Abstract

Nicotine abuse is one of the major health problems in the world today. The use of nicotine via cigarette smoking forms lifelong memories that are recalled in response to environmental cues associated with previous nicotine use. This recall increases drug craving and is a factor for the continued use of nicotine. Understanding how the long-lasting memories are formed may aid in developing therapies for preventing the relapse, and thereby promote smoking cessation. Increasing evidence indicates that nicotine produces addictive behavior by causing long-lasting changes at synapses. The long-term objective of this project is to determine how nicotine promotes long-lasting changes at synapses in the hippocampus, a brain region associated with memory formation. The behavioral and cellular effects of nicotine are mediated by its interaction with nicotinic acetylcholine receptors (nAChRs) that are normally activated by the neurotransmitter acetylcholine. When nicotine is administered systemically, it is slowly delivered to the brain where it bathes neurons for a relatively long time. Under these conditions, some nAChR subtypes are continuously activated, whereas other subtypes are inactivated by desensitization. We hypothesize that these effects of nicotine set up a condition, which promotes long-lasting changes at synapses.
The specific aim of this proposed research is to determine whether continuous activation of a distinct nAChR subtype in the hippocampus during nicotine exposure modulates circuit operation to facilitate different forms of synaptic plasticity. The proposed research will be carried out using electrophysiological and optical recording techniques, as well as morphological techniques. Animals lacking a particular nAChR subtype will also be used. Results from these studies will help determine not only the cellular basis of nicotine-mediated enhancement of learning and memory, but may also aid in the development of effective treatments for long-lasting memory of nicotine abuse, by identifying a nAChR subtype involved in the effects of nicotine.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA014542-07
Application #
7894928
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Wu, Da-Yu
Project Start
2002-08-05
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
7
Fiscal Year
2010
Total Cost
$297,395
Indirect Cost

  Institution

Name
University of California Irvine
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697

  Publications

Nakauchi, Sakura; Malvaez, Melissa; Su, Hailing et al. (2015) Early postnatal nicotine exposure causes hippocampus-dependent memory impairments in adolescent mice: Association with altered nicotinic cholinergic modulation of LTP, but not impaired LTP. Neurobiol Learn Mem 118:178-88
Nakauchi, Sakura; Sumikawa, Katumi (2014) Endogenous ACh suppresses LTD induction and nicotine relieves the suppression via different nicotinic ACh receptor subtypes in the mouse hippocampus. Life Sci 111:62-8
Ishibashi, Masaru; Yamazaki, Yoshihiko; Miledi, Ricardo et al. (2014) Nicotinic and muscarinic agonists and acetylcholinesterase inhibitors stimulate a common pathway to enhance GluN2B-NMDAR responses. Proc Natl Acad Sci U S A 111:12538-43
Nakauchi, Sakura; Sumikawa, Katumi (2012) Endogenously released ACh and exogenous nicotine differentially facilitate long-term potentiation induction in the hippocampal CA1 region of mice. Eur J Neurosci 35:1381-95
Jia, Yousheng; Yamazaki, Yoshihiko; Nakauchi, Sakura et al. (2010) Nicotine facilitates long-term potentiation induction in oriens-lacunosum moleculare cells via Ca2+ entry through non-alpha7 nicotinic acetylcholine receptors. Eur J Neurosci 31:463-76
Jia, Yousheng; Yamazaki, Yoshihiko; Nakauchi, Sakura et al. (2009) Alpha2 nicotine receptors function as a molecular switch to continuously excite a subset of interneurons in rat hippocampal circuits. Eur J Neurosci 29:1588-603
Nakauchi, Sakura; Brennan, Robert J; Boulter, Jim et al. (2007) Nicotine gates long-term potentiation in the hippocampal CA1 region via the activation of alpha2* nicotinic ACh receptors. Eur J Neurosci 25:2666-81
Nakauchi, Sakura; Yamazaki, Yoshihiko; Sumikawa, Katumi (2007) Chronic nicotine exposure affects the normal operation of hippocampal circuits. Neuroreport 18:87-91
Yamazaki, Yoshihiko; Jia, Yousheng; Wong, Jamie K et al. (2006) Chronic nicotine-induced switch in Src-family kinase signaling for long-term potentiation induction in hippocampal CA1 pyramidal cells. Eur J Neurosci 24:3271-84
Yamazaki, Yoshihiko; Jia, Yousheng; Niu, Rong et al. (2006) Nicotine exposure in vivo induces long-lasting enhancement of NMDA receptor-mediated currents in the hippocampus. Eur J Neurosci 23:1819-28

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