[Paleopsych] PLoS Biology: Nicotine as Therapy

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PLoS Biology: Nicotine as Therapy
Volume 2 | Issue 11 | November 2004

    Tabitha M. Powledge^

    Abbreviations: ADHD, attention deficit hyperactivity disorder; nAChR,
    nicotinic acetylcholine receptor

    Tabitha M. Powledge is a freelance science writer who specializes in
    neuroscience, genomics, and science policy. E-mail: [12]tam at nasw.org

    Published November 16, 2004

    DOI: 10.1371/journal.pbio.0020404

    Citation: Powledge TM (2004) Nicotine as Therapy. PLoS Biol 2(11):

    There's a cheap, common, and mostly safe drug, in daily use for
    centuries by hundreds of millions of people, that only lately has been
    investigated for its therapeutic potential for a long list of common
    ills. The list includes Alzheimer disease, Parkinson disease,
    depression and anxiety, schizophrenia, attention deficit hyperactivity
    disorder (ADHD), and even pain and obesity. Why has interest in this
    potential cure-all been slow to develop? One reason: in its current
    forms the drug offers pharmaceutical companies no possibility of
    substantial profit. Another, perhaps more important: the drug is
    reviled as the world's most addictive. The drug, of course, is

    Nicotine is an alkaloid in the tobacco plant Nicotiana tabacum, which
    was smoked or chewed in the Americas for thousands of years before
    European invaders also succumbed to its pleasures and shipped it back
    to the Old World. Nicotine has always been regarded as medicinal and
    enjoyable at its usual low doses. Native Americans chewed tobacco to
    treat intestinal symptoms, and in 1560, Jean Nicot de Villemain sent
    tobacco seeds to the French court, claiming tobacco had medicinal
    properties and describing it as a panacea for many ailments. Higher
    doses are toxic, even lethal--which is why nicotine is used around the
    world as an insecticide. Yet few of the horrendous health effects of
    smoking are traceable to nicotine itself--cigarettes contain nearly
    4,000 other compounds that play a role. Until recently, nicotine
    research has been driven primarily by nicotine's unparalleled power to
    keep people smoking, rather than its potential therapeutic uses.

    Nicotine locks on to one group of receptors that are normally targeted
    by the neurotransmitter acetylcholine. Nicotinic acetylcholine
    receptors (nAChRs) are ion channels threaded through cell membranes.
    When activated, either by acetylcholine or by nicotine, they allow
    selected ions to flow across the cell membrane. In vertebrates nAChRs
    are all over the autonomic and central nervous sytems and the
    neuromuscular junction. A nAChR is composed of five polypeptide
    subunits ([13]Figure 1), but there are many nAChR subtypes made of
    different subunit combinations, a diversity that helps explain why
    nicotine can have so many different physiological and cognitive

    [14]Figure 1. Schematic Illustration of an Acetylcholine Receptor
    (Illustration: Giovanni Maki)

    It is now conventional wisdom that acetylcholine and nicotine act at
    these receptors to alter electrochemical properties at a variety of
    synapses, which can in turn affect the release of several other
    neurotransmitters. This wisdom exists thanks in part to work by Lorna
    Role and her colleagues at Columbia University in New York City. "In
    1995, we turned people's attention to how nicotine works as a
    modulator, tuning synapses and increasing the gain on transmitter
    release," Role recalls. Although all nAChRs are activated by nicotine,
    other drugs could be found or designed that affect only a subset of
    these receptor types. "If you can dissect out the important players
    with respect to which nicotine receptors are tuning [a] particular set
    of synapses, then that provides another way to potentially target the

    Nicotine and the Brain

    People with depressive-spectrum disorders, schizophrenia, and adult
    ADHD tend to smoke heavily, which suggested to researchers that
    nicotine may soothe their symptoms. Common to all these disorders is a
    failure of attention, an inability to concentrate on particular
    stimuli and screen out the rest. Nicotine helps. Researchers at the
    National Institute on Drug Abuse have shown via functional magnetic
    resonance imaging that nicotine activates specific brain areas during
    tasks that demand attention ([15]Box 1). This may be because of its
    effects, shared with many other addictive drugs, on the release of the
    neurotransmitter dopamine. "Schizophrenia is a disorder largely of the
    dopamine system," says John Dani of the Baylor College of Medicine in
    Houston, Texas. Dopamine signals in the brain occur in two modes--a
    kind of background trickle, punctuated by brief bursts. "It's thought
    that schizophrenics have a hard time separating that background
    information from important bursts. We've shown that nicotine helps to
    normalize that signaling by depressing the background but letting the
    bursts through well," he says. "I'll be surprised if there's not a
    co-therapy [to help schizophrenics] that takes advantage of nicotine
    systems in less than a decade."

