Category: Cocaine

Raising levels of the neurotransmitter dopamine in the frontal cortex of the brain significantly decreased impulsivity in healthy adults, in a study conducted by researchers at the Ernest Gallo Clinic and Research Center at the University of California, San Francisco.

"Impulsivity is a risk factor for addiction to many substances, and it has been suggested that people with lower dopamine levels in the frontal cortex tend to be more impulsive," said lead author Andrew Kayser, PhD, an investigator at Gallo and an assistant professor of neurology at UCSF. "We wanted to see if we could decrease impulsivity by raising dopamine, and it seems as if we can."

The study was published on July 4 in the Journal of Neuroscience.

In a double-blinded, placebo-controlled study, 23 adult research participants were given either tolcapone, a medication approved by the Food and Drug Administration (FDA) that inhibits a dopamine-degrading enzyme, or a placebo. The researchers then gave the participants a task that measured impulsivity, asking them to make a hypothetical choice between receiving a smaller amount of money immediately ("smaller sooner") or a larger amount at a later time ("larger later"). Each participant was tested twice, once with tolcapone and once with placebo.

Participants — especially those who were more impulsive at baseline — were more likely to choose the less impulsive "larger later" option after taking tolcapone than they were after taking the placebo.

Magnetic resonance imaging conducted while the participants were taking the test confirmed that regions of the frontal cortex associated with decision-making were more active in the presence of tolcapone than in the presence of placebo.

"To our knowledge, this is the first study to use tolcapone to look for an effect on impulsivity," said Kayser.

The study was not designed to investigate the reasons that reduced dopamine is linked with impulsivity. However, explained Kayser, scientists believe that impulsivity is associated with an imbalance in dopamine between the frontal cortex, which governs executive functions such as cognitive control and self-regulation, and the striatum, which is thought to be involved in the planning and modification of more habitual behaviors.

"Most, if not all, drugs of abuse, such as cocaine and amphetamine, directly or indirectly involve the dopamine system," said Kayser. "They tend to increase dopamine in the striatum, which in turn may reward impulsive behavior. In a very simplistic fashion, the striatum is saying 'go,' and the frontal cortex is saying 'stop.' If you take cocaine, you're increasing the 'go' signal, and the 'stop' signal is not adequate to counteract it."

Kayser and his research team plan a follow-up study of the effects of tolcapone on drinking behavior. "Once we determine whether drinkers can safely tolerate this medication, we will see if it has any effect on how much they drink while they're taking it," said Kayser.

Tolcapone is approved as a medication for Parkinson's disease, in which a chronic deficit of dopamine inhibits movement.

Co-authors of the paper are Daicia C. Allen, BS, Ana Navarro-Cebrian, PhD, Jennifer M. Mitchell, PhD and senior author Howard L. Fields, MD, PhD, of the Gallo Center and UCSF.

The study was supported by funds from the Wheeler Center for the Neurobiology of Addiction, the U.S. Army Telemedicine and Advanced Technology Research Center, the Alcoholic Beverage Medical Research Foundation/The Foundation for Alcohol Research and the State of California.

New research by scientists at the University of Cambridge suggests that chronic cocaine abuse accelerates the process of brain aging. The study, published in Molecular Psychiatry, found that age-related loss of grey matter in the brain is greater in people who are dependent on cocaine than in the healthy population.

For the study, the researchers scanned the brains of 120 people with similar age, gender and verbal IQ. Half of the individuals had a dependence on cocaine while the other 60 had no history of substance abuse disorders.

The researchers found that the rate of age-related grey matter volume loss in cocaine-dependent individuals was significantly greater than in healthy volunteers. The cocaine users lost about 3.08 ml brain volume per year, which is almost twice the rate of healthy volunteers (who only lost about 1.69 ml per year). The accelerated age-related decline in brain volume was most prominent in the prefrontal and temporal cortex, important regions of the brain which are associated with attention, decision-making, and self-regulation as well as memory.

Previous studies have shown that psychological and physiological changes typically associated with old age such as cognitive decline, brain atrophy and immunodeficiency are also seen in middle-aged cocaine-dependent individuals. However, this is the first time that premature aging of the brain has been associated with chronic cocaine abuse.

