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  1. mrsolearyscow
    Nicotine primes the brain to embrace cocaine, study says

    Nicotine appears to be a potent "gateway" drug that enhances the effects of cocaine and possibly boosts the chances of becoming addicted, researchers reported Wednesday in a landmark paper on drug addiction.

    While the study was performed in lowly mice, the findings suggest that reducing smoking and the use of other tobacco products -- and even nicotine replacement products and exposure to secondhand smoke -- in humans may have the bilateral impact of curbing addiction to other addictive substances.

    "If our findings in mice apply to humans, a decrease in smoking rates in young people would be expected to lead to a decrease in cocaine addiction," the authors wrote.

    Researchers led by Dr. Amir Levine at Columbia University in New York treated mice with nicotine and then exposed them to cocaine. The mice whose brains had been exposed to nicotine responded differently to the cocaine (exhibiting more characteristics of addiction) compared to mice who weren't exposed first to nicotine. Reversing the order of the drugs by exposing mice to cocaine first then nicotine had no such effect on behavior.

    Further, the study demonstrated that nicotine influences substances called histone proteins in the reward center of the brain that in turn activates certain genes and leads to an exaggerated response to cocaine.

    The research needs to be confirmed and raises many questions. But the implications are numerous and profound, such as whether reduced nicotine usage would lower the rates of other drug addictions. In a related analysis, Levine and his colleagues reviewed data on cocaine use among a group of high school students. They found that 81% of the youths who started using cocaine did so in a month when they were actively smoking tobacco and only 18.8% did so when they were not smoking.

    Moreover, treatment of nicotine addiction may help promote recovery of cocaine addiction, the authors note. Currently, many individuals in substance-abuse recovery programs who also smoke are prescribed nicotine-replacement products to help them quit smoking. But behavioral smoking cessation strategies may be more appropriate if nicotine is actually augmenting cocaine addiction.

    Finally, do the findings of this study apply to other gateway drugs? It's not clear if the relationship is specific to nicotine and cocaine or whether alcohol and marijuana -- substances that are also described as gateway drugs because they are typically used prior to experimentation with other drugs -- bolster the risk of addiction as well.

    "One wonders whether the prevailing focus on marijuana as a putative premier precursor drug might have kept researchers from more seriously exploring the possibility that nicotine -- which is, in fact, one of the two drugs (the other being alcohol) that children and adolescents are most likely to obtain first -- could have a strong claim to that moniker," said Dr. Nora Volkow, director of the National Institute on Drug Abuse, in a commentary accompanying the study.

    The papers are published in the journal Science Translational Medicine.

    Source: http://www.latimes.com/health/boost...-addiction-20111102,0,2537496.story?track=rss


  1. Docta
    [imgr=white] https://www.drugs-forum.com/forum/attachment.php?attachmentid=22985&stc=1&d=1320371857[/imgr]NIDA-funded research in mice shows that nicotine primes the brain to enhance cocaine's effects

    A landmark study in mice identifies a biological mechanism that could help explain how tobacco products could act as gateway drugs, increasing a person's future likelihood of abusing cocaine and perhaps other drugs as well, according to the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health. The study is the first to show that nicotine might prime the brain to enhance the behavioral effects of cocaine.

    The gateway drug model is based upon epidemiological evidence that most illicit drug users report use of tobacco products or alcohol prior to illicit drug use. This model has generated significant controversy over the years, mostly relating to whether prior drug exposure (to nicotine, alcohol or marijuana) is causally related to later drug use. Before now, studies have not been able to show a biological mechanism by which nicotine exposure could increase vulnerability to illicit drug use.

    In the current study, by researchers at Columbia University, New York City, and published in today's Science Translational Medicine, mice exposed to nicotine in their drinking water for at least seven days showed an increased response to cocaine. This priming effect depended on a previously unrecognized effect of nicotine on gene expression, in which nicotine changes the structure of the tightly packaged DNA molecule, reprograms the expression pattern of specific genes, in particular the FosB gene that has been related to addiction, and ultimately alters the behavioral response to cocaine.

    To examine whether the results from this study paralleled findings in humans, the researchers reexamined statistics from the 2003 National Epidemiological Study of Alcohol Related Consequences to explore the relationship between onset of nicotine use and degree of cocaine dependence. They found that the rate of cocaine dependence was higher among cocaine users who smoked prior to starting cocaine compared to those who tried cocaine prior to smoking.

    These findings in mice suggest that if nicotine has similar effects in humans, effective smoking prevention efforts would not only prevent the negative health consequences associated with smoking but could also decrease the risk of progression and addiction to cocaine and possibly other illicit drug use. In the meantime, this mouse model provides a new mechanism to study the gateway theory from a biological perspective.

    "Now that we have a mouse model of the actions of nicotine as a gateway drug this will allow us to explore the molecular mechanisms by which alcohol and marijuana might act as gateway drugs," said Eric Kandel, M.D., of Columbia University Medical Center and a senior author of the study. "In particular, we would be interested in knowing if there is a single, common mechanism for all gateway drugs or if each drug utilizes a distinct mechanism."

