Chronic exposure to nicotine leads, in some individuals, to the set of behaviors that constitute nicotine dependence. Chronic nicotine exposure produces selective upregulation of certain high-sensitivity (HS) nicotinic acetylcholine receptors (nAChRs). This project works within an emerging hypothesis that selective upregulation of certain nAChRs is both necessary and sufficient for the initial stages of nicotine dependence- minutes, hours, days, and weeks. The power of the emerging hypothesis derives from the selectivity displayed by upregulation at every level thus far examined-brain region, cell type, subcellular region, major pharmacological subtype, and detailed subunit composition. These are """"""""tiers of selectivity"""""""" in upregulation. As a result, upregulation selectively modifies neuronal excitability and neuronal interactions. These pathological patterns comprise, in part, the cellular and circuit basis of nicotine dependence.
Aim 1 studies selective upregulation in the ventral tegmental area-nucleus accumbens (VTA-NAcc) pathway, which accounts for some aspects of both tolerance and sensitization to the rewarding aspects of nicotine. Previous data, especially on the substantia nigra-dorsal striatum pathway, show tiers of selectivity in upregulation. Now five linked sub- hypotheses will be tested about the cellular and subcellular details of alpha4beta2 nAChR upregulation in the VTA and NAcc.
Aim 2 tests hypotheses about upregulation in medial entorhinal cortex and dorsal hippocampus, a partial model for cognitive sensitization during chronic exposure to nicotine. Sub-hypothesis 2.1 further characterizes the known upregulation of a4* nAChRs by chronic nicotine on the axons of the medial perforant path. This upregulation leads to increased glutamate release in the presence of nicotine. Sub- hypothesis 2.2 states that chronic nicotine upregulates a4* nAChRs in some hippocampal interneurons.
Aim 2 also characterizes upregulation in dorsal hippocampus after only 24 hours of nicotine exposure.
Aim 3 tests hypotheses about the amygdala, which is a partial locus for nicotine's calming responses to environmental stress. The project tests whether nicotine effects in amygdala arise partially via alpha4beta2 nAChRs on axon terminals of dopaminergic VTA projections. Experiments will focus on two amygdala cell types with dense dopaminergic innervation: intercalated neurons, and corticotrophin-releasing factor neurons in central amygdala, lateral region. The project then tests whether upregulation of these nAChRs amplifies the response to acute nicotine, providing a form of sensitization to the calming effects of nicotine during environmental stress.
Aim 4 tests a hypothesis linking the alpha5 subunit to aspects of nicotine addiction. Specifically, the project tests whether lower levels of the alpha5 subunit produce more alpha4beta2 nAChRs, and therefore greater upregulation by chronic nicotine. The techniques, all established in the investigator's laboratory, will be applied as appropriate: a. Patch-clamp electrophysiology in brain slices;b, Electrochemical measurements of DA release;c, Quantitative fluorescence measurements in existing mouse strains with fully functional a4* receptors;d, Measurements in KO mice for the a5 subunits, and selectively in other strains;e, Multielectrode array-based single-unit extracellular recordings from intact mice. This project is a part of a broad context. Tobacco use presents challenges requiring data at many levels-from genome-wide association studies, through the intracellular molecular bases of upregulation, through more complex circuits, through animal and human behavior, through public policy.

Public Health Relevance

Roughly 400,000 Americans and roughly 4,000,000 people worldwide die annually of the sequelae to nicotine dependence. This project attempts to explain nicotine dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA017279-09
Application #
8469842
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (02))
Program Officer
Sorensen, Roger
Project Start
2003-12-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2013
Total Cost
$339,422
Indirect Cost
$129,902
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Henderson, Brandon J; Wall, Teagan R; Henley, Beverley M et al. (2016) Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward. J Neurosci 36:2957-74
Xiao, Cheng; Miwa, Julie M; Henderson, Brandon J et al. (2015) Nicotinic receptor subtype-selective circuit patterns in the subthalamic nucleus. J Neurosci 35:3734-46
Henderson, Brandon J; Lester, Henry A (2015) Inside-out neuropharmacology of nicotinic drugs. Neuropharmacology 96:178-93
Marotta, Christopher B; Dilworth, Crystal N; Lester, Henry A et al. (2014) Probing the non-canonical interface for agonist interaction with an *5 containing nicotinic acetylcholine receptor. Neuropharmacology 77:342-9
Marotta, Christopher B; Rreza, Iva; Lester, Henry A et al. (2014) Selective ligand behaviors provide new insights into agonist activation of nicotinic acetylcholine receptors. ACS Chem Biol 9:1153-9
Henderson, Brandon J; Srinivasan, Rahul; Nichols, Weston A et al. (2014) Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptors. J Gen Physiol 143:51-66
O'Neill, Heidi C; Laverty, Duncan C; Patzlaff, Natalie E et al. (2013) Mice expressing the ADNFLE valine 287 leucine mutation of the Î’2 nicotinic acetylcholine receptor subunit display increased sensitivity to acute nicotine administration and altered presynaptic nicotinic receptor function. Pharmacol Biochem Behav 103:603-21
Henley, Beverley M; Williams, Brian A; Srinivasan, Rahul et al. (2013) Transcriptional regulation by nicotine in dopaminergic neurons. Biochem Pharmacol 86:1074-83
Chatterjee, Susmita; Santos, Nathan; Holgate, Joan et al. (2013) The α5 subunit regulates the expression and function of α4*-containing neuronal nicotinic acetylcholine receptors in the ventral-tegmental area. PLoS One 8:e68300
Miles, Timothy F; Dougherty, Dennis A; Lester, Henry A (2013) The 5-HT3AB receptor shows an A3B2 stoichiometry at the plasma membrane. Biophys J 105:887-98

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