    Nicotine may be the link between two genes that appear to figure in
    schizophrenia. Sherry Leonard and Robert Freedman of the University of
    Colorado in Denver, Colorado, have shown that expression of the gene
    for the alpha 7 neuronal nicotinic receptor is reduced in
    schizophrenics, and have argued that alpha 7 abnormalities lead to
    attention problems. Researchers in Iceland and elsewhere have shown
    that a different gene, for the growth factor neuregulin, also appears
    to figure in the disease. Neuregulin, Role and her colleagues have
    shown, governs the expression of nAChRs in neurons and helps to
    stabilize the synapses where they are found. The researchers are
    currently studying interactions between neuregulin and alpha 7, which
    Role thinks will prove important.

    Smokers also have lower rates of neurodegenerative disorders, and
    nicotine improves cognitive and motor functioning in people with
    Alzheimer disease and Parkinson disease. The prevailing hypothesis is
    that nicotine increases release of neurotransmitters depleted in those
    diseases. Dani and his colleagues have recently shown that
    acetylcholinesterase inhibitors--which block the degradation of
    acetylcholine and hence prolong its action--used to treat Alzheimer
    disease also stimulate dopamine release. They suspect that
    malfunctioning of the dopamine system may be affecting noncognitive
    aspects of dementia such as depressed mood, and that this might be
    alleviated by nicotine.

    Paul Newhouse and his colleagues at the University of Vermont in
    Burlington, Vermont, are studying nicotine drugs as potential
    therapeutic agents for cognitive dysfunction. Newhouse, a long-time
    nicotine researcher, is heading the first study ever to examine the
    efficacy and safety of nicotine patches for treating mild cognitive
    impairment, thought to be a precursor of Alzheimer disease. The
    researchers hope to see a positive effect on attention and learning.
    Newhouse also heads two studies of nicotinic stimulation in ADHD,
    using the patch, nicotine blockers, and some novel drugs that activate
    nicotine receptors.

    Nicotine and Pain

    Nicotine's salutary effects in patients with neurodegenerative and
    mental disorders have been studied a lot and are fairly well known.
    Two much newer topics of academic research are nicotine's potential
    for pain relief and for treating obesity.Nicotine itself has provided
    modest pain relief in animal studies. Although the analgesic effect of
    drugs that mimic acetylcholine were originally attributed to a
    different class of receptors, it is now clear that nAChRs play an
    important role in the control of pain. For instance, epibatidine, a
    drug that is extracted from the skin of an Ecuadorian frog and that
    acts at nAChRs, has been shown to be 200 times more potent than
    morphine at blocking pain in animals. Current animal research is aimed
    at discovering just where, how, and which classes of nAChRs work
    against pain, with the aim of developing more selective drugs.

    Meanwhile, nicotine is also being investigated as an analgesic in
    humans. For example, Pamela Flood, an anesthesiologist at Columbia, is
    investigating nicotine's future as a postoperative analgesic. She
    recently completed a pilot study of 20 women undergoing gynecological
    surgery. All the women had access to unlimited morphine and also got
    either a single 3-mg dose of nicotine nasal spray or a placebo. The
    placebo group had peak pain scores of eight out of a possible ten in
    the first hour after surgery. Women who got nicotine averaged a pain
    score of five. Despite the small sample size, Flood says, the results
    were highly significant. "As far as I know this is the first clinical
    study to use nicotine for analgesia, and it was much more successful
    than I ever would have imagined."