    NIH study examines nicotine as a gateway drug
    For Release November 2, 2011
  2. frog
    I see two different concepts here. One, nicotine addiction enhances cocaine cravings. Two, tobacco acts as a gateway drug.

    I'm inclined to believe the former (what do I know?), but the latter doesn't make much sense. Maybe it's a question of definition. To me, a gateway drug is a drug that leads to using other, harder, drugs. I don't think many people believe that tobacco leads to using harder drugs, and I'm not entirely sure that's the claim being made here.

    I've always been told that cannabis was a gateway drug, but I take issue with that statement as well. Many of my friends smoked joints, but none of them ever touched the "harder" drugs. And while I am the only one among my friends who ever touched cocaine (and developped an addiction to it), it just so happens that I never enjoyed cannabis.

    If people are curious about drugs, ultimately they will try them.
  3. Reuq
    I have often played with the idea of tobacco being the 'real' gateway drug: Both from my own experience, and that of others. I think that the addiction to nicotine is a factor, and allows users to justify harder drugs. However a bigger factor I think is that smoking tobacco is one of the first things people learn to smoke, and without that introduction they would be far less likely to smoke anything else that is offered. Although I don't think that it is fair to say that something is a 'gateway drug' because it was the first thing that a person tried, that doesn't fully fit the definition. Opinions (on what I'm not even sure?!)
  4. Dinneen
    I believe cannabis is more likely to act as a gateway drug than tobacco but for one reason - prohibition, not the drugs effects as if anything tobacco is far closer to the effects of cocaine and other addictive drugs than cannabis. This is because those who use cannabis generally have to buy it off a dealer as opposed to their local store, and therefore have a greater chance of coming into contact with users and dealers of harder drugs. This DOES NOT of course justify many parents concerns that cannabis is a dangerous gateway drug, in reality this view means cannabis would be less harmfull if legalised...
  5. Fiery_Zen
    Molecular mechanism found for controversial 'gateway drug' hypothesis

    Nicotine causes changes in gene regulation that enhance the brain's subsequent response to cocaine. The finding, in mice, provides the first clear evidence for a molecular mechanism supporting the idea of 'gateway drugs'.

    Epidemiologist Denise Kandel at Columbia University, New York, reported back in 1975 that drug-using adolescents had tended to start with cigarettes, which contain the addictive substance nicotine, and alcohol before progressing to more illicit substances such as cocaine. The idea that smoking and alcohol act as a gateway, making teenagers more likely to experiment with other drugs, has proved controversial ever since.

    Now Kandel has collaborated with her husband of 56 years, neurobiologist Eric Kandel, and other colleagues at Columbia, to probe the molecular biology underlying the gateway effect. In a study published today in Science Translational Medicine, the team shows that, in mice at least, nicotine causes epigenetic changes — long-lasting changes in the control of gene expression — that subsequently boost the response to cocaine.

    Neurobiologists Eric Nestler and Alfred Robison of the Mount Sinai School of Medicine in New York suggested in a review published earlier this month that such gene priming is likely to be at work in drug addiction. But their prediction was based on limited existing evidence. "This paper is exciting because it is one of the first well-defined characterizations of gene priming by a drug," says Robison.

    Amir Levine, a member of the Columbia team, acknowledges that there could be other reasons, such as social factors, for the progression from soft to hard drugs, but "adolescence is a time when the brain is very malleable", he points out. "We wondered if drug-induced brain alterations could have long-term molecular impacts."

    To investigate, the researchers plied mice with nicotine, followed seven days later by cocaine. What they found was striking. Compared with mice on cocaine who had not previously received nicotine, the animals were 98% more active and 78% more likely to return to areas previously associated with the cocaine.

    The reverse didn't hold, however. Cocaine had no effect on nicotine-induced behaviour.

    To determine how nicotine boosts cocaine's impact, the researchers studied molecular markers of drug addiction, including the transcription of FosB, a gene implicated in addiction to many drugs of abuse, and the structural changes that regulate FosB expression.

    "We found that nicotine works on the DNA-packaging system, known as chromatin," says Levine. Nicotine loosens chromatin, a complex material in which DNA is packaged up by histones and other proteins, by enhancing a process called histone acetylation, catalyzed by acetylase enzymes. Acetylation effectively opens up the packaging, enabling greater transcription of the FosB gene, he says. Nicotine does this by inhibiting another enzyme involved in gene regulation, histone deacetylase, which has the opposite effect on chromatin.

    The authors backed up their results with additional experiments showing, for example, that the drug suberoylanilide hydroxamine acid, which inhibits deacetylases, simulates the effect of nicotine.

    The team also re-evaluated existing epidemiological data on the drug use of 1,160 high school students and found that it confirmed that smoking increased the risk of cocaine dependency in people – consistent with the findings in mice.

