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Views', See Rahwan, 1974; Rahwan, 1975) INFORMATION TO USERS This was produced from a copy of a document sent to us for microfilming. While the most advanced technological means to photograph and reproduce this document have been used, the quality is heavily dependent upon the quality of the material submitted. The following explanation of techniques is provided to help you understand markings or notations which may appear on this reproduction. 1.The sign or “target” for pages apparently lacking from the document photographed is “Missing Page(s)”. If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting through an image and duplicating adjacent pages to assure you of complete continuity. 2. When an image on the film is obliterated with a round black mark it is an indication that the film inspector noticed either blurred copy because of movement during exposure, or duplicate copy. Unless we meant to delete copyrighted materials that should not have been filmed, you will find a good image of the page in the adjacent frame. 3. When a map, drawing or chart, etc., is part of the material being photo­ graphed the photographer has followed a definite method in “sectioning” the material. It is customary to begin filming at the upper left hand comer of a large sheet and to continue from left to right in equal sections with small overlaps. If necessary, sectioning is continued again—beginning below the first row and continuing on until complete. 4. For any illustrations that cannot be reproduced satisfactorily by xerography, photographic prints can be purchased at additional cost and tipped into your xerographic copy. Requests can be made to our Dissertations Customer Services Department. 5. Some pages in any document may have indistinct print. In all cases we have filmed the best available copy. University Micrdrilms International 300 N. ZEEB ROAD, ANN ARBOR, Ml 48106 18 BEDFORD ROW. LONDON WC1 R 4EJ, ENGLAND THE ROLE OF THE TETRAHYDROISOQUINOLINE, SALSOLINOL, IN THE MECHANISM OF ETHANOL TERATOGENICITY DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Christine Ann Nesterick, B .A. ***** The Ohio State University 1979 Reading Committee: Approved By Allan M. Burkman Duane D. Miller Ralf G. Rahwan Adviser College of Pharmacy Norman J. Uretsky To Mom, Dad and Al ii ACKNOWLEDGMENTS I would like to express my sincere appreciation to: Dr. Ralf G. Rahwan, for his direction and constant support, and supply of "crying towels" during difficult periods in this work. My parents and family, for their unfailing confi­ dence and prayers that provide me with the courage to begin new endeavors. My fiance, Alexander, for his understanding of all that graduate education demands and his encouragement to pursue meaning in life. Drs. Allan M. Burkman, Dennis R. Feller, Duane D. Miller and Norman J. Uretsky for advice whenever it was called upon. The American Foundation for Pharmaceutical Educa­ tion for financial support during this work. Mrs. Jean Freeman for her work in the typing of this dissertation. iii VITA June 14, 1953......... Born - Erie, Pennsylvania 1975 ................. B.A. , magna cum laude, in Chemistry, Clarion State College, Clarion, Pennsylvania 1975-1976 19 78-19 79............. University Fellow, The Ohio State University, Columbus, Ohio 1975-197 6 ............. Teaching Assistant, College of Pharmacy, The Ohio State University, Columbus, Ohio 1976-197 7 ............. Fellow of the American Foundation for Pharmaceutical Education 19 77-1978............. William E. Weiss Memorial Fellow of the American Foundation for Pharmaceutical Education 1976-1979............. Research Assistant, College of Pharmacy, The Ohio State University, Columbus, Ohio PUBLICATIONS "Detection of Endogenous Salsolinol in Neonatal Rat Tissue by a Radioenzymatic/Thin-Layer Chromatographic Assay." Pharmacologist 21: 428, 1979. "Detection of Endogenous Salsolinol in Neonatal Rat Tissue by a Radioenzymatic/Thin-Layer Chromatographic Assay." J. Chromatogr. 164; 205-216, 1979. iv "Absence of a Role for Salsolinol in the Mechanism of Ethanol Teratogenicity." Submitted for publication. FIELDS OF STUDY Major Field: Pharmacology Pharmacology of Ethanol Teratology Toxicology v TABLE OF CONTENTS Page DEDICATION........................................... ii ACKNOWLEDGMENTS ..'.................................. iii VITA.................................................. iv LIST OF TABLES. ............................... i* LIST OF PLATES...................................... ix LIST OF FIGURES .................................... X Chapter 1. INTRODUCTION TIQ Theory of Alcoholism.............. 1 The Fetal Alcohol Syndrome Human Observations................. 18 Animal Investigations ............. 