cocaine alters the way the genes in your brain operate

It's hardly a secret that taking cocaine can change the way you feel and the way you behave. Now, a study published in the Jan. 8 issue of Science shows how it also alters the way the genes in your brain operate. Understanding this process could eventually lead to new treatments for the 1.4 million Americans with cocaine problems, and millions more around the world. The study, which was conducted on mice, is part of a hot new area of research called epigenetics, which explores how experiences and environmental exposures affect genes. "This is a major step in understanding the development of cocaine addiction and a first step toward generating ideas for how we might use epigenetic regulation to modulate the development of addiction," says Peter Kalivas, professor of neuroscience at the Medical University of South Carolina, who was not associated with the study. Though we think about our genes mostly in terms of the traits we pass on to our children, they are actually very active in our lives every day, regulating how various cells in our bodies behave. In the brain this can be especially powerful. Any significant experience triggers changes in brain genes that produce proteins — those necessary to help memories form, for example. But, says the study's lead author, Ian Maze, a doctoral student at Mount Sinai School of Medicine, "when you give an animal a single dose of cocaine, you start to have genes aberrantly turn on and off in a strange pattern that we are still trying to figure out." Maze's research focused on a particular protein called G9a that is associated with cocaine-related changes in the nucleus accumbens, a brain region essential for the experience of desire, pleasure and drive. The role of the protein appears to be to shut down genes that shouldn't be on. One-time use of cocaine increases levels of G9a. But repeated use works the other way, suppressing the protein and reducing its overall control of gene activation. Without enough G9a, those overactive genes cause brain cells to generate more dendritic spines, which are the parts of cells that make connections to other cells. <br /> Increases in the number of these spines can reflect learning. But in the case of addiction, that may involve learning to connect a place or a person with the desire for more drugs. Maze showed that even after a week of abstinence, mice given a new dose of cocaine still had elevated levels of gene activation in the nucleus accumbens, meaning G9a levels were still low. It is not known how long these changes can last. Maze also showed that when he intervened and raised G9a levels, the mice were less attracted to cocaine. <br /> It's a big leap from a mouse study to a human study, of course — and an even bigger leap to consider developing a G9a-based treatment for addiction. The protein regulates so many genes that such a drug would almost certainly have unwanted and potentially deadly side effects. But a better understanding of the G9a pathways could lead to the development of safer, more specific drugs. And studying the genes that control G9a itself could also help screen people at risk for cocaine addiction: those with naturally lower levels of the protein would be the ones to watch. Still, there's a lot to be learned even from further mouse studies — particularly if the work involves younger mice, unlike the adults used in Maze's research. <br /> <blockquote>"We know that the greatest vulnerability [to addiction] occurs when adolescents are exposed," says Dr. Nora Volkow, director of the National Institute on Drug Abuse, which funded the study. "Would you see the same results in adolescent [mice]? And what happens during fetal exposure?" </blockquote><br /> New treatments are definitely needed for cocaine addiction: there are helpful medications for addiction to heroin and similar drugs, but so far, none are particularly useful against stimulants like cocaine and methamphetamine. And with federal reports now showing that more than two-thirds of all cocaine in the country is cut with a veterinary deworming drug called levamisole, which can cause potentially fatal immune-system problems, the risks from cocaine are greater — and the search for new answers more urgent than ever.

cocaine alters the way the genes in your brain operate

It's hardly a secret that taking cocaine can change the way you feel and the way you behave. Now, a study published in the Jan. 8 issue ...