    The research promises to reinvigorate the gateway-drug hypothesis, which Levine says has gained a bad reputation. "People think it's backed by conservative movements to make a case for making marijuana illegal, when it is simply the sequence of adolescent drug use as found in epidemiological studies," he says.

    Frances Leslie, a neuropharmacologist at the University of California at Irvine, who was not involved in the study, says that part of the problem is that people don't want to believe that teenage smoking will sensitize them to other drugs. And because it's difficult to tease out social factors in human studies, animal work has an important role. Her own group has shown that nicotine is associated with 'risky' behaviour, including an increase in self-administration of cocaine, in adolescent rats.

    The molecular mechanism revealed by the Columbia team's work "is exciting because it may lead to therapeutic interventions", says Leslie. "Hopefully this paper will make it less controversial to use the term 'gateway drug' in future papers and grants," she adds.

    The policy implications of the findings will undoubtedly be debated. Laura Bierut, a psychiatrist at Washington University in St Louis, Missouri, who focuses on the genetic epidemiology of addiction, says the Columbia study suggests that existing policies aimed at cutting smoking may be having a larger effect on public health than thought.

    It should also help to guide epidemiological studies to tease apart the relationship between cocaine use and smoking, she says, including the effects of the age that someone starts smoking, how much they smoke, and what other drugs they take.

    Levine and Eric Kandel now hope to determine whether alcohol and marijuana similarly prime the response to illicit drugs or have a different effect. "Is there a common gateway mechanism or a family of gateway mechanisms?" says Kandel.

    Virginia Gewin
    Published online 2 November 2011

    Gateway drugs? Personally, I don't believe it. Yes, mouse biochemistry is uncannily similar to that of humans (which is the reason we use them for research) but I think this is a misinterpretation of results. I am not a neuroscientist, though.
  6. Gradient
    Re: Molecular mechanism found for controversial 'gateway drug' hypothesis

    I urge you to check out the research paper, published in Science Translational Medicine (a high impact journal). It's excellent, from a respected lab with good pedigree.

    Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine

    This is an example of an approach to addiction research that's gaining more and more inertia: drugs influence more than just neurotransmitter systems - they induce epigenetic changes in the ways by which a human's genome is expressed, with long-term repercussions beyond immediate substance dependency.

    In this case, the pathway elucidated involves increased dopaminergic signaling in the ventral striatum - inducing activation of a cascade that ends up inhibiting histone deacetylase (HDAC), which likely fosters the transcription of a wide variety of genes by widespread acetylation of chromatin. This literally changes the shape that genomic DNA is stored.

    This is good, important research.
  7. Fiery_Zen
    Re: Molecular mechanism found for controversial 'gateway drug' hypothesis

    Thank you very much for the link to the actual research paper!
    I'm much more a physicist than a chemist, so I don't *completely* understand the paper. I'll be the first to admit that my opinion on this is heavily coloured and biased. Also, I'm only subscribed to Nature and Nature Physics, so actual research papers are usually out of my reach (unless I can get access to them through my uni, which is a convoluted process.)

    But yes, as you say, this is important research, not matter the personal opinions that pertain to it.
  8. c-m 444
    Re: Molecular mechanism found for controversial 'gateway drug' hypothesis

    this is an awesome paper man .. i always found weed wasn't the gateway drug but nicotine was ..
    no one ever admits smoking to be the first drug experience in most kids...mainstream often forgets it is a drug ... once you get over smoking cigs you can natural have no fear for smoking herb ..only sad part is you may never quit cigs ... and herb never hurt anybody ..
  9. Gradient
    Re: Molecular mechanism found for controversial 'gateway drug' hypothesis

    After taking a closer look at the stats reported in this paper, there are two significant problems in the way mice were treated with nicotine and cocaine in my opinion.

    11 days total for this sensitization paradigm is arguably insufficient - and, more importantly - irrelevant to human physiology; 4 days for cocaine sensitization and 7 days for nicotine are not a solid treatments - as I know many researchers that believe anything under 2 weeks is not thorough enough. This doesn't necessarily invalidate their argument, but does call into question the strength of the sensitization - and therefore, the capacity for nicotine to predispose people to enjoying & becoming addicted to cocaine.

    Also - 20mg/kg is quite a high dose of cocaine in one injection. Again - unrealistic to doses of cocaine. Crack, perhaps - but not cocaine. Giving massive doses of a drug, rather than giving doses comparable to what humans take over a longer period of time, does not induce the same physiological reaction in mice.

    I get the sense that someone was rushed early in this project's experiments, and the principle investigator later decided to acquire more data before publishing. They likely did not expect to see what they did in the behavioral component - and when they did, they decided to perform the biochemistry and electrophysiology.

    The biochemistry and electrophysiology are still interesting, if not convincing - but I'd still like to see longer treatments of both drugs.
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