A fundamental goal in neurobiology is understanding the relationship between structure and function. This proposal consists of two inter-related interdisciplinary projects: (a) defining the anatomical organization of the cholinergic afferent connections to the central biogenic amine neuron systems, and (b) investigation a now well-defined function of the central noradrenergic system--the regulation of cerebral capillary permeability. In order to study the anatomical interactions of the central cholinergic system, specific anti-sera to choline acetyltransferase were prepared and a method developed for the simultaneous localization of the cholinergic system and the three biogenic amine systems using dual label immunohistochemistry. A large pontomesencephalic cholinergic nucleus has been shown to make afferent connections with neurons containing all three biogenic amines. It is hypothesized that this cholinergic nucleus integrates a wide variety of ascending and descending information with which it coordinates the activity of the major amine systems. The present thrust of the anatomical project is to precisely define and map the interconnections between this cholinergic nucleus and the three biogenic amine systems. Previous anatomical work has defined possible neuronal circuits which may mediate physiologically induced changes in vascular permeability in response to increased blood pressure and osmolarity. These circuits will be tested using a combination of physiological and pharmacological techniques. The receptors mediating these responses will be defined. The structure and function of the central biogenic amine systems has many clinical implications. Most centrally acting drugs effect this system either directly or indirectly. A clear understanding of the action of these drugs has been hampered by the lack of a well- defined and measureable function to study. Our discovery that this system regulates capillary permeability to water has provided such a function. In addition, this finding has broadened the concept of the blood-brain barrier. The aims of the present proposal is to define the anatomical circuits utilized in permeability regulation and to determine the pharmacological means of manipulation this function.