Dr Karen Ersche, of the Behavioural and Clinical Neuroscience Institute (BCNI) at the University of Cambridge, said: "As we age, we all lose grey matter. However, what we have seen is that chronic cocaine users lose grey matter at a significantly faster rate, which could be a sign of premature aging. Our findings therefore provide new insight into why the cognitive deficits typically seen in old age have frequently been observed in middle aged chronic users of cocaine."

The scientists also highlight concerns that premature aging in chronic cocaine users is an emerging public health concern. The United Nations Office on Drugs and Crime estimates that cocaine is used by up to 21 million individuals worldwide, with approximately 1 per cent of these individuals becoming dependent.

Dr Ersche said: "Our findings clearly highlight the need for preventative strategies to address the risk of premature aging associated with cocaine abuse. Young people taking cocaine today need to be educated about the long-term risk of aging prematurely."

The concern of accelerated aging is not limited to young people but also affects older adults who have been abusing drugs such as cocaine since early adulthood.

Dr Ersche added: "Our findings shed light on the largely neglected problem of the growing number of older drug users, whose needs are not so well catered for in drug treatment services. It is timely for heath care providers to understand and recognise the needs of older drug users in order to design and administer age-appropriate treatments."

New research from Mount Sinai Medical Center in New York reveals that repeated exposure to cocaine decreases the activity of a protein necessary for normal functioning of the brain's reward system, thus enhancing the reward for cocaine use, which leads to addiction. Investigators were also able to block the ability of repeated cocaine exposure, to induce addiction. The findings, published online April 22 in the journal Nature Neuroscience, provide the first evidence of how cocaine changes the shape and size of neuron rewards in a mouse model.

Repeated exposure to cocaine decreases the expression of a protein necessary for normal functioning of the brain's reward system, thus enhancing the reward for cocaine use and stimulating addiction. Using the protein's light-activated form in real time, in a technique known as optogenetics, investigators were also able to block repeated cocaine exposure from enhancing the brain's reward center from cocaine. Even though the results are very early and many steps will be important in moving from mice to humans, the researchers say that the finding opens the door to a new direction for treatment for cocaine addiction.

"There are virtually no medication regimens for cocaine addiction, only psychotherapy, and some early work with vaccines," said the study's senior investigator, Eric Nestler, MD, PhD, Nash Family Professor of Neuroscience, Chairman of the Neuroscience and Director of the Friedman Brain Institute at Mount Sinai School of Medicine. The protein, Rac1, is found in many cells in mice, rats, monkeys, and humans, and it is known to be involved in controlling the growth of nerve cells.

Investigators "knocked out," or deleted, the gene responsible for Rac1 production, or injected a virus to enhance expression of Rac1.

"The research gives us new information on how cocaine affects the brain's reward center and how it could potentially be repaired," said Dr. Nestler. "This is the first case in the brain in vivo where it's been possible to control the activity of a protein, inside nerve cells in real time. Our findings reveal new pathways and target — a proof of principle study really — for treatment of cocaine addiction."

 Scientists at The Scripps Research Institute have shown that an injectable solution can protect mice from an otherwise lethal overdose of cocaine. The findings could lead to human clinical trials of a treatment designed to reverse the effects of cocaine in case of emergency. Cocaine is involved in more than 400,000 emergency-room visits and about 5,000 overdose deaths each year in the United States.

The findings, reported recently in the journal Molecular Pharmaceutics, demonstrate the therapeutic potential of a human antibody against cocaine.

"This would be the first specific antidote for cocaine toxicity," said Kim Janda, PhD, senior author of the report. A pioneer in the field of vaccines against drugs of abuse, Janda is the Ely R. Callaway, Jr. Chair in Chemistry, a professor in the Department of Immunology and Microbial Science, and director of The Worm Institute for Research and Medicine, all at Scripps Research. "It's a human antibody so it should be relatively safe, it has a superior affinity for cocaine, and we examined it in a cocaine overdose model that mirrors a real-life scenario," he said.

Janda and his laboratory colleagues have been developing candidate vaccines against cocaine, heroin, nicotine, and even Rohypnol, the "date-rape" drug. But most of these have been active vaccines — solutions of drug-mimicking molecules that provoke a long-term antibody response against a drug, greatly reducing its ability to reach the brain. These are potentially useful against addiction and relapse, but take weeks to stimulate an effective antibody response and thus are of limited value in drug overdose emergencies, which require a fast-acting antidote. Cocaine is a leading cause of illegal-drug overdoses in developed countries; it can cause hyperthermia, irregular heartbeats, seizures and death.

