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BDNF and NGF Protein Levels in the Brains of Rats Neonatally Treated with Methamphetamine: Implications for Spatial Learning and Memory Deficits

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BDNF and NGF Protein Levels in the Brains of Rats Neonatally Treated with Methamphetamine: Implications for Spatial Learning and Memory Deficits UNIVERSITY OF CINCINNATI Date:___________________ I, _________________________________________________________, hereby submit this work as part of the requirements for the degree of: in: It is entitled: This work and its defense approved by: Chair: _______________________________ _______________________________ _______________________________ _______________________________ _______________________________ Interaction of Brain Derived Neurotrophic Factor and the HPA Axis Stress Response System with Neonatal d-Methamphetamine Induced Spatial Learning and Memory Deficits. A dissertation submitted to the Division of Research and Advanced Studies of the University of Cincinnati in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY In the Graduate Program in Molecular and Developmental Biology of the College of Medicine of the University of Cincinnati 2005 by Carrie A. Brown-Strittholt B.A., A.A., Thomas More College, 1999 Committee Chair: Charles V. Vorhees, Ph.D. Committee Members: Floyd R. Sallee, MD, Ph.D. James P. Herman, Ph.D. Michael T. Williams, Ph.D. Renu Sah, Ph.D. This research was supported by NIH grant DA06733 (CVV), and training grant ES07051 (CAS). ABSTRACT Neonatal methamphetamine (MA) exposure P11-20 or P11-15 in rats is known to produce long-term spatial learning and memory deficits. However, little is known concerning the mechanism by which this results. Data from experiments exploring behavior indicate a role for neurotrophins and corticosterone (CORT) in learning and memory processes. It is hypothesized that neonatal MA alters levels of neurotrophins and/or alters the stress/CORT response resulting in impaired spatial learning and memory deficits in the Morris water maze (MWM). The current set of experiments explored first the levels of brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) during the neonatal dosing period and in adulthood. Treatment effects were observed for BDNF P15. Sex differences in hippocampal and hypothalamic protein content for BDNF were found at P11; higher levels occurring in male pups. Sex differences in hippocampal protein content for NGF were found at P15 and sex differences in the hypothalamus were found at P68; higher levels in females at both ages. Behavioral tests in the MWM mimicked previous results demonstrating a clear MA-induced spatial learning deficit. Anxiety testing demonstrated more exploratory behavior in female animals. Secondly, pharmacological and surgical methods of corticosterone regulation were explored. Metyrapone (MET) injection and bilateral adrenalectomy (ADX) approaches were successful in the adult animal. Swimming ability was impaired only in ADX animals without CORT replacement. Zero maze data indicated increased activity among animals treated neonatally with MA 20 mg/kg. Trends were apparent among MWM data ii indicating a slight correction of the MA-induced learning and memory deficit when CORT levels were controlled; however, the MA effect was not clear among control animals to enable a definitive comparison. Overall results suggest a role for neurotrophins and CORT in the mechanism of MA’s effects on the developing brain but neither appears to be the sole source of insult. iii ACKNOWLEDGEMENTS I would like to acknowledge my advisor, Dr. Charles Vorhees, for his guidance and for giving me the opportunity to do this research. I would like to acknowledge the members of my dissertation committee for their help and support throughout my candidacy. I would like to acknowledge the members of the Vorhees’ lab, past and present, for their help, with special recognition to Ms. Mary Moran and Dr. Martha Cohen for their immeasurable help learning and interpreting statistical procedures. I would like to acknowledge members of the Molecular and Developmental Biology Graduate Program for their support during my graduate career. I would like to extend a special thank you to the MDB secretarial staff for keeping me up to date despite my many moves within the division, the tri-state area, and even the nation. I would like to thank the members of the Division of Infectious Diseases, where I began my graduate studies, for their continued support and friendship throughout my graduate career. I would like to thank Dr. Lawrence Stanberry for accepting me as a graduate student in the division. Also, a very special thank you to Dr. Richard Pyles; he made my education a priority in his work and remains one of the most influential teachers in my educational career as well as a friend. I would like to acknowledge Gerald Franzen, Ph.D. for his contributions of chemical