Nicotine is a drug that is widely abused in this society costing millions of dollars in health care. It is clear that the starting point of any pharmacological approach to target nicotine addiction must begin with the understanding of the mechanistic details of the action of this drug. It is known that the actions of nicotine are mediated by its ability to activate nicotinic acetylcholine receptors (nAChRs). In this proposal we ask what physiological functions of nAChRs in the brain are. One effect of activation of nAChRs is that they increase neurotransmitter release in the brain, possibly facilitating synaptic plasticity. This effect is commonly mediated by a subset of nAChRs, one containing the alpha7 subunit (a7-nAChRs), a subset that is very effective at raising intracellular calcium levels and mediating calcium-dependent signal transduction in the brain. In this proposal we examine the mechanisms underlying increased glutamate release mediated by these receptors at the mossy fiber-CA3 synapses in the hippocampus. In the previous funding period we show that nAChR activation results in a dramatic increase in frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) dependent on ER store calcium. In this proposal we investigate whether there are ER calcium stores at the mossy fiber terminals and what their properties might be using fluorescence microscopy. We then ask whether the mechanisms underlying nAChR modulation of release are specific to mEPSCs or whether they can also influence evoked release at these synapses. We will also investigate the nature and population of vesicles that are mobilized by nAChRs using styryl dyes and photoconversion followed by electron microscopy. These studies will arrive at the mechanistic details of a novel form of plasticity discovered in our lab. Lastly, we investigate the biological significance of the effect using relevant doses of nicotine and a newly developed transgenic mouse model where cholinergic fibers are labeled with GFP-tau. These studies will set the stage for the development of pharmacological tools and therapeutic strategies to combat nicotine addiction, ones that are based on realistic models of receptor physiology.

Public Health Relevance

The abuse of nicotine costs our society millions in health care costs to combat the resultant heart disease, cancer, and other debilitating illnesses. In this project we examine how nicotine acts as a powerful modulator of brain functions, by examining its ability to usurp important signaling pathways in the brain. Our studies will form the basis for developing effective drugs to combat nicotine addiction, one that will take into account the entirety of nicotine's effects on the brain, an approach sorely lacking at present.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Rapaka, Rao
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University of Colorado Denver
Schools of Medicine
United States
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Groessl, Florian; Jeong, Jae Hoon; Talmage, David A et al. (2013) Overnight fasting regulates inhibitory tone to cholinergic neurons of the dorsomedial nucleus of the hypothalamus. PLoS One 8:e60828
D'Souza, Rinaldo D; Vijayaraghavan, Sukumar (2012) Nicotinic receptor-mediated filtering of mitral cell responses to olfactory nerve inputs involves the ?3?4 subtype. J Neurosci 32:3261-6
Grybko, Michael J; Hahm, Eu-Teum; Perrine, Wesley et al. (2011) A transgenic mouse model reveals fast nicotinic transmission in hippocampal pyramidal neurons. Eur J Neurosci 33:1786-98
Grybko, Michael; Sharma, Geeta; Vijayaraghavan, Sukumar (2010) Functional distribution of nicotinic receptors in CA3 region of the hippocampus. J Mol Neurosci 40:114-20
Vijayaraghavan, Sukumar (2009) Glial-neuronal interactions--implications for plasticity and drug addiction. AAPS J 11:123-32
Sharma, G; Vijayaraghavan, S (2008) Nicotinic receptors containing the alpha7 subunit: a model for rational drug design. Curr Med Chem 15:2921-32
Sharma, Geeta; Vijayaraghavan, Sukumar (2008) Nicotinic Receptors: Role in Addiction and Other Disorders of the Brain. Subst Abuse 2008:81
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
Ghatpande, Ambarish S; Sivaraaman, Kartik; Vijayaraghavan, Sukumar (2006) Store calcium mediates cholinergic effects on mIPSCs in the rat main olfactory bulb. J Neurophysiol 95:1345-55
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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