One possibility for an antidote is a "passive" cocaine vaccine, a ready-made solution of antibodies much like those used to treat snakebite. As Janda and his colleagues have shown in previous research, injected drug-specific antibodies can swiftly remove drug molecules from the bloodstream. This immediately reduces a drug's direct effects on the heart and nearby organs, but it also pulls the drug from the organ where it does the most damage — the brain. If the drug molecules are small enough to cross the blood-brain barrier, the sudden lowering of their bloodstream concentration causes them to diffuse rapidly out of brain tissue.

Cocaine molecules are small enough to diffuse this way, and in 2005 Janda and his lab reported that injections of a mouse-derived anti-cocaine antibody, GNC92H2, could keep mice alive despite cocaine doses that killed unprotected mice. Mouse antibodies are not ideal for use in humans, though; they are "foreign" enough that human immune systems eventually develop a reaction against them.

In the new study, Janda and Jennifer B. Treweek, PhD, a research associate in Janda's laboratory, used a genetically engineered mouse that can produce fully human antibodies against cocaine molecules. The best of these antibodies, GNCgzk, showed ten times the cocaine-binding affinity of GNC92H2, the molecule in the 2005 study.

In a preliminary test, the scientists showed an injection of GNCgzk antibodies 30 minutes before an injection of a lethal cocaine dose greatly reduced the signs of overdose — such as awkward movements and seizures — and kept all treated mice alive. By contrast, about half of untreated mice and 15 percent of GNC92H2-treated mice died.

In a test that better simulated a real-life emergency situation, mice were first given a cocaine overdose, and three minutes later were infused with GNCgzk. About half of untreated mice were killed by such a dose. While GNC92H2 reduced that rate to about 28 percent, the new GNCgzk antibodies reduced the mortality rate further, to 20 percent.

More strikingly, a stripped-down version of GNCgzk — F(ab')₂-gzk, which contains only the antibody's cocaine-binding segments — reduced the mortality to zero, as well as significantly reducing overdose signs such as seizures. It also did so at a much smaller, clinically feasible dose than GNC92H2's. "There was a reversal of the signs of cocaine toxicity within seconds of the injection," said Treweek.

Janda and Treweek are now trying to find ways to produce their F(ab')₂-gzk antidote economically and in large quantities. "If we can do that, then there would be no reason not to push it into clinical trials," Janda said.

He notes that such a treatment could be useful not only in reducing the immediate effects of an overdose, but also in preventing near-term relapses. "A lot of people that overdose end up going back to the drug rather quickly," Janda said, "but this antibody would stay in their circulation for a few weeks at least, and during that time the drug wouldn't have an effect on them." Likewise, this antibody could be administered to patients in addiction recovery or detox programs as a prophylactic treatment to supplement other medications, such as antidepressants, and counseling. An acute relapse during this recovery period would be immediately nullified by the antibody dose that is already in circulation.

Scientists are reporting development and successful testing in laboratory mice of a substance that shows promise for becoming the first antidote for cocaine toxicity in humans. According to a report in ACS' journal Molecular Pharmaceutics, the new so-called "passive vaccine" reversed the motor impairment, seizures and other dangerous symptoms of a cocaine overdose, which claims thousands of lives each year among users of the illicit drug.

Kim D. Janda and Jennifer B. Treweek explain that their previous research established the validity of using vaccines as treatments for drug addiction and contributed to the promotion of one cocaine active vaccine (and three nicotine active vaccines) to clinical evaluation in humans. These so-called "active" vaccines elicit antibodies that bind circulating cocaine (and nicotine) molecules in the blood and prevent these drug molecules from reaching the brain. In doing so, vaccinated patients are "immune" to the drug's effects, and as a result, they feel no pleasurable effects from the drug if they backslide during recovery.

