CLOCK GENES AND SLEEP HOMEOSTASIS: NOVEL TREATMENT TARGETS IN ALCOHOL USE DISORDERS

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Perreau-Lenz, SP1
1SRI International, Center for Neuroscience, Biosciences Division, Menlo Park, USA
Chronic alcohol use and abuse is associated with sleep disturbances and circadian desynchrony. Disruption of sleep and circadian rhythms may in turn exacerbate the detrimental effects of alcohol and promote development of alcohol dependence. Circadian clock genes have been shown to be key players in various aspects of alcohol abuse, from sensitivity to consumption, from abuse to relapse. Targeting sleep pattern and circadian clock-regulating molecules may thus represent novel therapeutic approaches. The clock gene Per2 has shown to be of particular interest, as it has been shown (1) to modulate central alcohol sensitivity, (2) to prevent excessive alcohol intake, and (3) is associated with stress-induced alcohol use disorders. In addition, molecules targeting the clock machinery, and PER2 in particular using compounds such as casein kinase 1 (CK1) inhibitors, can influence alcohol relapse. Hence inhibiting CK1 activity, enzyme modulating PER2 cell availability, is able to prevent alcohol relapse-like drinking in alcoholic dependent rats. We further investigated the implication of the clock gene PER2 in alcohol binge drinking, highly relevant to the onset of alcohol abuse development.
To that hand, we used a novel model of alcohol binge drinking as well as the efficacy of casein kinase 1 inhibition on alcohol binge drinking and alcohol-induced sleep disturbances. We developed a novel longitudinal murine model of chronic alcohol binge drinking while simultaneously characterizing associated sleep disruptions. We showed that chronic alcohol binge drinking (1) enhances intermittent free-choice consumption, (2) incrementally fragments sleep distribution during binging with a significant decrease of REM/NREM ratio, revealing dynamic impact on sleep/wake during chronic heavy alcohol exposure. We further revealed that casein kinase 1e/d inhibition (PF-0670462) decreases alcohol intake during binging specifically without affecting two-bottle choice intake. We also characterized the daily alcohol drinking behavior and associated sleep patterns of a murine model of the human Familial Advanced Sleep Phase Syndrome (FASPS), the hPER2S662G transgenic mutants. Acknowledgements: Study funded funded by the NIAAA (Grant 1R21 AA0023078-01) and supported by a NARSAD Young Investigator Grant Award 2014 (Grant 22646) from the Brain and Behavior Research Foundation, and compounds were provided under a CTA with Pfizer.

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