This proposal is for an ADAMHA Research Scientist Award. The importance of local neuronal circuits (LNCs) and particularly inhibitory pathways in the central nervous system (CNS) for information processing and the action of neuroactive drugs has become increasingly apparent. The development of in vitro slice preparations of various regions of the vertebrate CNS has overcome most of the technical problems that have limited our knowledge in this field. During the past five years we have studied in detail with intracellular recording inhibitory pathways in two model cortical systems: the olfactory bulb, a sensory system, and the hippocampus, an integrative system. In addition to characterizing a number of inhibitory pathways, we have found that inhibitory interneurons in these regions may be primary targets for a number of diffusely or nonspecifically organized neurotransmitter systems, (e.g., those involving norepinephrine (NE) and enkephalin), many of which have been strongly implicated in normal and abnormal behavior. My research will focus on the action of NE which best typifies the nonspecifically organized class of cortical afferent. However, the proposed experiments will be equally useful in studying other non-specific afferent systems. We have preliminary evidence that NE exerts a direct action on relay neurons to increase the signal to noise ratio and an indirect action involving a blockade of inhibitory pathways. The direct action appears to involve a cyclic AMP modulation of a Ca++ activated K+ conductance, while the site of action on inhibitory pathways in unclear. Both of these actions stand in marked contrast to the traditional view that NE is an inhibitory transmitter. The specific goal of this proposal is to elucidate the receptor types and mechanisms underlying these two actions of NE. The NE-containing locus cooruleus neurons are thought to be involved in such global brain functions as arousal and transitions between behavioral states as well as in numerous psychiatric disorders. The proposed experiments will not only provide deeper insight in the neurophysiological and neuropharmacological organization of NE in cortical regions and how NE is involved in processing information, but also may well provide important clues about the role of NE in normal and abnormal behavior.
