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      Neuronal Mechanisms Underlying Development of Nicotine Dependence: Implications for Novel Smoking-Cessation Treatments

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      , M.D., Ph.D., , Ph.D.
      Addiction Science & Clinical Practice
      National Institute on Drug Abuse

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          Abstract

          Tobacco smoking causes high rates of mortality and morbidity throughout the world. Despite the availability of smoking-cessation medications, maintenance of long-term abstinence is difficult, and most individuals who attempt to quit smoking relapse. Although tobacco smoke contains many substances, researchers and policymakers agree that nicotine is a major cause of tobacco dependence. Understanding the neural substrates of nicotine dependence is essential for the development of more effective antismoking medications than those currently available. This article focuses on the neural substrates, especially nicotinic acetylcholine receptors, that mediate the reinforcing effects of nicotine and the development of nicotine dependence. Neuroadaptations in the function of the neurotransmitters dopamine, glutamate, and gamma-aminobutyric acid (GABA), which have been shown to be critically involved in nicotine dependence, are also reviewed. Finally, the article discusses progress in the discovery and development of smoking-cessation medications.

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          Most cited references54

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          Shape of the relapse curve and long-term abstinence among untreated smokers.

          To describe the relapse curve and rate of long-term prolonged abstinence among smokers who try to quit without treatment. Systematic literature review. Cochrane Reviews, Dissertation Abstracts, Excerpt Medica, Medline, Psych Abstracts and US Center for Disease Control databases plus bibliographies of articles and requests of scientists. Prospective studies of self-quitters or studies that included a no-treatment control group. Two reviewers independently extracted data in a non-blind manner. The number of studies was too small and the data too heterogeneous for meta-analysis or other statistical techniques. There is a paucity of studies reporting relapse curves of self-quitters. The existing eight relapse curves from two studies of self-quitters and five no-treatment control groups indicate most relapse occurs in the first 8 days. These relapse curves were heterogeneous even when the final outcome was made similar. In terms of prolonged abstinence rates, a prior summary of 10 self-quitting studies, two other studies of self-quitters and three no-treatment control groups indicate 3-5% of self-quitters achieve prolonged abstinence for 6-12 month after a given quit attempt. More reports of relapse curves of self-quitters are needed. Smoking cessation interventions should focus on the first week of abstinence. Interventions that produce abstinence rates of 5-10% may be effective. Cessation studies should report relapse curves.
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            Habenular α5* nicotinic receptor signaling controls nicotine intake

            Genetic variation in CHRNA5, the gene encoding the α5 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco addiction and lung cancer, but underlying mechanisms are unknown. Here, we report dramatically increased nicotine consumption in mice with null mutation in Chrna5. This effect was `rescued' in knockout mice by re-expressing α5 subunits in medial habenula (MHb), and recapitulated in rats through α5 subunit knockdown in MHb. Remarkably, α5 subunit knockdown in MHb did not alter the rewarding effects of nicotine but abolished the inhibitory effects of higher nicotine doses on brain reward systems. The MHb extends projections almost exclusively to the interpeduncular nucleus (IPN). We found diminished IPN activation in response to nicotine in α5 knockout mice and disruption of IPN signaling increased nicotine intake in rats. Our findings suggest that nicotine activates the habenulo-interpeduncular pathway through α5-containing nAChRs, triggering an inhibitory motivational signal that acts to limit nicotine intake.
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              Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system.

              Nicotinic receptors - a family of ligand-gated ion channels that mediate the effects of the neurotransmitter acetylcholine - are among the most well understood allosteric membrane proteins from a structural and functional perspective. There is also considerable interest in modulating nicotinic receptors to treat nervous-system disorders such as Alzheimer's disease, schizophrenia, depression, attention deficit hyperactivity disorder and tobacco addiction. This article describes both recent advances in our understanding of the assembly, activity and conformational transitions of nicotinic receptors, as well as developments in the therapeutic application of nicotinic receptor ligands, with the aim of aiding novel drug discovery by bridging the gap between these two rapidly developing fields.
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                Author and article information

                Journal
                Addict Sci Clin Pract
                101316917
                Addiction Science & Clinical Practice
                National Institute on Drug Abuse
                1940-0632
                1940-0640
                July 2011
                : 6
                : 1
                : 4-16
                Affiliations
                Department of Psychiatry School of Medicine, University of California, San Diego, La Jolla, California
                Author notes
                CORRESPONDENCE: Professor Athina Markou, Ph.D., Department of Psychiatry, M/C 0603, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093; e-mail: amarkou@ 123456ucsd.edu .
                Article
                ascp-06-1-4
                3188825
                22003417
                47b526d8-4fe9-49e0-9928-7427552a5d6c
                Copyright @ 2011
                History
                Categories
                Research Reviews

                Health & Social care
                Health & Social care

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