Full-Gestational Exposure to Nicotine and Ethanol Results in Long-Term Dysregulation in the Ventral Tegmental Area

Abstract

DEDICATIONI dedicate this work in memory of my father George F. Roguski for instilling in me the importance of hard work to achieve your goals and all the years of unconditional love and support.I also dedicate my dissertation work in memory my mentor Dr. Shannon G. Matta for all her hours of reflecting, reading, encouraging, and patience. Most of all for taking a chance on me and helping me further my education.iv ACKNOWLEDGEMENTS I wish to thank my committee members who were more than generous with their expertise and precious time. A special thanks to Dr. Jeff Steketee, my committee chairman for always being there for help when need and most importantly for stepping in to help me finish. I would also like to thank Dr. Burt M Sharp for always having extra time throughout all my years at UT. Thank you Dr. Andrea J Elberger, Dr. Edwards A Park, and Dr. Steve Tavalin for agreeing to serve on my committee.I would like to thank the University of Tennessee Health Science Center Neuroscience Institute for their support over the years.Thank you to Dr. Hao Chen for teaching me every technique used in my experiments. I truly would not have been able to accomplish these experiments without your help.Finally, to my Mum, Alex, and Bobbi Jo thank you for being there at any time and the love and support over the years.v ABSTRACT Nicotine is considered a gateway drug for other drugs of abuse. The majority of smokers that begin smoking in adolescence, continue into adulthood. Multiple factors have been linked with smoking initiation, including maternal smoking. Drug exposure during pregnancy has long been suspected to exert deleterious effects on the fetal brain. Concurrent use of smoking and drinking alcohol throughout pregnancy is an all too frequent occurrence in the human population especially in disadvantaged and younger women.The present study investigated the potential contributing factors for the enhanced nicotine self-administration as seen in offspring with gestational exposure to nicotine and ethanol (Nic+EtOH).* We focused on the mesocorticolimbic pathway, specifically the λ-aminobutyric acid (GABA) and glutamate modulators of ventral tegmental area (VTA) dopamine (DA) neurons that project to the nucleus accumbens (NAcc).Our animal model of full gestational exposure to Nic+EtOH exposes the developing brain to both drugs throughout the entire 3 trimester human equivalent [i.e. gestational days (GD) 1-22 and postnatal days (PN) 2-12]. Using self-administration (SA), in vivo microdialysis, quantitative PCR, and western blot analysis, we investigated alterations in the VTA of offspring.We found that the enhancement of nicotine SA acquisition of offspring with gestational Nic+EtOH exposure is not due to changes in maternal-pup interactions. The offspring with gestational Nic+EtOH exposure have a dramatic change in neurotransmitter release in response to 30µg i.v. nicotine; that displays a 75% increase of NAcc DA and a 50% reduction of VTA GABA release. In comparison, pair-fed (PF) offspring show a 20% increase in NAcc D...