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Nicotinic receptors on hippocampal neurons

Institution: University of California, San Diego
Investigator(s): Wagner Zago, Ph.D.
Award Cycle: 2002 (Cycle 11) Grant #: 11FT-0099 Award: $69,940
Subject Area: Nicotine Dependence
Award Type: Postdoctoral Fellowship Awards
Abstracts

Initial Award Abstract
Tobacco smoking is the most frequent form of substance abuse and is a major health problem that is estimated to cause 4 million deaths a year worldwide. Several studies have shown that the addictive process is strongly driven by the pharmacological actions of nicotine in the central nervous system. This alkaloid has been identified as exerting its effects in the body by binding to a family of cell surface proteins called nicotinic receptors. In the central nervous system (CNS), nicotinic receptors normally respond to chemical acetylcholine (ACh) and cause electrical events to occur inside the cells. These electrical events represent one of the basic signaling mechanisms used for cellular comunication in the nervous system, and it is thought that nicotine, by changing the normal function of these receptors, induces the addiction. One of the most abundant nicotinic receptors in the nervous system is species termed the alpha7-receptor because of its composition. In addition to inducing electrical events it allows calcium to enter the cell. Calcium is a critically important element that regulates fundamental processes in the brain. Evidence from many sources indicate that alpha7-receptors are capable of many functions in the brain in part because of the calcium effect. When inappropriately activated or regulated, nicotinic receptors may contribute to diverse neuropathologies including schizophrenia and Alzheimer's disease. How alpha7-receptors achieve their effects, what are the physiological functions, and how they are influenced by prolonged exposure to nicotine are questions that remain largely unanswered.

The fact the alpha7-receptors can display multiple functions depending on their location on the cell surface directs attention to the mechanisms responsible for maintaining the receptors at specific sites. The experiments proposed here will provide basic information about the localization of alpha7-receptor at synapses and the impact of chronic nicotine exposure on this process. One of the most interesting brain structures for these studies is the hippocampus because it is necessary for memory, contains high levels of alpha7-receptors, and can be grown as dissociated cells in culture. To examine alpha7-receptor localization, the experiments proposed here use fluorescent-molecules to bind to the receptors on living neurons so that the receptors can be visualized with fluorescence microscopy. First, I will determine the kinds of synapses at which the receptors are localized. Second, I will examine the mechanisms determining receptor localization (such as electrical activity or receptor activation) by apply drugs (activators or inhibitors) to the neurons and quantifying the effects. Particularly relevant will be chronic treatment with nicotine at levels normally produced by tobacco usage.

The studies outlined here may provide useful insight into the physiological significance of nicotinic receptors and indicate some of the likely consequences of repeated exposure to nicotine that comes with habitual tobacco usage. Since alpha7-receptors have been implicated in a variety of behaviors, including learning and memory, and in multiple neuropathologies, including Alzheimer's disease and schizophrenia, understanding where and how the receptors are located and how they are influenced by tobacco usage is likely to have significant biomedical implications.
Publications

Nicotinic alpha7 receptor clusters on hippocampal GAPAergic neurons: regulation by synaptic activity and neurotrophins.
Periodical: Journal of Neuroscience Index Medicus:
Authors: Kawai H, Zago W, Berg DK ART
Yr: 2002 Vol: 22 Nbr: 18 Abs: Pg: 7903-7912

Regulation of nicotinic alpha7-receptor clusters on gabaergic hippocampal neurons.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Zago W, Kawai H, Berg D ABS
Yr: 2002 Vol: Nbr: Abs: Pg:

Nicotinic receptors on hippocampal GABAergic neurons.
Periodical: TRDRP Annual Report to the State of California Legislature Index Medicus:
Authors: Zago W, Berg D ABS
Yr: 2002 Vol: Nbr: Abs: Pg: