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Effects of TI-299423 on Neuronal Nicotinic Acetylcholine Receptors

Citation

Wall, Teagan Rose (2015) Effects of TI-299423 on Neuronal Nicotinic Acetylcholine Receptors. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9JD4TQ5. http://resolver.caltech.edu/CaltechTHESIS:03262015-100311493

Abstract

Nicotinic acetylcholine receptors (nAChRs) are pentameric, ligand-gated, cation channels found throughout the central and peripheral nervous system, whose endogenous ligand is acetylcholine, but which can also be acted upon by nicotine. The subunit compositions of nAChR determine their physiological and pharmacological properties, with different subunits expressed in different combinations or areas throughout the brain. The behavioral and physiological effects of nicotine are elicited by its agonistic and desensitizing actions selectively on neuronal nAChRs. The midbrain is of particular interest due to its population of nAChRs expressed on dopaminergic neurons, which are important for reward and reinforcement, and possibly contribute to nicotine dependence. The α6-subunit is found on dopaminergic neurons but very few other regions of the brain, making it an interesting drug target. We assayed a novel nicotinic agonist, called TI-299423 or TC299, for its possible selectivity for α6-containing nAChRs. Our goal was to isolate the role of α6-containing nAChRs in nicotine reward and reinforcement, and provide insight into the search for more effective smoking cessation compounds. This was done using a variety of in vitro and behavioral assays, aimed dually at understanding TI-299423’s exact mechanism of action and its downstream effects. Additionally, we looked at the effects of another compound, menthol, on nicotine reward. Understanding how reward is generated in the cholinergic system and how that is modulated by other compounds contributes to a better understand of our complex neural circuitry and provides insight for the future development of therapeutics.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Nicotine, nAChR, behavior, pharmacology
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Computation and Neural Systems
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Lester, Henry A.
Thesis Committee:
  • Camerer, Colin F. (chair)
  • Adolphs, Ralph
  • Dougherty, Dennis A.
  • Lester, Henry A.
Defense Date:13 March 2015
Funders:
Funding AgencyGrant Number
NIHPD30DA015663
NIH5U19DA019375
NIHDA033721;DA020686
NIH5U19DA019375
Record Number:CaltechTHESIS:03262015-100311493
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:03262015-100311493
DOI:10.7907/Z9JD4TQ5
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8805
Collection:CaltechTHESIS
Deposited By: Teagan Wall
Deposited On:24 Apr 2015 22:01
Last Modified:13 Oct 2016 20:22

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