Item Details

title

Behavioral and Neurobiological Effects of β2 Nicotinic Acetylcholine Receptor Subunit Sensitivity on Nicotine Self-administration

author

Walker, Noah

abstract

Nicotine is the primary psychoactive ingredient in tobacco products. As smoking tobacco is the leading cause of premature and preventable death, it is necessary to understand the mechanism of nicotine addiction. However, nicotine is a weak reinforcer, with both clinical and preclinical studies showing significant decreases in responding for nicotine in the absence of relevant cues. This emphasizes the need for a deeper understanding of the factors contributing to sustained use. Nicotine acts on nicotinic acetylcholine receptors (nAChRs) with the most abundant receptor subtype being the α4β2 nAChR. The α4β2 receptor subtype can be further divided into a high and low sensitivity isoform based on receptor subunit composition, indicating the importance of studying the neurobiological roles of individual nAChR subunits and their behavioral impact. As one of the most abundant nAChR subunits, the β2 subunit is known to play a key role in nicotine addiction through the activation of midbrain dopaminergic neurons. While multiple studies have examined sensitivity or specific activation of the α4 subunit, the same cannot be said for the β2 subunit. Furthermore, in vivo studies analyzing subunit sensitivity have mainly utilized mouse models. Thus, a gap in the literature exists regarding the role of β2 nAChR subunit sensitivity on nicotine self-administration in rats. This study uses a novel, hypersensitive L9′S mutation to the β2 nAChR subunit to investigate the role of selective activation of β2* nAChRs in factors related to nicotine use. In Chapter II, rats injected with the β2L9′S virus were trained to self-administer nicotine at two doses, indicating selective activation of these β2* receptors is sufficient for nicotine SA. In using this viral approach in a transgenic TH-Cre strain, we also show this effect is driven by VTA dopaminergic neurons. Chapter III expands on these findings by generating a dose response curve in L9′S injected and SD rats while showing the role of β2 nAChR activation on motivation to self-administer nicotine. This analysis of nicotine intake behaviors contributes to our understanding of the interplay between nAChR sensitivity, dopamine reward circuitry, nicotine reinforcement, the role of cues in nicotine SA, and motivation to self-administer nicotine.

subject

Beta 2

nAChR

Nicotine

Rat

Self-administration

VTA

contributor

Drenan, Ryan M (advisor)

Martin, Thomas J (committee member)

Czoty, Paul (committee member)

Jones, Sara R (committee member)

McCool, Brian (committee member)

date

2025-03-12T08:36:49Z (accessioned)

2025-03-12T08:36:49Z (available)

2025 (issued)

degree

Physiology and Pharmacology (discipline)

identifier

http://hdl.handle.net/10339/110325 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation