.............................................................................................................................. xiv CHAPTER 1 RESEARCH OBJECTIVES ................................................................................. 1 REFERENCE .......................................................................................................................................... 4 CHAPTER 2 BACKGROUND AND LITERATURE REVIEW ............................................. 7 2.1 Proton-coupled oligopeptide transporters ....................................................................... 7 2.1.1 Structural characteristics .................................................................................................................. 8 2.1.2 Transport function and mechanisms ........................................................................................... 9 2.1.3 Tissue distribution and expression regulation .................................................................... 10 2.2 L-Histidine transporters in brain ...................................................................................... 13 2.2.1 Transport of L-histidine across brain barrier systems ..................................................... 14 2.2.2 Transport of L-histidine in brain parenchyma ..................................................................... 16 2.3 Histamine in the central nervous system ....................................................................... 18 2.3.1 Histamine in nonneuronal tissues ............................................................................................. 19 2.3.2 Mast cells ............................................................................................................................................... 20 2.3.3 Histaminergic system ...................................................................................................................... 21 2.3.4 Histamine receptors ......................................................................................................................... 22 2.3.5 Function of histamine ...................................................................................................................... 23 FIGURES ............................................................................................................................................ 24 REFERENCE ....................................................................................................................................... 31 CHAPTER 3 A NOVEL ROLE FOR PHT1 IN THE DISPOSITION OF L-HISTIDINE IN BRAIN: IN VITRO SLICE AND IN VIVO PHARMACOKINETIC STUDIES IN WILDTYPE AND PHT1 NULL MICE ..................................................... 40 3.1 Abstract ...................................................................................................................................... 40 3.2 Introduction .............................................................................................................................. 41 3.3 Materials and methods .......................................................................................................... 43