Nicotine is a habit-forming drug that is widely used in our society. The widespread distribution of nicotinic acetylcholine receptors (nAChRs) in the brain suggests that the dynamics of nicotine use in humans is likely to be complex. Understanding mechanisms underlying the action of nicotine in the CNS must begin with the elucidation of the function of various brain nAChR subtypes. Our findings that hippocampal astrocytes express functional nAChRs suggest that these receptors might play a role in astrocytic signaling and that some of the actions of nicotine might be mediated by astrocytes. We propose to examine the spread of nAChR-activated calcium signals in stellate hippocampal astrocytes in culture, using fluorescence imaging techniques. The ability of nAChRs to cause release of glutamate consistent with vesicular exocytosis will be examined using HEK 293 cells transfected with NMDA receptors, combined with whole cell voltage-clamp measurements. The presence of nAChRs on astrocytes in situ will be determined by whole cell voltage-clamp measurements from astrocytes in hippocampal slices from GFAP/GFP transgenic mice. nAChR-mediated calcium signaling will be examined using fura 2 AM loaded astrocytes in hippocampal slices from the GFAP/GFP mice. The possibility that nicotine-induced modulation of glutamatergic miniature excitatory currents (mepscs) is due to amplification of signals from store calcium release will be examined using electrophysiological techniques in hippocampal slices. A potential role for astrocytic nAChRs in the regulation of synaptic activity will be examined using hippocampal neurons cultured in the presence and absence of astrocytes. Results from this project will demonstrate mechanisms by which nAChRs on astrocytes could alter hippocampal function specifically and neuronal signaling in general and also suggest a role for astrocytic nAChRs in mediating the effects of nicotine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010266-08
Application #
7049447
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Program Officer
Rapaka, Rao
Project Start
1998-01-15
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2008-03-31
Support Year
8
Fiscal Year
2006
Total Cost
$297,070
Indirect Cost
Name
University of Colorado Denver
Department
Physiology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Sharma, Geeta; Grybko, Michael; Vijayaraghavan, Sukumar (2008) Action potential-independent and nicotinic receptor-mediated concerted release of multiple quanta at hippocampal CA3-mossy fiber synapses. J Neurosci 28:2563-75
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Chen, Chunhe; Tsina, Efthymia; Cornwall, M Carter et al. (2005) Reduction of all-trans retinal to all-trans retinol in the outer segments of frog and mouse rod photoreceptors. Biophys J 88:2278-87

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