    "The nice thing about nicotine and drugs like nicotine is that they
    have opposite side effects to anesthetics. Instead of being
    respiratory depressants, they are respiratory stimulants. Instead of
    being sedating, they increase alertness. So theoretically this class
    of drugs is actually the perfect thing to add to an opioid regimen.
    The fact that they're synergistic was a fortuitous thing that we had
    never looked at, and neither had anybody else."

    Nicotine and Weight Gain

    Nicotine may be the most effective drug around for weight control. As
    ex-smokers know, to their rue, one of the worst things about quitting
    cigarettes is putting on pounds--as much as 10% of body weight.
    "Something about being addicted to nicotine and then going off it
    causes massive increase in weight," Role points out.

    Young-Hwan Jo in Role's lab is looking at a particular brain circuit
    involved in motivational behavior, especially feeding behavior. It is
    lodged primarily in the lateral hypothalamus but has projections all
    over the cortex, especially the nucleus accumbens, which is the center
    of reinforcement. "This is where information that has come in to the
    thalamus and the hypothalamus is relayed to cortical areas with some
    sense of salience or remembrance. It presumably is involved in
    changing perception and motivation for eating. It's not, `I have to
    eat this,' it's, `I want to eat this,'" says Role.

    Jo has been comparing the synaptic effects of nicotine, which reduces
    appetite, to those of cannabinoids, which stimulate it. "Control of
    these projection neurons seems to be oppositely regulated by these
    two," Role notes. "It doesn't necessarily mean we've found the root of
    the munchies, but it at least points to pathways that these things
    have in common." Jo is also examining how nicotine and cannabinoids
    modulate these pathways in genetically obese mice, and also their
    interactions with leptins. Role says tuning these pathways up or down
    might be a reasonable aim. "If that could be done in a selective
    fashion, maybe that could be introduced in appetite control. Certainly
    I see...antagonism of some of these pathways that nicotine activates
    or the complementary activation of the cannabinoid pathways as very
    important targets for therapeutics with respect to the anorexia that's
    associated with chemotherapy."

    Ming Li and his colleagues at the University of Texas in San Antonio,
    Texas, are studying nicotine's effects on weight and on expression of
    genes that nicotine upregulates orexin and neuropeptide Y and, more
    recently, that it also regulates leptin signaling. All three molecules
    regulate feeding behavior controlled by the hypothalamus. In the
    weight study, nicotine-treated rats not only lost weight, they lost
    about 20% of their body fat compared to saline-treated controls. The
    researchers suggest that, among its other effects, nicotine alters fat

    The University of Texas researchers have scoured the literature for
    genes related to nicotine, and they are developing microarrays to
    study the expression of these genes ([16]Figure 3). While nicotine
    seems to affect all the molecules known to influence weight, Li says
    it's clear the story is even more complex. "That's the reason we keep
    looking at different molecules, to find key targets involved in this
    regulation." The ultimate hope is to develop new drug applications.

    [17]Figure 3. Microarray Showing Patterns of Gene Expression
    Influenced by Nicotine

    (Image: Ming Li, University of Texas Health Science Center at San

    Dani predicts that weight control is likely to be one of the earliest
    nicotine-based therapies. "There's a very good chance that the first
    drug is unlikely to be...nicotine itself, but will take advantage of
    nicotinic receptors in the therapy," he says. "I know there are drugs
    now being tested by drug companies just for that purpose."

    Nicotine's Future

    Developing new drugs that selectively target specific subtypes of
    nicotine receptors is an expensive, albeit potentially lucrative,
    proposition. And therein lies a question. Will nicotine-based therapy
    consist mostly of costly new drugs from the pharmaceutical industry?
    Or can less expensive nicotine products like the patch, chewing gum,
    and nasal spray--which are generally intended for smoking cessation
    but widely available, usually without prescription--find their way
    into the world's medicine cabinets?

    "It's a little early to call whether nicotine will be used itself as a
    therapeutic agent or whether these more specific drugs that are being
    produced or maybe even used in combination with other drugs may be the
    most important way to go," says Dani. But he doesn't see the medicinal
    use of plain nicotine as very likely. Dani points out that the body's
    own agent, acetylcholine, acts over milliseconds to activate nicotinic
    receptors, whereas nicotine itself stimulates these receptors for
    hours. That lengthy action means that, although nicotine activates the
    receptors, it then often turns particular receptor subtypes off again,
    a process called desensitization. "It's hard to predict inside of a
    body what you're getting. Am I getting an activation or am I turning
    the receptors off?"

