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The role of nicotine receptors in nicotine dependence

Institution: University of California, Irvine
Investigator(s): Katumi Sumikawa, Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6RT-0083 Award: $381,317
Subject Area: Nicotine Dependence
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
It is well known that nicotine is the active component that produces both the pleasurable sensations and cognitive enhancement associated with tobacco use, as well as the unpleasant physical effects of withdrawal when the user is deprived of this addictive substance. It is presently unknown, however, how long-term nicotine exposure (via extensive tobacco use) affects the various regions of the brain to turn a pleasurable behavior into a potentially life-threatening addiction. Recently, specific receptors for nicotine, which normally bind the neurotransmitter acetylcholine, have been discovered in brain regions that are involved in reward and emotion and in areas associated with learning and memory.

The goal of the proposed project is to determine how long-term exposure to nicotine may change the number, type, and functioning of nicotinic acetylcholine receptors in the hippocampus. The hippocampus is a brain region associated with the formation of memories that also connects directly to the cortex (which controls higher cognitive functioning) and the mesolimbic system (which is involved in emotion and reward). Therefore, the hippocampus is a key candidate for the site where nicotine may exert its cognitive enhancing and addiction-forming effects.

We propose to chronically expose rats to nicotine and examine the hippocampus using biochemical, electrophysiological, and pharmaco-logical tests to determine exactly how nicotine modifies the normal functioning of the receptor present there. Results of experiments using 1) unexposed, 2) nicotine-exposed, and 3) nicotine-withdrawn animals will be compared to determine the extent of receptors modification before, during, and after exposure to nicotine.

Understanding the mechanism of nicotine-induced changes in a critical brain area such as the hippocampus is crucial to the development of behavioral and pharmacological strategies to block the addictive properties of nicotine thereby reducing the development of dependence and also to reduce the unpleasant side-effects of nicotine withdrawal experienced following the cessation of tobacco use.

Final Report
Preventing nicotine dependence and thereby reducing the extent of cigarette smoking may be an effective way of reducing the numerous health problems associated with long-term tobacco smoking. To develop therapeutic strategies for the prevention and reduction of nicotine dependence, it is necessary to understand how long-term nicotine use and subsequent nicotine withdrawal alter the normal functioning of brain.

Tobacco smoking and nicotine treatment can enhance cognitive functions, a property that has been linked with the continued use of tobacco. The action of nicotine on nicotine receptors in the hippocampus, a structure in the brain involved in learning and memory, is one likely mechanism underlying the cognitive enhancement effects of nicotine. Our studies in rats have shown that acute and chronic nicotine exposure inactivate one type of nicotine receptor and persistently activate the other type of nicotine receptor in the hippocampus. Both nicotine actions strengthen the connections between the principal neurons present there. The strengthening of the connections has been suggested to be particularly important for learning and memory. Thus, this effect of nicotine may represent the cellular basis of nicotine-mediated cognitive enhancement, which may produce a positive feeling, contributing to nicotine-seeking behavior. We have also found that an acute dose of nicotine was no longer effective in strengthening connections between principal brain cells in the nicotine-withdrawn hippocampus, suggesting that nicotine withdrawal alters the functioning of the hippocampus. We hypothesize that the observed change causes the negative feeling associated with nicotine withdrawal and is an additional contributing factor to tobacco-seeking behavior.

Further understanding of the mechanism of nicotine-induced changes in the hippocampus is crucial to the development of pharmacological strategies to reduce the unpleasant side-effects of nicotine withdrawal experienced following the cessation of tobacco use.
Publications

Low concentrations of nicotine persistently activate interneurons in the CA1 of rat hippocampus
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Jia Y, Sumikawa K ABS
Yr: 1999 Vol: 25 Nbr: 892 Abs: 2 Pg:

Acute and chronic nicotine exposure differentially facilitate the induction of LTP
Periodical: Brain Research Index Medicus:
Authors: Fujii S, Ji Z, Morita N, Sumikawa K ART
Yr: 1999 Vol: 846 Nbr: Abs: Pg: 137-143

Inactivation of alpha7 ACh receptors and activation of non-alpha7 ACh receptors both contribute to long term potentiation induction in the hippocampal CA1 region
Periodical: Neuroscience Letters Index Medicus:
Authors: Fujii S, Ji Z, Sumikawa K ART
Yr: 2000 Vol: 286 Nbr: Abs: Pg: 134-138

Nicotine reverses GABAergic inhibition of long-term potentiation induction in the hippocampal CA1 region
Periodical: Brain Research Index Medicus:
Authors: Fujii S, Jia Y, Yang A, Sumikawa K ART
Yr: 2000 Vol: 863 Nbr: Abs: Pg: 259-265

Nicotine accelerates reversal of long-term potentiation and enhances long-term depression in the rat hippocampal CA1 region
Periodical: Brain Research Index Medicus:
Authors: Fujii S, Sumikawa K ART
Yr: 2001 Vol: 894 Nbr: Abs: Pg: 340-346

Acute and chronic nicotine exposure reverse age-related declines in the induction of LTP in the hippocampus of aged rats
Periodical: Brain Research Index Medicus:
Authors: Fujii S, Sumikawa K ART
Yr: 2001 Vol: 894 Nbr: Abs: Pg: 347-353