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We were theorizing that maybe it was something in the cocaine, levamisole

It was a medical mystery. In the summer of 2008, a man and woman, both in their 20s and both cocaine users, were separately admitted to a Canadian hospital with unremitting fevers, flulike symptoms and dangerously low white blood cell counts. Their symptoms were consistent with a life-threatening immune-system disorder called agranulocytosis, which kills 7% to 10% of patients and is rare except in chemotherapy patients and those taking certain antipsychotic medications.Neither of the Canadian patients fit that bill, but they did have one thing in common: illegal drug use, says Dr. Nancy Zhu, who treated the patients during her hematology fellowship at the University of Alberta Hospital in Edmonton. "We were theorizing that maybe it was something in the cocaine," she says. The medical literature didn't contain any studies linking agranulocytosis with cocaine. However, earlier that same year, in April, a New Mexico lab had identified a small number of unexplained cases of the disorder, also in people who had snorted, injected or smoked cocaine. Later, in 2009, a few cocaine addicts in San Francisco — crack smokers, mostly — began displaying even stranger symptoms, like dead, darkened skin. "It looked like people were getting burns all over their body," says Dr. Jonathan Graf, a rheumatologist at the University of California, San Francisco. "[Their skin was] black, as if you had taken a cigarette butt to it. In some people, it was all over, on their legs and bellies."By this time, back in Canada, a toxicologist at Alberta Hospital had noticed an unusual chemical in the urine of the two cocaine-using patients: levamisole. Zhu contacted him and they put the puzzle together. Further research revealed that levamisole, a drug that was once used to treat colon cancer but is now reserved for veterinary use as a medication to get rid of worms, can cause agranulocytosis in humans. The "burns" seen in Californian patients, who were also suffering from agranulocytosis, were the result of skin infections related to patients' compromised immunity. There have now been several dozen cases of cocaine-related agranulocytosis reported in North America — and one known death. "For some reason, this drug called levamisole keeps popping up," Zhu says. Where is it coming from? According to the U.S. Drug Enforcement Agency, levamisole has become increasingly popular as a "cut" or diluting agent in cocaine and possibly some heroin. It is now found in 70% of all cocaine seized in the United States, up from 30% in 2008. Unlike most cuts — usually inert or relatively harmless substances like the B-vitamin inositol, which are added by lower-level dealers looking to stretch supplies — levamisole appears to be added to cocaine from the outset, in the countries of origin. The substance has been found in various concentrations in cocaine analyzed in various countries around the world, from Switzerland to Australia. And urine tests of cocaine users attending a drug clinic in San Francisco General Hospital in 2009 — one floor above Graf's office — found that 90% of samples were positive for levamisole; similar tests in Seattle revealed that 80% of cocaine users there had levamisole in their systems too."If it's showing up in all those different places, that's a prima facie indicator that it's happening at the highest levels of production," says Craig Reinarman, a sociologist at the University of California, Santa Cruz who has long studied cocaine. But since cocaine is illegal, there's no easy way to remove levamisole from the supply chain. Law enforcement could instead target large purchasers, possibly putting pressure on dealers to switch to other cuts.<br /> <blockquote>Levamisole is cheap, widely available and seems to have the right look, taste and melting point to go unnoticed by cocaine users, which may alone account for the popularity of the cut. </blockquote>"Ease of availability seems likely to be important," says Reinarman. "Let's remember that producer countries are widely agrarian." Levamisole is used on farms and its cost per gram is minimal.An understanding of how levamisole affects the body, however, may better explain its explosive popularity. A 1998 paper found that levamisole relieved symptoms of heroin withdrawal in rats and also raised levels of various brain chemicals related to drug highs. "It may increase dopamine and by so doing may enhance cocaine effects," speculates Dr. Nora Volkow, director of the National Institute on Drug Abuse. Research conducted by Eldo Kuzhikandathil, assistant professor of pharmacology at University of Medicine and Dentistry of New Jersey, suggests that levamisole may indirectly increase the number of D1 dopamine receptors in the brain by affecting gene expression there. "Cocaine increases D1 expression," he says, "And this would probably accentuate that," which could enhance both highs and craving.Levamisole also affects acetylcholine receptors throughout the body, which can boost heart rate — and studies of cocaine users show that they associate jumps in heart rate with getting high, spurring good feelings even before the drug hits the brain. A cut that accelerates heart rate might make them think that they're getting the real thing. In the brain, levamisole may affect the same acetylcholine receptors activated by nicotine, another addictive drug that raises dopamine levels — and another possible clue to levamisole's lure. <br /> But despite the wide use of levamisole, cases of agranulocytosis are relatively uncommon. According to government surveys, nearly two million Americans have taken cocaine at least once in the last month. "Why aren't 90% of cocaine users [in San Francisco] getting sick?" says Graf, who says he sees about one case every few weeks, mostly in women. He suspects that men are less likely to be affected because they are less vulnerable to autoimmune disorders than women, but says that the truth is, no one really knows why certain users become ill. Zhu and Graf urge users who are suffering from fever or unexplained infections to seek medical help immediately — the sooner agranulocytosis is treated, the greater the odds of survival.<br /> <br /> <br /> <br /> To both physicians, the biggest mystery may be the power of cocaine addiction itself. Some of Graf's patients waited months before seeking help, as patches of painful, blackened skin continued to grow — and some continued to use cocaine despite learning that it caused their immune problems and that they could require plastic surgery to avoid permanent disfigurement. Zhu has treated several patients with life-threatening infections, some needing breathing tubes and intensive care. "It's quite sad, every time they use [cocaine], it happens. They wind up in the hospital for several weeks and almost die. But as soon as they go home and back into that environment, the cycle begins again."