    Yet much of the work to date showing nicotine's effectiveness on a
    huge range of disorders has involved products available at any
    drugstore and intended to help people quit smoking. Newhouse is using
    patches for mild cognitive impairment. Flood has demonstrated pain
    relief with nasal spray and will use patches in her next study. And
    Role feels that gum hasn't been adequately explored for its
    therapeutic potential. Nicotine gum, she notes, is a better imitator
    of smoking than the patch because it delivers brief hits rather than a
    steady supply. She's also uncertain whether natural nicotine has been
    studied enough. But Role also points out that nicotine has its serious
    problems--addictive potential, cardiovascular damage, and (especially
    when delivered through the mucosa) cancer.

    Dani says, "People are probably going to have to find creative ways to
    understand which subtypes of nicotinic receptors they're turning on
    and which ones they're desensitizing. Maybe drug delivery methods will
    matter. Maybe subtype specificity will matter. It's less than a decade
    that we've known how important nicotinic receptors are. Now we have to
    move forward from there."

    "We've made an enormous amount of progress on understanding the
    biology of these receptor systems and how to target them. What has
    been trickier has been to develop an appropriate pharmacology that
    allows one to selectively target agents for particular therapeutic
    purposes with an adequate safety index," Newhouse says. "But some of
    the drugs that are coming on in human trials now are very promising.
    So I'm cautiously optimistic that we're on the road to developing some
    useful nicotinic therapies."

    Further Reading

    Flood P, Sonner JM, Gong D, Coates KM (2002) Isoflurane hyperalgesia
    is modulated by nicotinic inhibition. Anesthesiology 97: 192-198.
    [18]Find this article online

    Freedman R, Adams CE, Adler LE, Bickford PC, Gault J, et al. (2000)
    Inhibitory neurophysiological deficit as a phenotype for genetic
    investigation of schizophrenia. Am J Med Genet 97: 58-64. [19]Find
    this article online

    Li MD, Kane JK (2003) Effect of nicotine on the expression of leptin
    and forebrain leptin receptors in the rat. Brain Res 991: 222-231.
    [20]Find this article online

    McGehee DS, Heath MJ, Gelber S, Devay P, Role LW (1995) Nicotine
    enhancement of fast excitatory synaptic transmission in CNS by
    presynaptic receptors. Science 269: 1692-1696. [21]Find this article

    Newhouse PA, Potter A, Singh A (2004) Effects of nicotinic stimulation
    on cognitive performance. Curr Opin Pharmacol 4: 36-46. [22]Find this
    article online

    Yang X, Kuo Y, Devay P, Yu C, Role L (1998) A cysteine-rich isoform of
    neuregulin controls the level of expression of neuronal nicotinic
    receptor channels during synaptogenesis. Neuron 20: 255-270. [23]Find
    this article online

    Zhang L, Zhou FM, Dani JA (2004) Cholinergic drugs for Alzheimer's
    disease enhance in vitro dopamine release. Mol Pharmacol 66: 538-544.
    [24]Find this article online

    Box 1. Nicotine's Effect on Attention

    Using functional magnetic resonance imaging, scientists at the
    National Institute on Drug Abuse provided the first evidence that
    nicotine-induced enhancement of parietal cortex activation is
    associated with improved attention. They compared brain activity
    during a task demanding sustained attention--rapid visual information
    processing (RVIP)--with that during an undemanding sensorimotor
    control task ([25]Figure 2). Group results from 15 smokers (right)
    illustrate the effects of nicotine and placebo patches in left and
    right parietal cortex (1 and 2) and left and right occipital cortex (3
    and 4). Nicotine significantly increased activation in occipital
    cortex during both the control and rapid visual information processing
    tasks, suggesting a general modulation of attention. In contrast,
    nicotine increased activity in the parietal cortex only during rapid
    visual information processing, suggesting a specific modulation on
    task performance.
    [26]Figure 2. The Brain on Nicotine (Image: Elliot Stein, National
    Institute on Drug Abuse)

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