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Roles of the circadian and reward systems in alcoholism

2011, PHD, Kent State University, College of Arts and Sciences / Department of Biological Sciences.
The circadian timing system is closely tied to the reward system. This dissertation addresses primary mechanisms for alcoholism through the assessment of ethanol disruption to the mammalian circadian pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. The mouse strain utilized (C57BL/6J) demonstrated moderate ethanol intake (~12 g/kg/day), preference (50%), and relapse risk. Chronic ethanol intake, its withdrawal, and subsequent re-introduction had adverse effects on entrainment to a weak photic stimulus and the temporal structure of general circadian locomotor activity. An acute, systemic ethanol challenge and chronic ethanol intake dose-dependently attenuated light-induced phase-delays of behavioral circadian rhythms. In vivo microdialysis administration of ethanol (500 mM) in the SCN revealed that the SCN is a direct site of ethanol disruption to photic entrainment processes. An acute ethanol challenge at midday attenuated 8-OH-DPAT-induced phase-advances, while chronic ethanol intake and an intra-SCN microdialysis perfusion had no effect on this response. Disruption of behavioral circadian entrainment through long-term housing under constant light potentiated ethanol intake and preference. A nonfunctional homolog of the clock gene, PER2, in wild-type mice also elevated ethanol intake and preference, owing, in part, to an additional circadian phase of ethanol intake. Ethanol intake and preference associated with PER2 gene mutations were rescued to wild-type levels through a systemic administration of acamprosate or constant-release acamprosate microimplants in circadian and reward areas. Brain mapping with acamprosate microimplants also identified circadian (SCN, intergeniculate leaflet) and reward (ventral tegmental, accumbal, and penducular areas) sensitive to the (ethanol) suppressive effects of acamprosate, though the extent of suppression was significantly less in PER2-mutant vs. wild-type mice. These results suggest that the disruptive effects of acute (binging) and chronic ethanol abuse on circadian entrainment can facilitate a downward spiral of alcohol dependence and chronobiological disturbances. This research also demonstrates the need for enhanced behavioral and genetic screening and circadian treatment strategies for the treatment of alcoholism and prevention of relapse.
J. David Glass (Advisor)
Eric Mintz (Committee Member)
John Johnson (Committee Member)
R. Scott Olds (Committee Member)
John Updegraff (Committee Member)
236 p.

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Brager, A. (2011). Roles of the circadian and reward systems in alcoholism. (Electronic Thesis or Dissertation). Retrieved from https://etd.ohiolink.edu/

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Brager, Allison. "Roles of the circadian and reward systems in alcoholism." Electronic Thesis or Dissertation. Kent State University, 2011. OhioLINK Electronic Theses and Dissertations Center. 22 Feb 2017.

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Brager, Allison "Roles of the circadian and reward systems in alcoholism." Electronic Thesis or Dissertation. Kent State University, 2011. https://etd.ohiolink.edu/

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