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  1. talltom
    Synthetic Spirits: Can we use science to reduce the harms of alcohol?

    Alcohol is the oldest of all recreational drugs. While its psychological complications have long been known, only in the past century have its medical complications, such as liver cirrhosis, cardiovascular disease, and cancers, become recognized.

    In many Western countries these medical problems have increased at an alarming rate. In the United Kingdom, for example, the death rate from liver disease has risen 500% over the past 40 years. It is predicted that, within a decade, liver disease will overtake cardiovascular disease as the leading cause of death in the UK. For these reasons, a recent systematic assessment of drug-related health hazards in the UK scored alcohol as the worst drug overall (Nutt et al., Lancet, 376:1558-66, 2010).

    These facts raise two questions: why is alcohol so widely available if it is so toxic and what can we do about it? The answer to the first question appears to be partly due to the fact that many people (and governments) take an ostrich-like view of the health hazards of alcohol. This attitude is compounded by the argument (probably false) that, at low doses and in some populations, alcohol may, in fact, have certain health benefits. Both attitudes belie the facts.

    If alcohol were invented today and subjected to current safety-of-use assessments, it would fail badly. Ethanol, the active ingredient, is toxic itself, which is why it is used to protect food from microbial infections and to sterilize skin. An amount only three times higher than a common intoxicating dose leads to death in naive users. And there is no antidote. Moreover, ethanol is converted to acetaldehyde as part of its elimination process. This is a highly toxic substance that in effect pickles the liver and other organs of regular drinkers.

    So what can we do about it? I think it is time to use the now-considerable knowledge of the neuropsychopharmacology of alcohol to develop safer, alternative intoxicants whose effects can be reversed by antidotes. A prime target of alcohol in the brain is the GABA-A receptor. Alcohol enhances the actions of the endogenous neurotransmitter GABA, which regulates the major inhibitory system in the brain. Since GABA-A receptors are found on most neurons, alcohol has a wide range of effects.

    Other drugs that enhance GABA at this receptor mimic the relaxing, antianxiety effects of alcohol. The best examples are the benzodiazepines, which enhance GABA action. Drinkers report that agonists at benzodiazepine receptors behave just like alcohol And there exist potent and effective antagonist/antidotes, which are currently clinically available.

    The Scientist Magazine



  1. Terrapinzflyer
  2. talltom
    And here is more on the pharmacology of alcohol abuse and how it relates to drug abuse

    CREB, alcohol, and anxiety

    How pharmacogenomics might help alcohol addiction treatment

    Addiction pathways in the brain are complicated, and alcoholism might be the most complex. "Drugs act very differently in the brain, and among them alcohol is the most different," says Markus Heilig, clinical director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). While most drugs of abuse are receptor-mediated, "the problem with alcohol is it gets into everything. It gets into proteins in the membrane, it gets into lipids," says Antonio Noronha, NIAAA's director of the Division of Neuroscience and Behavior.

    Still, alcoholism and addiction to drugs of abuse have some molecular similarities and, perhaps not surprisingly, cAMP-response-element-binding protein (CREB) is one of them. In 1993, a group from the Indiana University School of Medicine and the Veterans Administration Medical Center described the characteristics of a selectively bred strain of rats. These P rats (for alcohol-preferring) drank more alcohol than control rats, and they also showed higher levels of anxiety when they were not under the influence.1

    Another quality of the rats interested Subhash Pandey of the University of Illinois at Chicago. "When they drink alcohol," Pandey says, "their anxiety disappears." Pandey wanted to find out what was responsible. He turned to CREB and one of its targets, neuropeptide Y (NPY), a potent, endogenous anxiolytic compound.

    Heilig, when he was a postdoc with George Koob at the Scripps Research Institute, had shown that NPY acts in opposition to corticotropin releasing factor, also known as corticotropin releasing hormone (CRH).2 "NPY is an antistress system that basically antagonizes the effects of CRH," Heilig says. NPY is also important in alcohol-drinking behaviors: NPY-deficient mice drink more alcohol, and mice with an overexpression of NPY drink less.3

    Mark Goddard
    Because of the amygdala's role in anxiety, Pandey looked at CREB levels there; he found lower levels in the central and medial amygdala among rats that prefer drinking more alcohol. "Decreases in CREB in the amygdala increase anxiety," Noronha says, "and when you have increased anxiety you have increased alcohol consumption and a propensity for addiction."

    When P rats were given alcohol, the activated form of CREB increased. "If that is the case," Pandey conjectures, "these animals are drinking to elevate CREB function," and induce the anxiolytic effects of NPY. Pandey went one step upstream of CREB and looked at protein kinase A (PKA), which regulates CREB activity. He infused a PKA activator or NPY straight into the amygdala, which decreased alcohol consumption and anxiety in P rats. When he blocked PKA, he saw the opposite effect.4 "When we block PKA, they have less CREB phosphorylation, less NPY expression, and they become more anxious and drink more alcohol," Pandey says. The results supported Pandey's hypothesis.

    It's unclear whether alcoholics have similar low levels of NPY as P rats, but that could be resolved soon. David Goldman's group at NIAAA is just one of a number of groups collaborating to explore NPY - including measuring serum protein levels in patients with alcoholism, and gene-expression studies in postmortem samples. "We've found new functional variation in NPY," Goldman says. The NPY locus his team has identified accounts for variation in RNA expression and protein levels in vivo, he says. "This new functional genetic variation we're exploring for its linkage to anxiety and addictions." He expects to publish his findings later this year.

    1. R.B. Stewart et al., "Comparison of alcohol-preferring (P) rats and nonpreferring (NP) rats on tests of anxiety and for the anxiolytic effects of ethanol," Alcohol, 10:1-10, 1993. [PUBMED]
    2. M. Heilig et al., "Corticotropin-releasing factor and neuropeptide-Y - Role in emotional integration," Trends Neurosci, 17:80-5, 1994. [PUBMED]
    3. T.E. Thiele et al., "Ethanol consumption and resistance are inversely related to neuropeptide Y levels," Nature, 396:366-9, 1998. [PUBMED]
    4. S.C. Pandey et al., "Deficits in amygdaloid cAMP-responsive element-binding protein signalizing play a role in genetic predisposition to anxiety and alcoholism," J Clin Invest, 115:2762-73, 2005. [PUBMED]

    Kerry Grens
    The Scientist - Magazine of the Life Sciences

    June 1 2007

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