Neuronal nicotinic cholinergic receptors are expressed throughout the brain, in the spinal cord, and in the autonomic ganglia. Eleven neuronal nAChR subunit genes were cloned and sequenced in the 1980's. Some of these subunits closely resemble the a1 subunit that is included in the nAChR that is expressed at the neuromuscular junction (the so-called peripheral-type receptor). These a1-like subunits are called: a2, a3...a10 and, with the exception of a5, provide the binding site for nicotine and other nicotinic agonists. The three remaining subunits, ?2-?4, are referred to as structural subunits. Enormous progress has been made towards understanding the structure and function of neuronal nAChRs using expression systems (cell lines, Xenopus laevis oocytes). For example, expression system studies have shown that subunit composition has profound effects on biophysical and pharmacological properties. The value of expression system studies has been limited, somewhat, because some of the more interesting subunits (e.g. a6, ?3) are not easily expressed in artificial systems. These, and other concerns, have prompted researchers to develop gene knockout (null mutant) mice for virtually every one of the known nAChR subunits. Transgenic mice have also been developed that express several gain of function mutations, or mutations that are associated with human diseases. These transgenic mice are being used to address questions such as: 1) What are the subunit compositions of naturally-occurring (i.e. native) nAChRs? 2) Where are these native receptors expressed? 3) What role do they play in modulating brain function (behavior?), and 4) What function do these receptors play in modulating addiction to nicotine, alcohol and other drugs? We have the world's most complete collection of nAChR mutant mice that are being used in several funded research projects that are centered at the University of Colorado. During the last 4 years we have built our colony from five mutant strains to 18 and have established a system where we have sent mice and/or breeding pairs to other researchers in the US and, more recently around the world (3 continents, to date). This application requests funds to support the continued maintenance and distribution of these mouse stocks.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Center Core Grants (P30)
Project #
5P30DA015663-10
Application #
8261997
Study Section
Special Emphasis Panel (ZDA1-RXL-E (02))
Program Officer
Pollock, Jonathan D
Project Start
2003-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2012
Total Cost
$519,960
Indirect Cost
$203,702
Name
University of Colorado at Boulder
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Stoker, Astrid K; Marks, Michael J; Markou, Athina (2015) Null mutation of the ?2 nicotinic acetylcholine receptor subunit attenuates nicotine withdrawal-induced anhedonia in mice. Eur J Pharmacol 753:146-50
Wilking, Jennifer A; Stitzel, Jerry A (2015) Natural genetic variability of the neuronal nicotinic acetylcholine receptor subunit genes in mice: Consequences and confounds. Neuropharmacology 96:205-12
Bates, R C; Stith, B J; Stevens, K E et al. (2014) Reduced CHRNA7 expression in C3H mice is associated with increases in hippocampal parvalbumin and glutamate decarboxylase-67 (GAD67) as well as altered levels of GABA(A) receptor subunits. Neuroscience 273:52-64
McClure-Begley, Tristan D; Grady, Sharon R; Marks, Michael J et al. (2014) Presynaptic GABAB autoreceptor regulation of nicotinic acetylcholine receptor mediated [(3)H]-GABA release from mouse synaptosomes. Biochem Pharmacol 91:87-96
Wageman, Charles R; Marks, Michael J; Grady, Sharon R (2014) Effectiveness of nicotinic agonists as desensitizers at presynaptic *4*2- and *4*5*2-nicotinic acetylcholine receptors. Nicotine Tob Res 16:297-305
Koranda, Jessica L; Cone, Jackson J; McGehee, Daniel S et al. (2014) Nicotinic receptors regulate the dynamic range of dopamine release in vivo. J Neurophysiol 111:103-11
O'Neill, Heidi C; Laverty, Duncan C; Patzlaff, Natalie E et al. (2013) Mice expressing the ADNFLE valine 287 leucine mutation of the ýý2 nicotinic acetylcholine receptor subunit display increased sensitivity to acute nicotine administration and altered presynaptic nicotinic receptor function. Pharmacol Biochem Behav 103:603-21
Quik, Maryka; Campos, Carla; Grady, Sharon R (2013) Multiple CNS nicotinic receptors mediate L-dopa-induced dyskinesias: studies with parkinsonian nicotinic receptor knockout mice. Biochem Pharmacol 86:1153-62
Marks, Michael J (2013) Genetic matters: thirty years of progress using mouse models in nicotinic research. Biochem Pharmacol 86:1105-13
Soll, Lindsey G; Grady, Sharon R; Salminen, Outi et al. (2013) A role for *4(non-*6)* nicotinic acetylcholine receptors in motor behavior. Neuropharmacology 73:19-30

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