Defense Date

2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Darlene Brunzell

Abstract

Pharmacotherapies for tobacco and alcohol cessation are only modestly successful, so it is important to better understand mechanisms underlying their use and abuse. The overarching goal of this research is to assess a6b2 subunit containing nicotinic acetylcholine receptor (a6b2*nAChR; *denotes possible assembly with other subunits) contributions to abuse-related effects of nicotine and alcohol. In the absence of a6b2*nAChR-selective agonists, a6b2*nAChR gain-of-function (a6L9’S) mice provide a tool for selective activation of a6b2*nAChRs. Using the a6L9’S mice together with nicotine doses sub-threshold for stimulation of native nAChRs, these studies tested the hypothesis that activation of a6b2*nAChRs is sufficient to promote neurochemical and behavioral effects relevant to nicotine addiction. Intracranial infusions of an a6b2*nAChR-selective antagonist further tested the neuroanatomical locus of a6b2*nAChR contributions to mesolimbic dopamine (DA) release and nicotine reward behavior. Our in vivo microdialysis and nicotine conditioned place preference (CPP) studies reveal that stimulation of a6b2*nAChRs on ventral tegmental area (VTA) DA neurons, as well as on DA terminals in the nucleus accumbens (NAc) shell support nicotine reward. VTA a6b2*nAChR stimulation is required for elevated basal NAc DA levels in a6L9’S mice, who also show elevated nicotine CPP. These studies also showed elevated anxiety-like behavior in a6L9’S mice, but no change in a6 subunit null mutant (a6KO) mice to suggest that elevated cholinergic tone at a6b2*nAChRs promotes anxiety-like behavior. To better define the molecular make-up of a6b2*nAChRs supporting nicotine reward and anxiety-like behavior, these studies crossed a6L9’S to a4 subunit knockout mice to differentiate (non-a4)a6b2* and a4a6b2*nAChR contributions. (non-a4)a6b2*nAChRs appear to promote nicotine reward behavior, while the a6b2*nAChR subtype that regulates anxiety-like behavior depends on the anxiety assay. Finally, these studies developed a mouse model of oral operant ethanol (EtOH) self-administration and assessed EtOH reinforcement in a6 heterozygous (a6HET) and a6KO mice to characterize the role of a6b2*nAChRs in EtOH reinforcement. EtOH self-administration was similar to wild type mice in a6KO mice, but not a6HET mice, suggesting that expression of a6b2*nAChRs modulates EtOH reinforcement. Together, these preclinical studies implicate a6b2*nAChRs in various abuse-related effects of nicotine and alcohol, identifying this receptor as a potential therapeutic target for treatment of dependence.

Rights

© Alexandra Stafford

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-9-2017

Available for download on Sunday, May 08, 2022

Included in

Pharmacology Commons

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