PhD (Doctor of Philosophy)
Date of Award
Committee Chair or Co-Chairs
Matthew I. Palmatier PhD
Russell W. Brown PhD, Richard M. Kostrzewa PhD, Eric W. Sellers PhD, Jon R. Webb PhD
Nicotine has multiple behavioral effects as a result of its action in the central nervous system. Nicotine strengthens the behaviors that lead to nicotine administration (primary reinforcement), and this effect of nicotine depends on mesotelencephalic systems of the brain that are critical to goal directed behavior, reward, and reinforcement. Nicotine also serves as a ‘reinforcement enhancer’ – drug administration enhances behaviors that lead to other drug and nondrug reinforcers. Although the reinforcement enhancing effects of nicotine may promote tobacco use in the face of associated negative health outcomes, the neuroanatomical systems that mediate this effect of nicotine have never been described. The ventral tegmental area (VTA) is a nucleus that serves as a convergence point in the mesotelencephalic system, plays a substantial role in reinforcement by both drug and nondrug rewards and is rich in both presynaptic and postsynaptic nicotinic acetylcholine receptors (nAChRs). Therefore, these experiments were designed to determine the role of the VTA and nAChR subtypes in the reinforcement enhancing effect of nicotine. Transiently inhibiting the VTA with a gamma amino butyric acid (GABA) agonist cocktail (baclofen and muscimol) reduced both primary reinforcement by a visual stimulus and the reinforcement enhancing effect of nicotine, without producing nonspecific suppression of activity. Intra-VTA infusions of a high concentration of mecamylamine a nonselective nAChR antagonist, or methylycaconitine, an α7 nAChR antagonist, did not reduce the reinforcement enhancing effect of nicotine. Intra-VTA infusions of a low concentration of mecamylamine and dihydro-beta-erythroidine (DHβE), a selective antagonist of nAChRs containing the *β2 subunit, attenuated, but did not abolish, the reinforcement enhancing effect of nicotine. In follow-up tests replacing systemic nicotine injections with intra-VTA infusions (70mM, 105mM) resulted in complete substitution of the reinforcement enhancing effects – increases in operant responding were comparable to giving injections of systemic nicotine. These results suggest that *β2-subunit containing nAChRs in the VTA play a role in the reinforcement enhancing effect of nicotine. However, when nicotine is administered systemically these reinforcement enhancing effects may depend on the action of nicotine at nAChRs in multiple brain nuclei.
Dissertation - Open Access
Sheppard, Ashley B., "Role of the Ventral Tegmental Area and Ventral Tegmental Area Nicotinic Acetylcholine Receptors in the Incentive Amplifying Effect of Nicotine" (2014). Electronic Theses and Dissertations. Paper 2362. https://dc.etsu.edu/etd/2362
Copyright by the authors.