The report describes the development of a cocaine passive vaccine, which consists of pre-formed human antibodies against cocaine that are 10 times more potent in binding cocaine molecules. This improved potency accelerates their ability to reverse cocaine toxicity, where time is of the essence. When administered by emergency medical teams or in hospital emergency departments, these passive vaccines could represent a life-saving therapeutic for overdose victims. The vaccine "represents a viable treatment strategy for the human condition of cocaine overdoses," the report concludes.

The authors acknowledge funding from the Skaggs Institute for Chemical Biology and the National Institute on Drug Abuse.

Intense, passionate feelings of love can provide amazingly effective pain relief, similar to painkillers or such illicit drugs as cocaine, according to a new Stanford University School of Medicine study.

"When people are in this passionate, all-consuming phase of love, there are significant alterations in their mood that are impacting their experience of pain," said Sean Mackey, MD, PhD, chief of the Division of Pain Management, associate professor of anesthesia and senior author of the study, which will be published online Oct. 13 in PLoS ONE. "We're beginning to tease apart some of these reward systems in the brain and how they influence pain. These are very deep, old systems in our brain that involve dopamine — a primary neurotransmitter that influences mood, reward and motivation."

Scientists aren't quite yet ready to tell patients with chronic pain to throw out the painkillers and replace them with a passionate love affair; rather, the hope is that a better understanding of these neural-rewards pathways that get triggered by love could lead to new methods for producing pain relief.

"It turns out that the areas of the brain activated by intense love are the same areas that drugs use to reduce pain," said Arthur Aron, PhD, a professor of psychology at State University of New York at Stony Brook and one of the study's authors. Aron has been studying love for 30 years. "When thinking about your beloved, there is intense activation in the reward area of the brain — the same area that lights up when you take cocaine, the same area that lights up when you win a lot of money."

The concept for the study was sparked several years ago at a neuroscience conference when Aron, an expert in the study of love, met up with Mackey, an expert in the research of pain, and they began talking.

"Art was talking about love," Mackey said. "I was talking about pain. He was talking about the brain systems involved with love. I was talking about the brain systems involved with pain. We realized there was this tremendous overlapping system. We started wondering, 'Is it possible that the two modulate each other?'"

After the conference, Mackey returned to Stanford and collaborated with postdoctoral scholar Jarred Younger, PhD, now an assistant professor of anesthesia, who was also intrigued with the idea. Together the three set up a study that would entail examining the brain images of undergraduates who claimed to be "in that first phase of intense love."

"We posted fliers around Stanford University and within hours we had undergrads banging on our door," Mackey said. The fliers asked for couples who were in the first nine months of a romantic relationship.

"It was clearly the easiest study the pain center at Stanford has ever recruited for," Mackey said. "When you're in love you want to tell everybody about it.

"We intentionally focused on this early phase of passionate love," he added. "We specifically were not looking for longer-lasting, more mature phases of the relationship. We wanted subjects who were feeling euphoric, energetic, obsessively thinking about their beloved, craving their presence.

"When passionate love is described like this, it in some ways sounds like an addiction. We thought, 'Maybe this does involve similar brain systems as those involved in addictions which are heavily dopamine-related.' Dopamine is the neurotransmitter in our brain that is intimately involved with feeling good."

Researchers recruited 15 undergraduates (eight women and seven men) for the study. Each was asked to bring in photos of their beloved and photos of an equally attractive acquaintance. The researchers then successively flashed the pictures before the subjects, while heating up a computer-controlled thermal stimulator placed in the palm of their hand to cause mild pain. At the same time, their brains were scanned in a functional magnetic resonance imaging machine.

The undergraduates were also tested for levels of pain relief while being distracted with word-association tasks such as: "Think of sports that don't involve balls." Scientific evidence has shown in the past that distraction causes pain relief, and researchers wanted to make sure that love was not just working as a distraction from pain.

Results showed that both love and distraction did equally reduce pain, and at much higher levels than by concentrating on the photo of the attractive acquaintance, but interestingly the two methods of pain reduction used very different brain pathways.

"With the distraction test, the brain pathways leading to pain relief were mostly cognitive," Younger said. "The reduction of pain was associated with higher, cortical parts of the brain. Love-induced analgesia is much more associated with the reward centers. It appears to involve more primitive aspects of the brain, activating deep structures that may block pain at a spinal level — similar to how opioid analgesics work.

"One of the key sites for love-induced analgesia is the nucleus accumbens, a key reward addiction center for opioids, cocaine and other drugs of abuse. The region tells the brain that you really need to keep doing this," Younger said.

"This tells us that you don't have to just rely on drugs for pain relief," Aron said. "People are feeling intense rewards without the side effects of drugs."

Other Stanford contributors include research assistants Sara Parke and Neil Chatterjee.

Funding for the study was received from the Chris Redlich Pain Research Fund.

When it comes to addiction, sex matters. A new brain imaging study by Yale School of Medicine researchers suggests stress robustly activates areas of the brain associated with craving in cocaine-dependent women, while drug cues activate similar brain regions in cocaine-dependent men.  The study, expected to be published online Jan. 31 in the American Journal of Psychiatry, suggests men and women with cocaine dependence might benefit more from different treatment options.

"There are differences in treatment outcomes for people with addictions who experience stress-induced drug cravings and those whose cravings are induced by drug cues," said Marc Potenza, professor of psychiatry, child study, and neurobiology and first author of the study. "It is important to understand the biologic mechanisms that underlie these cravings."

The researchers conducted functional magnetic resonance imaging scans of 30 cocaine-dependent individuals and 36 control subjects who were recreational drinkers. While undergoing brain scans, researchers then presented subjects with personalized cues (situations or events) the participants had indicated were personally stressful and other cues involving cocaine or alcohol.

As expected, cocaine-dependent individuals showed greater activation in broad regions of the brain linked to addiction and motivation than the control subjects. Patterns of activation between the groups, however, differed markedly in men and women when presented with stress or drug cues.

Potenza said the findings suggest that women with cocaine dependence might benefit from stress-reduction therapies that specifically target these cravings. Men, on the other hand, might derive more benefit from elements of cognitive behavioral therapy or 12-step programs based on the principles of Alcoholics Anonymous.

The senior author of the paper is Rajita Sinha of Yale. Other Yale authors are Kwang-ik Adam Hong, Cheryl M. Lacadie, Robert K. Fulbright, and Keri L. Tuit.

The study was supported by the Yale Stress Center, Women's Health Research at Yale, the Connecticut Department of Mental Health and Addiction Services, and grants from the National Institutes of Health and its Office of Research on Women's Health.

A single injection of cocaine or methamphetamine in mice caused their brains to put the brakes on neurons that generate sensations of pleasure, and these cellular changes lasted for at least a week, according to research by scientists at the Salk Institute for Biological Studies.

Their findings, reported March 7, 2012 in Neuron, suggest this powerful reaction to the drug assault may be a protective, anti-addiction response. The scientists theorize that it might be possible to mimic this response to treat addiction to these drugs and perhaps others, although more experiments are required to explore this possibility.

"It was stunning to discover that one exposure to these drugs could promote such a strong response that lasts well after the drug has left the body," says Paul Slesinger, an associate professor in the Clayton Foundation Laboratories for Peptide Biology. "We believe this could be the brain's immediate response to counteract the stimulation of these drugs."

Scientists are trying to better understand the brain's response to psychoactive drugs in hopes of finding new ways to prevent and treat addiction. This research has become especially important as the number of deaths due to drug abuse now exceeds those due to car accidents, with more than 37,000 people dying from drugs in 2009, according to the Centers for Disease Control and Prevention. Slesinger and Christian Lüscher, a long-time collaborator at the University of Geneva, have been investigating the cellular changes in the brain that occur with drug abuse.

Dopamine is a primary neurotransmitter used in the brain's reward pathway — generally speaking, the activity of dopamine neurons in the reward pathway increases in response to rewards, such as sex, food and drugs. Psychostimulants, such as methamphetamine and cocaine, co-opt this pathway and alter the brain's response to dopamine. Understanding the neuroadaptations that occur in the reward pathway in response to drugs of abuse may lead to the development of a treatment for drug addiction.

Previous research has shown that use of cocaine and methamphetamine in mice enhances excitatory connections to dopamine neurons. While most research has focused on these excitatory neurons, Slesinger and his colleagues looked at neurons that inhibit dopamine transmission, and found that one injection of cocaine or methamphetamine produces a profound change in the function of these inhibitory GABA neurons. These neurons were not able to control how they fired, so they would release more than the usual amount of inhibitory neurotransmitter.

