The long-term objective of this research is understanding how long-term nicotine use and subsequent nicotine withdrawal alter the normal functioning of synapses in the hippocampus. Cigarette smoking and acute and chronic administration of nicotine can enhance cognitive function, a property that has been linked with the continued use of cigarettes. Our studies have demonstrated that acute and chronic nicotine exposure facilitate the induction of N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP; considered to be a cellular substrate for learning and memory) in the hippocampus. Following nicotine withdrawal, however, the threshold for LTP induction fluctuates and nicotine is no longer effective in facilitating the induction of LTP. These nicotine effects may represent the cellular basis of nicotine-mediated cognitive enhancement and unpleasant withdrawal symptoms, contributing to cigarette-seeking behavior. Nicotine enhances NMDAR responses in pyramidal cells via three different pathways, two involving disinhibition of pyramidal cells and the other involving activation of muscarinic acetylcholine receptors (AChRs). Our working hypothesis is that long-term nicotine exposure and withdrawal differentially alter these pathways, affecting NMDAR responses and thereby LTP induction. The proposed experiments will test this hypothesis by identifying altered pathways in hippocampi from chronic-nicotine-treated and withdrawn rats with combinations of electrophysiological, histochemical, and molecular biological approaches.
The specific aims are to determine: (1) which pathways of nicotine action, leading to the enhancement of NMDAR responses, are altered, (2) if the normal functioning of a7 and non-a7 nicotinic AChRs on GABAergic interneurons are affected, (3) if feedforward GABAergic inhibition is altered, and (4) if muscarinic AChR-mediated signaling is affected. Results from these studies are expected to provide significant insights into mechanisms that underlie nicotine dependence, which may aid in the development of novel therapeutic strategies.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-5 (01))
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Wu, Da-Yu
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University of California Irvine
Other Basic Sciences
Schools of Arts and Sciences
United States
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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; Yamazaki, Yoshihiko; Sumikawa, Katumi (2007) Chronic nicotine exposure affects the normal operation of hippocampal circuits. Neuroreport 18:87-91
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
Miura, Masami; Ishii, Katsuyoshi; Aosaki, Toshihiko et al. (2006) Chronic nicotine treatment increases GABAergic input to striatal neurons. Neuroreport 17:537-40
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

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