This is a request for a level II Research Scientist Development Award. The effects of ethanol exposure on mammalian central nervous system function will be pursued using both extracellular and intracellular recording in the intact brain in situ, in the in vitro brain slice and in intraocular brain transplants. Studies will focus on genetic variants manifesting differential alcohol-related behaviors as model systems for examing acute ethanol actions as well as for studying tolerance and dependence to alcohol. The long-term objectives of this research program are three fold. First, the mechanism of electrophysiological responses to ethanol will be characterized as direct, modulatory or involving local circuit interneurons. Second, changes in responses to ethanol, as well as functional changes in neurotransmitter systems, will be determined after induction of tolerance or dependence. Finally, using the genetic variants, ethanol-induced electrophysiological responses will be correlated with alcohol-induced behaviors. A greater understanding of how ethanol alters CNS function should furnish new insights into the problems of alcohol intoxication and alcoholism. During the tenure of my RSDA level II award, my professional growth plans include augmented interactions with a number of laboratories. 1) I will extended collaborations with local alcohol investigators in Denver and in Boulder, 2) I will visit to the laboratory Dr. Lars Olson at the Karolinska Institute in Stockholm, Sweden to continue characterizing intracranial and intraocular brain grafts as models of isolated brain circuits to study acute and chronic ethanol actions and to combine to study the effects of ethanol on brain development. I will visit Dr. Roy Wise at Concordia University in Montreal, Canada to learn behavioral Methods for studying self administration and drug preference. I will spend time with Dr. John Carbbe at the VA Hospital Research Service in Portland, Oregon to learn methods of studying ethanol dependence. I will extend my collaboration with Dr. Olof Tottmar at the University of Uppsala in Sweden to continue our studies of interactions between ethanol and monoamine metabolites as well as condensation products. Finally, I will work with Dr. Yun Wang at the National Defense Medical Center in Taiwan to continue our studies of sigma and kappa opiate mechanisms. Through these collaborations, visits and discussions I hope to expand the methodology used in my laboratory to study ethanol; specifically in the areas of 1) in vivo electrochemistry, 2) chronic unit recording, 3) high performance liquid chromotgraphy, 4) genetics and selective breeding, and 5) intracellular recording. My present work concentrates on the electrophysiological effects of acute and chronic ethanol exposure. In terms of future directions, I would also like to pursue studies of the mechanisms of ethanol preference and dependence, as well as investigations of the effects of ethanol on pre- and postnatal brain development.