"This persistent change in the inhibitory neurons occurs simultaneously with enhancement of excitatory inputs, indicating a possible compensatory mechanism that could be protective during exposure to drugs," Slesinger says.

The Salk researchers identified a change in the biochemical pathway in inhibitory GABA neurons that led to this protective effect. It involved a change in the activity of a protein, known as a phosphatase, which controls the levels of a receptor known to be important for controlling the electrical activity of the GABA neuron.

"This particular pathway — involving a GABA type B receptor and a particular type of potassium channel — was affected by psychostimulants in these inhibitory neurons," Slesinger says. "We noticed a dramatic reduction in the strength of this signaling pathway, which we showed was due to a decrease in the activity of the GABA_B receptor and the potassium channel on the neuron's membrane surface."

"If we could tap into this pathway — enhance the ability of inhibitory neurons to control the activity of dopamine neurons — we might be able to treat some types of drug addiction," Slesinger says.

What is not known is how long the drug response lasts — this study only looked at the brains of mice at two time points, 24 hours and seven days, after drug use — and why addiction ultimately develops with chronic drug use. These are questions Slesinger and his colleagues are now investigating.

The study's two lead authors are Claire Padgett, a former postdoctoral researcher in the Slesinger laboratory, and Arnaud Lalive, a doctoral student at the University of Geneva, who is working in the laboratory of Christian Lüscher, also a co-author. Other participating investigators include: Michaelanne Munoz, of the University of California San Diego; Stephen Moss and colleagues from Tufts University School of Medicine; Rafael Luján, from the Universidad de Castilla-La Mancha in Albacete, Spain; and investigators from Hokkaido University School of Medicine in Sapporo, Japan; University College in London; and AstraZeneca in Cheshire, United Kingdom.

The study was funded by the National Institute on Drug Abuse, the National Institute of Neurological Disorders and Stroke, Catharina Foundation and the Spanish Ministry of Education and Science.

A high childhood IQ may be linked to subsequent illegal drug use, particularly among women, suggests research published online in the Journal of Epidemiology and Community Health.

The authors base their findings on data from just under 8,000 people in the 1970 British Cohort Study, a large ongoing population based study, which looks at lifetime drug use, socioeconomic factors, and educational attainment.

The IQ scores of the participants were measured at the ages of 5 and 10 years, using a validated scale, and information was gathered on self reported levels of psychological distress and drug use at the age of 16, and again at the age of 30 (drug use only) .

Drug use included cannabis; cocaine; uppers (speed and wiz); downers (blues, tanks, barbiturates); LSD (acid); and heroin.

By the age of 30, around one in three men (35.4%) and one in six women (15.9%) had used cannabis, while 8.6% of men and 3.6% of women had used cocaine, in the previous 12 months.

A similar pattern of use was found for the other drugs, with overall drug use twice as common among men as among women.

When intelligence was factored in, the analysis showed that men with high IQ scores at the age of 5 were around 50% more likely to have used amphetamines, ecstasy, and several illicit drugs than those with low scores, 25 years later.

The link was even stronger among women, who were more than twice as likely to have used cannabis and cocaine as those with low IQ scores.

The same associations emerged between a high IQ score at the age of 10 and subsequent use of cannabis, ecstasy, amphetamines, multiple drug use and cocaine, although this last association was only evident at the age of 30.

The findings held true, irrespective of anxiety/depression during adolescence, parental social class, and lifetime household income.

"Although most studies have suggested that higher child or adolescent IQ prompts the adoption of a healthy lifestyle as an adult, other studies have linked higher childhood IQ scores to excess alcohol intake and alcohol dependency in adulthood," write the authors.

Although it is not yet clear exactly why there should be a link between high IQ and illicit drug use, the authors point to previous research, showing that highly intelligent people are open to experiences and keen on novelty and stimulation.

Other research has also shown that brainy children are often easily bored and suffer at the hands of their peers for being different, "either of which could conceivably increase vulnerability to using drugs as an avoidant coping strategy," explain the authors.

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Journal Reference:

1. James White, G. David Batty. Intelligence across childhood in relation to illegal drug use in adulthood: 1970 British Cohort Study. Journal of Epidemiology and Community Health, 2011; DOI: 10.1136/jech-2011-200252