21 Possible Mechanisms of Ethanol Teratogenicity............. 30 Statement of the Problem............... 40 II. MATERIALS AND METHODS Development of a Radioenzymatic/ Thin-Layer Chromatographic Assay for Salsolinol in Neonatal Rat Tissue R a t i o n a l e .......................... 43 Chemicals and Equipment ........... 44 Separation of O-Methylated Derivatives of Salsolinol, Dopamine, Epinephrine and Norepinephrine by T L C ............. 47 Radioenzymatic Reaction ........... 4 8 Aqueous Standard Curve............. 49 Plasma Standard Curve ............. 50 vi Page Tissue Standard Curve ............. 50 Verification of the Identity of Trace Amounts of Tissue Salsolinol.......................... 51 Determination of Endogenous Salsolinol in Neonatal Rat Tissue................. 53 Assessment of the Placental Transfer of Salsolinol Animal Experimentation............. 54 Salsolinol Assay. ’. •........... 55 Assessment of Salsolinol Formation after Acute Alcohol Administration Preliminary Studies of Alcohol Disappearance ...................... 57 Animal Experimentation............. 57 Salsolinol > Assay................... 58 Ethanol Assay ...................... 58 Statistical Analysis............... 59 III. RESULTS Development of a Radioenzymatic/Thin Layer Chromatographic Assay for Salsolinol in Neonatal Rat Tissue Separation of O-Methylated Derivatives of Salsolinol, Dopamine, Epinephrine and Norepinephrine by T L C ............. 60 Aqueous Standard Curve............. 60 Plasma Standard Curve ....... 65 Tissue Standard Curve ............. 68 Verification of the Identity of Trace Amounts of Tissue Salsolinol.......................... 68 Determination of Endogenous Salsolinol in Neonatal Rat Tissue................. 73 Assessment of the Placental Transfer of Salsolinol .......................... 74 vii Page Assessment of Salsolinol Formation after Acute Alcohol Administration Preliminary Studies of Alcohol Disappearance ............. 76 Determination of Salsolinol F o r m a t i o n .......................... 76 IV. DISCUSSION Development of a Radioenzymatic/Thin- Layer Chromatographic Assay ........... 80 Assessment of the Placental Transfer of Salsolinol.......................... 82 Assessment of Salsolinol Formation after Acute Alcohol Administration. 83 APPENDIX. ........................................... 88 BIBLIOGRAPHY......................................... 92 viii LIST OF TABLES Table Page 1. Radioenzymatic Assay in the Absence of C O M T ....................................... 72 2. Placental Transfer of Salsolinol in R a t s ....................................... 75 3. Rate of Ethanol Disappearance in Sprague-Dawley Female Rats................. , . 77 4. Rat Fetal Salsolinol Content after Maternal Alcohol Treatment................... 78 LIST OF PLATES 1. Thin-Layer Chromatographic Separation of Normetanephrine/ Metanephrine, 3-Methoxytyramine and Salsoline .............. 62 ix LIST OF FIGURES Figure Page 1. Pictet-Spengler Condensation of Acetalde- hyde and the Catecholamines to Form the Simple Tetrahydroisoquinolines....... 3 2. Catechol-O-Methyltransferase Catalyzed O-Methylation of Salsolinol in the Presence of S-Adenosy1-Methionine ........... 6 3. The Formation of Tetrahydropapaveroline from the Condensation of Dopamine and Dopaldehyde .............................. 9 4. Aqueous Standard Curve for Salsolinol .... 64 5. Plasma Standard Curve for Salsolinol..... 67 6. Tissue Standard Curve for Salsolinol. 70 x CHAPTER I INTRODUCTION TIQ Theory of Alcoholism Recent evidence in both laboratory animals and in humans suggests that tetrahydroisoquinoline (TIQ) and tetrahydro-0-carboline (TBC) alkaloidal metabolites, formed endogenously from interactions between acetaldehyde and catecholamines or serotonin during alcohol consumption, may play a role in the development of physical dependence to ethanol (for reviews', see Rahwan, 1974; Rahwan, 1975). The simple TIQs were proposed to be formed by the direct condensation of acetaldehyde with endogenous catecholamines to form substituted 6,7-dihydroxy TIQs (Fig. 1)(Cohen and Collins, 1970). The similarity in structure between these TIQs and the catecholamines suggested that the TIQs might interact with mechanisms which normally regulate the physiologic properties of catecholamines. Indeed, Heikkila et al. (1971) have shown that TIQs may act as false transmitters in that they are taken up and accumulated in rat brain synaptosomes, and interfere with the uptake and release of catecholamines by the synaptosomes. In addition, TIQ alkaloids are formed in acetaldehyde and 1 2 Figure 1. Pictet-Spengler condensation of acetaldehyde and a catecholamine to form first an unstable
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