Component 7 represents the continuation of 2/3 of Component #3 from the current PARC. (Dr. Gallaher's mapping project for ataxia-related QTLs is not being continued in the PARC). EtOH acutely disrupts thermoregulation, and tolerance develops with chronic administration. A different pattern of changes accompanies withdrawal from chronic EtOH dependence, and these changes appear to reflect significant dysregulation of metabolism (specifically, a state of basal hypermetabolism), and decreased overall metabolic scope). In turn, the sequelae of a hypermetabolic state have radiating adverse consequences for a wide range of behavioral responses. EtOH thermal tolerance and withdrawal severity have been found to be negatively genetically correlated, suggesting that some genes affect both traits (Crabbe et al., 1983, Crabbe & Kosobud, 1986). The goal of this component is to explore the genetic determinants of the neuroadaptations that follow the development of ethanol tolerance and withdrawal. Two phenotypes will be addressed. Tolerance to the hypothermic effect of a third daily ip injection of EtOH in a room temperature environment has been analyzed in BXD RI strains and a B6D2F2 population, and marker gene frequencies will be monitor to detect the presence of nearby QTLs. Second, to elucidate the metabolic consequences of chronic ethanol administration, BXD RI strains will be rendered physically dependent on EtOH via vapor inhalation for 72 hr administration, BXD RI strains will be rendered physically dependent on EtOH via vapor inhalation for 72 hr and withdrawn. During withdrawal, disruptions in thermoregulatory and metabolic state in the BXD RIs will be assessed by analysis of core temperature and respiratory gases. Their ability to thermoregulate accurately will be assessed by manipulating ambient temperatures during withdrawal. Provisional QTLs from the BXD RI analysis of these data will be followed up by similar studies in a B6D2F2 population.
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