Chronic alcohol abuse is associated with many physiological disturbances, resulting in numerous sleep disruptions, circadian desynchrony, and circadian clock gene dysregulation that may aggravate alcohol's negative effects and potentiate alcohol dependence. Circadian clock genes such as per2 are known to influence the development of alcohol abuse. Casein-kinase-1 epsilon and delta (CK1?/?), key post- translational players in the molecular circadian clock, regulates the availability of the clock protein PER2. CK1?/? have been implicated in sleep disorders as well as in drug abuse-related behaviors. I have recently shown that systemic administration of PF-670462, a CK1?/? inhibitor, prevents alcohol relapse-like drinking in chronic alcohol self-administering rats (Neuropsychopharmacology, 2012). The goal of the proposed research is to further test the beneficial effects of CK1?/? inhibition on alcohol abuse and comorbid sleep and circadian disturbances and provide insight into the neurobiological mechanisms involved. We will test whether the beneficial effect of CK1?/? inhibition observed on alcohol relapse can be replicated and affect other behaviors leading to alcohol dependence (e.g. alcohol binge-drinking). We hypothesize that (1) repeated alcohol binge-drinking episodes will affect the circadian period of locomotor activity and induce sleep disturbances, and (2) CK1?/? inhibition will decrease alcohol binge-drinking, restore the circadian period and ameliorate the disrupted effects on sleep. Based on our preliminary results, we further hypothesize that the protective effect of CK1?/? inhibition on alcohol consumption is mediated via the CK1? isoform;and that CK1? will affect alcohol binge drinking and subsequent circadian and sleep disturbances via the regulation of PER2 availability. In Year 1, we will test the hypothesis that CK1?/? inhibition will reduce alcohol binge drinking and normalize circadian function and sleep disruption in C57BL/6J mice. We will use a binge-drinking mouse protocol, called "drinking-in-the-dark" (DID), where multiple cycles of 4- days alcohol access followed by 2-bottle free choice alcohol access will occur over the course of weeks. We will additionally test if PF-670462 (1) dose-dependently reduces alcohol intake during binge drinking and subsequent free access to alcohol, (2) improves comorbid circadian dysfunction (e.g. free-running period and PER2 expression) and (3) ameliorates the expected sleep disturbances. In Year 2, we will use humanized hPER2S662G transgenic mutant mice to test whether a specific mutation of a CK1? active binding site (S662) on the PER2 protein predisposes for alcohol binge-drinking. Alcohol intake, circadian function and sleep-wakefulness will be assessed using our established protocol. These results will provide insight into the role of CK1?/? in alcohol abuse, circadian rhythms and sleep mechanisms. Evaluation of the role of CK1?/? in the binge drinking model will help determine the utility of CK1?/? as a pharmaceutical target for the treatment of alcoholism.

Public Health Relevance

Alcohol abuse has detrimental biomedical consequences and represents a heavy financial burden to society. Alcohol induces disturbances in sleep and biological rhythms that further increase the risks of developing comorbid diseases;but the interrelationship between alcohol abuse, sleep and biological rhythms are not fully understood yet. A novel therapeutic was recently shown to target an enzyme involved both in sleep regulation and biological rhythms, and appears to prevent alcohol-relapse in rats. The results of the proposed study will further characterize this promising compound's effects on alcohol abuse and potential comorbid sleep and circadian disturbances and will provide novel insight for advancing drug development in the treatment of alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA023078-01
Application #
8683876
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Grandison, Lindsey
Project Start
2014-08-05
Project End
2016-07-31
Budget Start
2014-08-05
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$267,626
Indirect Cost
$132,626
Name
Sri International
Department
Type
DUNS #
009232752
City
Menlo Park
State
CA
Country
United States
Zip Code
94025