We were theorizing that maybe it was something in the cocaine, levamisole

It was a medical mystery. In the summer of 2008, a man and woman, both in their 20s and both cocaine users, were separately admitted to a Ca...

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Karl Barnes, 19, had been given a glowing progress report from Castington young offenders’ institution

Karl Barnes, 19, had been given a glowing progress report from Castington young offenders’ institution, Teesside Crown Court was told.Barnes, from South Bank, successfully completed a drug and alcohol abuse programme, and he was assessed as “polite” and “respectful”.He was arrested after he was spotted trying the door handles of five houses in Park Avenue, Teesville, after midnight on December 18. Barnes told police later: “I was off my head.”He had many previous convictions for dishonesty, and been sentenced to detention and training for robbery, the court heard yesterday.Richard Herrmann, defending, said: “He now realises it is his time to mature. He had taken drink and drugs and he has no recollection of where he was or what he was doing.”Barnes of Upper Princess Street, pleaded guilty to burglary with intent to steal on December 18.Judge Peter Bowers told him: “It seems to me that from the letter I have got from the prison officer that you are getting a lot of help in Castington."It seems to me that when you are not in custody your compliance with any probation and intervention is intermittent.” Barnes was sentenced to 12 months detention in a young offenders’ institution.The judge added: “You will be released after half of that, and perhaps you can sort your life out.”

Karl Barnes, 19, had been given a glowing progress report from Castington young offenders’ institution

Karl Barnes, 19, had been given a glowing progress report from Castington young offenders’ institution, Teesside Crown Court was told.Barnes...

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massive stash of amphetamines with a street value of £180,000

Cleveland Police made the discovery while searching a garage in Hartlepool last Friday.<br /> <br /> Inside they found a massive stash of amphetamines with a street value of £180,000.<br /> A search warrant was executed at a house on the town’s Irvine Road at 7.45am where officers found thousands of pounds in cash and an amount of suspected Class B drugs.Further inquiries led them to search a garage block near Innes Road in the town where they made the huge find.<br /> Sergeant John Hemsworth, of Hartlepool District Drugs Unit, said: “This was a substantial recovery of what we believe to be amphetamines which would have been destined for the streets of Hartlepool and further afield.“Residents can be assured that we will always act on any information from the public about the use and supply of drugs.”A 40-year-old man and a 39-year-old woman were arrested and have since been bailed while inquiries continue.

massive stash of amphetamines with a street value of £180,000

Cleveland Police made the discovery while searching a garage in Hartlepool last Friday. Inside they found a massive stash of amphetamines ...

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