friend’s house, where just under half of those who had taken cocaine reported doing so.

“These findings highlight the need to educate young people about the risks and health and social implications of cocaine use while they are still in compulsory education and under the age of 16. Children and young people must be empowered to refuse an offer of drugs. If and when the opportunity to experiment with cocaine presents itself, they must be well-equipped with the knowledge to make informed decisions on drug use.

“The study also highlights the need for a well-planned strategy to monitor trends of illicit drug use among young people, to help inform policy to deal with its impact. If the age of first use of cocaine is becoming younger, or the levels of cocaine use are increasing, the number of users who are likely to develop problems and place demands on drug treatment centres will increase in the future. This is something that health, social care, and education policy makers should take note of."

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Journal Reference:

1. McCrystal et al. A profile of adolescent cocaine use in Northern Ireland. International Journal of Drug Policy, 2009; 20 (4): 357 DOI: 10.1016/j.drugpo.2008.09.005

Parts of the brain involved in monitoring behaviors and emotions show different levels of activity in cocaine users relative to non-drug users, even when both groups perform equally well on a psychological test. These results — from a brain-imaging study conducted at the U.S. Department of Energy's Brookhaven National Laboratory and published online the week of May 25, 2009, by the Proceedings of the National Academy of Sciences — suggest that such impairments may underlie addictive vulnerability, and that treatments aimed at improving these functions could help addicted individuals resist drugs.

"Many studies have found decreased brain activity in drug-addicted individuals relative to healthy control subjects during psychological tests," said lead author Rita Goldstein, a psychologist at Brookhaven Lab. "But it's never been clear if these differences were due to varying levels of interest or ability between the two groups. This is the first study to look at two groups matched for performance and interest — and we still see dramatic differences in the brain regions that play a very significant role in the ability to monitor behavior and regulate emotion, which are both important to resisting drug use.

"Whether these brain differences are an underlying cause or a consequence of addiction, the brain regions involved should be considered targets for new kinds of treatments aimed at improving function and self-regulatory control," Goldstein said.

The researchers studied 17 active cocaine users and 17 demographically matched healthy control subjects. Both groups were trained to push one of four colored buttons corresponding to the color of type used to present words that were either related to drug use (e.g., crack, addict) or neutral household terms. Subjects were given monetary rewards for fast, accurate performance — up to 50 cents for each correct answer on some tests, for a maximum of $75.

After training, both groups performed equally well on this same test while lying in a magnetic resonance imaging (MRI) scanner, with performance improving when they knew they'd be earning the highest monetary reward. During the tests, the scientists used functional MRI (fMRI) to indirectly measure the amount of oxygen being used by specific regions of the brain, as an indicator of brain activity in those regions.

There were three main differences between the cocaine-addicted subjects and the healthy controls:

• The cocaine users had reduced activity in a portion of the anterior cingulate cortex that usually becomes more active (compared to a passive baseline) when monitoring behavior. Activity levels were lowest during the least "interesting," or salient, version of the test — when there was no monetary reward and the words shown were neutral household terms. Within the cocaine-user group, activity levels were lowest in the people who had used cocaine most frequently in the 30 days prior to the test.
• The cocaine users also had reduced activity in another part of the anterior cingulate cortex that usually becomes less active (compared to a passive baseline) when someone is successfully suppressing emotional feelings. Within the cocaine-user group, activity levels during the high-salience version of the test — when each fast, correct answer was rewarded with 50 cents and the words presented were drug-related — were lowest in the people who were most successful in suppressing the task-induced craving. In healthy controls, who did not report craving, activation in this region was not significantly different from baseline.
• The functions within the behavior-monitoring and emotion-monitoring brain regions were interconnected in the healthy control subjects but not in the addicted individuals. In all, these group differences in brain function and interconnectivity were quite robust and all the more meaningful in that there were no differences between the groups in performance on or interest ratings for the task.

"When you really have to suppress a powerful negative emotion, like sadness, anxiety or drug craving, activity in this brain region is supposed to decrease, possibly to tune out the background 'noise' of these emotions so you can focus on the task at hand," Goldstein said.

"Our results show that activity in this region indeed went down in the drug-using group, suggesting they were actively trying to suppress craving. Indeed subjects who reported the highest levels of task-induced craving were the least able to suppress activity in this particular brain region.

"This could be because these drug users were still being distracted by background 'noise' stimuli, like memories of having taken drugs or anticipation of further use," Goldstein said.

"This work gives us some clues as to what happens when drug users are unable to suppress craving — and how that might work together with a decreased ability to monitor behavior, even during neutral, non-emotional situations, to make some people more vulnerable to taking drugs," Goldstein said.

The findings point to the importance of improving activity in the behavior-monitoring brain region, possibly by using behavioral and pharmacological approaches to increase motivation and top-down monitoring. Treatments aimed at strengthening activity in the emotion-monitoring brain region may further help addicted individuals regain self-control, especially during hard to suppress highly emotional situations (e.g., during craving). Treatments aimed at strengthening the interconnectivity between these brain regions may decrease impulsivity.

This study was supported by grants from the National Institute on Drug Abuse and the General Clinical Research Center of Stony Brook University.

