PENTOBARBITAL ACTIVATION IN SELECTED MOUSE LINES

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This project is designed to develop outbred lines of mice which are differentially sensitive to low doses of pentobarbital in a circular locomotor activity apparatus. The lines, designated Pentobarbital Sensitive (PBS) and Pentobarbital Insensitive (PBI), along with a control line (PBC), will be developed at The University of Texas at Austin for the purpose of discerning behavioral correlates and neurochemical mechanisms of low-dose barbiturate intoxication. Pentobarbital is the prototype barbiturate for this project based upon extensive pilot tests already completed. This five-year study will encompass a "breeding" specific aim in which mice are tested for locomotor activity in response to pentobarbital, then selected and outbred through at least 14 selection generations. At various stages of the breeding and selection process, the lines will be "characterized" (the second specific aim) for their differential responses to higher doses of pentobarbital. Parameters to be measured in these lines will be sleeptime (loss of righting reflex), hypothermia, and tolerance to sleeptime. In the third specific aim, a search for "mechanisms" of the differential responses to pentobarbital among the lines will be undertaken, through studies of pentobarbital clearance; responses to ethanol, other hypnotics, a benzodiazepine, an opiate antagonist, and an amphetamine; and brain region levels and turnover of dopamine, and brain region synthesis and concentrations of opiopeptides. The hypothesis is that these lines will be useful for studying the specific neurochemical changes related to the intoxication seen when low doses of a barbiturate are given. The proposed studies will provide information on the mechanisms behind barbiturate's intoxicating effects in mice after low doses, and perhaps in man after abusable doses of pentobarbital.