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The Pennsylvania State University The Graduate School The Huck Institutes for Life Sciences THE NEUROBIOLOGICAL UNDERPINNINGS OF NICOTINE EXPOSURE ON LIMITED ACCESS ETHANOL CONSUMPTION IN PERIADOLESCENT FEMALE C57BL/6J MICE A Dissertation in Neuroscience by Alicia R. Revitsky © 2014 Alicia R. Revitsky Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy August 2014 ii The dissertation of Alicia R. Revitsky was reviewed and approved* by the following: Laura Cousino Klein Professor of Biobehavioral Health Dissertation Adviser Chair of Committee Byron C. Jones Professor of Biobehavioral Health Helen Kamens Assistant Professor of Biobehavioral Health David J. Vandenbergh Associate Professor of Biobehavioral Health Stephen Wilson Assistant Professor of Psychology Ping Li, Professor of Psychology Co-Director Interdisciplinary Graduate Program in Neuroscience, Huck Institutes of the Life Sciences, Neuroscience Graduate Program *Signatures on file in the Graduate School. iii Abstract Despite the deleterious effects resulting from cigarette use, almost 20% of the U.S. adult population currently smokes tobacco, and 80% of adult smokers begin smoking during adolescence (CDC, 2011a; USDHHS, 1994). The primary addictive ingredient in cigarettes is nicotine, and smokers smoke to self-administer nicotine (CDC, 2001b). Additionally, adolescents consume ethanol more than any other drug of abuse, and binge drinking among teens has become increasingly popular over the years (CASA, 2011; SAMHSA, 2002). Adolescents abuse tobacco and ethanol more than any other combination of illicit drugs and females are particularly vulnerable use of these drugs (Bobo & Husten, 2000; Denning et al., 2013). Nicotine and ethanol activate the mesolimbic dopamine pathway and increase synaptic dopamine levels in the NAc (Blomqvist et al., 1997; Corrigall et al., 1994). Although the mechanisms are different, both substances stimulate nAChRs on DA neurons in the VTA (Jones et al., 1999; Soderpalm et al., 2000). Because of the way in which these drugs of abuse activate the reward pathway, chronic exposure to nicotine and ethanol can result in neurobiological alterations that may lead to disordered behaviors. This is especially true for adolescent females as they undergo extensive psychological development and gross neuroanatomical changes during this period and are prone to use of these two drugs, respectively (Spear, 2000a). The purpose of this dissertation was to 1) examine the effects of nicotine exposure on subsequent binge ethanol drinking behavior and blood ethanol concentration in adolescent female C57BL/6J mice and 2) use autoradiography to examine density of nicotinic acetylcholine receptor (nAChR) subtypes in different reward pathway regions that may drive any changes seen in binge ethanol consumption between nicotine exposed mice and control mice. All mice (N= 38) had access to 3 drinking bottles for 7 days and each mouse was placed 1 of 3 nicotine iv conditions: water only, choice nicotine, or forced nicotine. At the end of 7-day treatment period, mice were exposed to a 4-day drinking in the dark (DID) protocol. Results from this study found that adolescent mice exposed to high concentrations of nicotine (i.e., forced nicotine mice) consumed a significantly higher ethanol consumption (g/kg) and displayed higher BECs than control mice. Autodradiography was then used in a subset of the first experiment’s mouse brains to examine the neurobiological underpinnings of increased ethanol consumption by investigating nAChR density in regions of the reward pathway in mice exposed to nicotine compared to control mice. Using 4 different radiolabeled isotopes, results from this experiment found that exposure to high concentrations of nicotine increased nAChR expression in frontal, orbitofrontal, outer, and inner cortices. These results suggest that nicotine exposure may induce increases in binge ethanol consumption through alterations in nAChRs activated reward-based decision making pathways in cortical regions. Additionally, BEC was a significant predictor of nAChRs in the cingulate cortex, striatum, and dorsal tegmental area. Thus, ethanol exposure may modulate firing of the reward pathway through stimulation of these receptor types. Overall, findings from this dissertation study support the hypothesis that exposure to high levels of nicotine during adolescence may increase subsequent binge ethanol consumption through increased nAChR density in higher functioning brain regions in female C57Bl/6J mice, and these changes may ultimately enhance activation of the reward pathway. TABLE OF CONTENTS List of Tables ................................................................................................................................. ix List of Figures ................................................................................................................................. x Abbreviations ................................................................................................................................. xi Acknowledgements ...................................................................................................................... xiii Chapter I – Introduction .................................................................................................................. 1 Cigarette Smoking and Nicotine ............................................................................................................... 1 Adolescence .............................................................................................................................................. 2 Cigarette Smoking. ............................................................................................................................... 4 Risky Behavior. ..................................................................................................................................... 5 Smoking and Sex Differences ................................................................................................................... 6 Women and Drugs of Abuse ..................................................................................................................... 8 Nicotine Pharmacokinetics ..................................................................................................................... 10 Humans. .............................................................................................................................................. 10 Mice. ................................................................................................................................................... 13 Drugs of Abuse and the Reward Pathway ............................................................................................... 15 Nicotine Pharmacodynamics ................................................................................................................... 18 Sex Differences in Rodents ................................................................................................................. 22 Adolescent Rodents. ........................................................................................................................... 23 Alcohol Binge Drinking Statistics .......................................................................................................... 25 Human Alcohol Pharmacokinetics .......................................................................................................... 28 Sex Differences. .................................................................................................................................. 31 Age Differences. ................................................................................................................................. 33 Alcohol Metabolism in Mouse Models ................................................................................................... 34 Sex Differences. .................................................................................................................................. 35 Age Differences .................................................................................................................................. 36 Alcohol Pharmacodynamics ................................................................................................................... 38 Age Differences. ................................................................................................................................. 46 Sex Differences. .................................................................................................................................. 48 Drinking in the Dark (DID) .................................................................................................................... 50 vi Cigarette and Alcohol Co-Administration .............................................................................................. 52 Nicotine and Alcohol Pharmacokinetics ................................................................................................. 54 Age Differences. ................................................................................................................................. 56 Sex Differences. .................................................................................................................................. 59 Nicotine and Alcohol Pharmacodynamics .............................................................................................