structures to this dissertation. I would like to acknowledge my family and friends, especially my husband and parents, for their support and encouragement in all areas of my life. I would like to dedicate this dissertation to my grandparents, Thomas and Elizabeth O’Daniel. From as early in my life as I can remember they have been pillars of support and taught me that after the presence of God and family in one’s life, that education and hard work are essential tools to success. In a growing family of 58 people that still gather for holidays and family events, this doctorate is the first and is dedicated to them with gratitude and with love. iv TABLE OF CONTENTS Chapter 1 – Methamphetamine, Neurotrophic Factors & Stress …. p.008-092 Methamphetamine………………….……………………………… p.008-026 Chemical structures and function …………….…………… p.009-013 History and prevalence of use ………….……………….… p.014-018 Developmental processes and vulnerability to injury ….…. p.018-021 Research review ……………………………….………….. p.025-043 Human studies ……………………………………. p.025-028 Animal studies ……………………………………. p.028-043 Dose comparisons across species ………………………… p.044 Model system ……………………………………………... p.045 Neurotrophic Factors ……………………………………………… p.046-064 Nerve Growth Factor …………………………………… p.050-055 Brain Derived Neurotrophic Factor ……………………….. p.055-059 Neurotrophin-3 ……………………………………………. p.059-061 Neurotrophin Receptors …………………………………… p.061-064 Stress ………………………………………………………………. p.065-083 Hypothalamic-Pituitary-Adrenal Axis …………………….. p.069-078 Development – Stress Hyporesponsive Period ……………. p.078-083 Hypotheses and aims ……………………………………………… p.084-087 CHAPTER 2 – BDNF and NGF Protein Levels in the Brains of Rats Neonatally Treated with Methamphetamine: Implications for Spatial Learning and Memory Deficits. …………………………………………………………… p.088-117 Abstract …………………………………………………………… p.088-089 Introduction ……………………………………………………….. p.089-092 Materials and methods ……………………………………………. p.093-100 Results …………………………………………………………….. p.100-104 Discussion ………………………………………………………… p.104-110 CHAPTER 3 – MA-Induced Increased Levels of CORT During the SHRP and Neonatal MA-Induced Long Term Changes in Basal CORT in the Adult: Implications for Spatial Learning and Memory Deficits..………... p.118-193 Abstract …………………………………………………………… p.118-119 Introduction ………………………………………………………. p.119-130 Materials and methods ……………………………………………. p.132-149 Results and discussion …………………………………………….. p.149-187 Summary discussion and conclusions……………………………… p.188-193 CHAPTER 4 – Summary ……..……………………….………... p.194-203 Conclusions ………………………………………………………. p.194-199 Future Directions …………………………………………………. p.199-203 1 INDEX OF FIGURES Chapter 1 – Methamphetamine, Neurotrophic Factors & Stress …. p.008-083 Figure 1.1: Chemical structures …………………………………. p.013 Figure 1.2: Neurotransmitter receptor subtype development….…. p.022 Figure 1.3: Brain region development – human/rat………………. p.023 Figure 1.4: Brain growth spurt – human/rat…………………..…. p.024 CHAPTER 2 – BDNF and NGF Protein Levels in the Brains of Rats Neonatally Treated with Methamphetamine: Implications for Spatial Learning and Memory Deficits. …………………………………………………………… p.088-117 Figure 2.1: MWM Annuli and direct swim diagrams ………..…. p.111 Figure 2.2: Neonatal CORT treatment effect …….……….…..…. p.111 Figure 2.3: Adult CORT treatment effect ………..……….…..…. p.112 Figure 2.4: Adult CORT sex by time interaction……………..…. p.112 Figure 2.5: Treatment effect ………………………………….…. p.113 Figure 2.6: BDNF sex effect ………………………….……....…. p.113 Figure 2.7: BDNF treatment by time interaction.…….……....…. p.114 Figure 2.8: NGF sex effect; sex by treatment interaction.….…... p.115 Figure 2.9: MWM treatment effect …………………………..…. p.116 Figure 2.10: Annuli and direct swim treatment effect ……..….…. p.117 CHAPTER 3 – MA-Induced Increased Levels of CORT During the SHRP and Neonatal MA-Induced Long Term Changes in Basal CORT in the Adult: Implications for Spatial Learning and Memory Deficits..………... p.118-193 Figure 3.1: Chemical structures …….……………….……….…. p.131 Figure 3.2: Neonatal MET injection series ……………….….…. p.152 Figure 3.3: Neonatal KTZ injection ……………..…….……..…. p.155 Figure 3.4: Adult MET injection, Preliminary CORT……….…. p.166 Figure 3.5: Adult MET injection, dosing weights...………….…. p.166 Figure 3.6: Adult MET injection, MWM AQ latency………..…. p.167 Figure 3.7: Adult MET injection, MWM RV latency………..…. p.167 Figure 3.8: Adult MET injection, MWM AQ probe trials...…. p.168 Figure 3.9: Adult ADX, Preliminary CORT.……….…..…….…. p.180 Figure 3.10: Adult ADX, post-behavioral CORT …….…………. p.180 Figure 3.11: Adult ADX, dosing weights………………..……….. p.181 Figure 3.12: Adult ADX, adult weights……………….…….……. p.182 Figure 3.13: Adult ADX, Straight channel ………………………. p.183 Figure 3.14: Adult ADX, Zero maze ……………………….……. p.184 Figure 3.15: Adult ADX, MWM Latency .…………………….…. p.185 Figure 3.16: Adult ADX, MWM learning curves...………………. p.186 Figure 3.17:
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