Withdrawal from chronic ethanol exposure results in a number of physiological responses. Two of those responses are altered sleep parameters and increased anxiety. However, little is known about either the factors that influence the severity of the alterations in sleep parameters or about whether there is a relationship between sleep: wake characteristics and anxiety during ethanol withdrawal. Two factors that have been shown to affect both sleep: wake characteristics and the severity of ethanol's withdrawal effects are the genetics or gender of the organism, and thus, the first experiment will test the hypotheses that genetics and/or gender or a combination of the two variables influences the severity of ethanol-induced changes in sleep. Testing of these hypotheses will be facilitated by the use of a novel system, the Piezo system, developed by the PI Dr. O'Hara. This system has the advantage of evaluating sleep patterns in a non-invasive fashion that also requires minimal labor investment. To test these hypotheses, DBA/2J (D2) and C57BL/6J (B6) mice as well as the BXD recombinant inbred mice generated by intercrossing the D2 and B6 mice will be examined. The addition of the BXD strains will allow us to not only address the hypotheses, but also to identify the region(s) of the genome that mediate any differential responses. Ethanol exposure will be given using vapor inhalation and following the multiple cycles of withdrawal and exposure of Veatch (2006), a technique that allows for the rapid induction of alcohol dependence. Comparisons of the sleep: wake parameters before ethanol exposure (baseline) will be compared to those during withdrawal. The second experiment will examine whether there is a relationship between the anxiety phenotypes of the animal and the severity of sleep alterations during ethanol withdrawal to determine whether the mice with the highest level of anxiety also show the most severe sleep disruptions during withdrawal. The anxiety phenotype of the mice will be addressed using several different behavioral paradigms including the elevated plus maze and locomotor activity in an activity chamber. Mice will be exposed to ethanol and the sleep: wake parameters monitored in the same manner as in the first experiment. Anxiety phenotypes will be assessed prior to ethanol exposure and during withdrawal. These experiments will provide insights into variables that need to be considered in the design of treatment programs for particular patients or in understanding the factors that mediate differences in treatment outcomes.
Sleep disruptions are one of the physiological responses that occur during alcohol withdrawal and have been shown to be a negative predictor of success in alcohol withdrawal. This proposal will provide insight into the role of gender and genetics in sleep disruptions following alcohol exposure and withdrawal as well as identify regions of the genome that underlie these differences.
| DuBose, Candis S; Chesler, Elissa J; Goldowitz, Dan et al. (2013) Use of the expanded panel of BXD mice narrow QTL regions in ethanol-induced locomotor activation and motor incoordination. Alcohol Clin Exp Res 37:170-83 |
| Du, Xiaoping; Elberger, Andrea J; Matthews, Douglas B et al. (2012) Heterozygous deletion of NR1 subunit of the NMDA receptor alters ethanol-related behaviors and regional expression of NR2 subunits in the brain. Neurotoxicol Teratol 34:177-86 |