Cocaine is one of the oldest drugs known to humans, and its abuse has become widespread since the end of the 19th century. At the same time, we know rather little about its effects on the human brain or the mechanisms that lead to cocaine addiction. The latest article by Dr. Marco Leyton, of the Montreal Neurological Institute (MNI), McGill University and the McGill University Health Centre, which was published in the journal Biological Psychiatry on May 15, 2009, not only demonstrates a link between cocaine and the reward circuits in the brain but also associates the susceptibility to addiction with these mechanisms.

The results of this study show that sniffing cocaine triggers high levels of dopamine secretion in a central region of the brain called the striatum. Dopamine is known to play a critical role in the brain's response to reward as well as in its response to addictive drugs.

This study was carried out in ten non-addicted users of cocaine, all of whom sniffed cocaine on one test day and placebo powder on another. Participants underwent blood tests before and after taking the drug, and dopamine release in the brain was measured using PET scans.

"The ability of cocaine to activate dopamine release varies markedly from person to person. Our study suggests that this is related to how much of the drug the person consumed in the past," explained Dr. Leyton. The more cocaine someone has used in his or her lifetime, the more the brain will secrete dopamine during subsequent cocaine use. "It's possible therefore that the intensity of the reward-circuit response is related to increased susceptibility to addiction," stated Dr. Leyton.

Although the relationship between the intensity of dopamine secretion and the frequency of drug use has been demonstrated, researchers still do not fully understand its mechanism of action. Is it the repeated stimulation of the reward circuit that leads to addiction, or is it an inherent sensitivity to addiction that leads to the increased secretion of dopamine? This question is not easy to answer, especially since other factors come into play, such as other aspects of the subject's personal history.

Whatever the answer, the relationship between dopamine and cocaine means that this hormone could be a potential target for treatment against addiction. More research is required before treatments are available, but this study opens a new door in this direction.

This study was funded with a grant from the Canadian Institutes for Health Research. Salary support was given by the Fond de recherche en santé du Québec

This study is a collaboration between several laboratories of the McGill University Health Centre and McGill University, involving : Dr Sylvia M.L. Cox, Dr Chawki Benkelfat, Dr Alain Dagher, Dr J. Scott Delaney, France Durand, Samuel A. McKenzie, Dr Theodore Kolivakis, Kevin F. Casey, Dr Marco Leyton.

— New research sheds light on how cocaine regulates gene expression in a crucial reward region of the brain to elicit long-lasting changes in behavior. The study, published by Cell Press in the May 14th issue of the journal Neuron, provides exciting insight into the molecular pathways regulated by cocaine and may lead to new strategies for battling drug addiction.

It is well established that addictive drugs induce persistent changes in the brain's reward circuits. Previous research has indicated that addiction to drugs such as cocaine is associated with altered gene expression in the nucleus accumbens (NAc), a region of the brain that is involved in motivation, pleasure, and reward.

"Although we have known for some time that changes in gene expression contribute to the long-lasting regulation of the brain's reward circuitry that is seen during drug addiction, how those specific genes are regulated is not well understood," explains senior study author, Dr. Eric J. Nestler from the Department of Neuroscience at the Mount Sinai School of Medicine.

Dr. Nestler and colleagues combined sophisticated and highly sensitive genetic isolation and screening techniques to study regulation of gene transcription in the mouse NAc, including regulation of chromatin structure, after repeated administration of cocaine. The results of this novel analysis significantly refined the understanding of cocaine-regulated gene transcription in general, and advanced knowledge of the specific role of two transcription factors known to play a prominent role in cocaine-induced addiction.

The researchers also identified a previously unrecognized family of genes, called the sirtuins, as being involved in cocaine addiction in the NAc. Chronic cocaine administration was linked with an increase in sirtuin gene transcription while increased sirtuin activity in NAc neurons was associated with a potentiation of the rewarding effects of cocaine. Importantly, pharmacological inhibition of sirtuins in the NAc reduced the rewarding effects of cocaine and the motivation to self-administer the drug.

Taken together, the results identify a subset of genes that are highly likely to be targets of cocaine and shed light on the specific mechanisms that underlie cocaine-induced changes in the NAc. "Our findings underscore the vast clinical potential of the many new gene targets identified in this study for the development of more effective treatments of cocaine and potentially other drug addictions," concludes Dr. Nestler.

The researchers include William Renthal, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Arvind Kumar, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Guanghua Xiao, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Matthew Wilkinson, Mount Sinai School of Medicine, New York, NY; Herbert E. Covington III, Mount Sinai School of Medicine, New York, NY; Ian Maze, Mount Sinai School of Medicine, New York, NY; Devanjan Sikder, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Alfred J. Robison, Mount Sinai School of Medicine, New York, NY; Quincey LaPlant, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, Mount Sinai School of Medicine, New York, NY; David M. Dietz, Mount Sinai School of Medicine, New York, NY; Scott J. Russo, Mount Sinai School of Medicine, New York, NY; Vincent Vialou, Mount Sinai School of Medicine, New York, NY; Sumana Chakravarty, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Thomas J. Kodadek, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Ashley Stack, Florida State University, Tallahassee, FL; Mohamed Kabbaj, Florida State University, Tallahassee, FL; and Eric J. Nestler, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, Mount Sinai School of Medicine, New York, NY.