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    Effects of nicotine in the hippocampus and implications for anti-smoking therapy

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    Author
    Almeida, Luis Eduardo Falcassa de
    Advisor
    Albuquerque, E. X.
    Pereira, Edna F. R.
    Date
    2004
    Type
    dissertation
    
    Metadata
    Show full item record
    Abstract
    This study was designed to investigate the expression and function of nicotinic acetylcholine receptors (nAChRs) in the rat hippocampus, their modulation by concentrations of nicotine equivalent to those found on the blood of smokers, and the actions of the opioid antagonist naltrexone, an agent used as an aid in smoking cessation programs. Specific agonists and antagonists revealed that CA1 pyramidal neurons in organotypic cultures express three nAChRs subtypes (alpha7, alpha3beta2 and another subtype). In contrast, there is a compartmentalized expression in interneurons of alpha7, alpha4beta2, and alpha3beta4 nAChRs as well as a new pharmacological nAChR subtype, proposed to be alpha2beta4, modulating gamma-aminobutyric acid (GABA) release onto CA1 pyramidal neurons. Incubation of younger (6--8 days in vitro), but not older (20--22 days in vitro) organotypic cultures with nicotine (24 h, 10 nM--10 muM) induced a concentration-dependent functional up-regulation of nAChRs in CA1 pyramidal neurons. Modulation of GABA release by nAChRs onto CA1 pyramidal neurons was insensitive to incubation with nicotine. The effects of naltrexone on alpha7 and alpha4beta2 nAChRs were investigated in primary hippocampal cultures and stably transfected HEK 293 cells, respectively. Both nAChRs were inhibited by naltrexone (IC50s = 25 muM and 140 muM, respectively). Incubation of primary hippocampal cultures with nicotine (1 h, 10 nM--10 muM) induced a concentration-dependent functional up-regulation of alpha7 nAChRs, detected in the continuous presence of nicotine. In contrast, exposure to naltrexone (30 muM, 1 h) induced no functional nAChR up-regulation, instead, it blocked nAChRs that had been up-regulated by nicotine. In primary hippocampal cultures that had been exposed for 3 days to nicotine (10 muM) followed by a 30-min washout, there was a functional up-regulation of alpha7 nAChRs in neurons and a higher number of neurons expressing non-alpha7 nAChRs; in this protocol, naltrexone (30 muM) induced selective functional up-regulation of alpha7 nAChRs. Interestingly, a 3-day exposure to nicotine (10 muM) plus naltrexone (0.3 or 30 muM) caused selective reduction of the non-alpha7 nAChR activity in the neurons. The ability of naltrexone to regulate nAChR function and expression in the brain may underlie its usefulness as an aid in smoking cessation programs.
    Description
    University of Maryland, Baltimore. Pharmacology and Experimental Therapeutics. Ph.D. 2004
    Keyword
    Biology, Neuroscience
    Health Sciences, Toxicology
    Health Sciences, Pharmacology
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/1093
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    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

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