Blockade of alcohol excessive and "relapse" drinking in male mice by pharmacological cryptochrome (CRY) activation
Related Experiment Video
Updated: Nov 22, 2025
Murine Drinking Models in the Development of Pharmacotherapies for Alcoholism: Drinking in the Dark and Two-bottle Choice
Published on: January 7, 2019
1Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, 10065, USA. zhouya@rockefeller.edu.
Rationale:
Metabolic dysfunction, mood disorders, anxiety disorders, and substance abuse disorders are associated with disruptions in circadian rhythm and circadian clock gene machinery. While the effects of alcohol on several core components of the clock genes have been described in rodent models, pharmacological activation or inhibition of clock gene functions has not been studied on alcohol drinking behaviors.
Objectives:
We investigated whether cryptochrome (CRY1/2) activator KL001 altered alcohol intake in mice in excessive and relapse-like alcohol drinking models.
Methods:
Mice, subjected to 3 weeks of chronic intermittent alcohol drinking (IAD) (two-bottle choice, 24-h access every other day) developed excessive alcohol intake and high preference. We evaluated the pharmacological effects of KL001 after either 1-day acute withdrawal from IAD or 1-week chronic withdrawal using the alcohol deprivation effect (ADE) model.
Results:
Single pretreatment with KL001 at 1-4 mg kg-1 reduced alcohol intake and preference after acute withdrawal in a dose-related manner. The effect of KL001 on reducing excessive alcohol consumption seems alcohol specific, as the compound does not alter sucrose (caloric reinforcer) or saccharin (noncaloric reinforcer) consumption in mice. Both single- and multiple-dosing regimens with an effective dose of KL001 (4 mg kg-1) prevented the ADE after chronic withdrawal, with no tolerance development after the multi-dosing regimen.
Conclusions:
Pretreatment with KL001 (a CRY1/2 activator) reduces excessive and "relapse" alcohol drinking in mice. Our in vivo results with a CRY activator suggest a possible novel target for alcohol treatment intervention.
Insights
Activating cryptochrome (CRY1/2) with KL001 reduced excessive alcohol intake and prevented relapse-like drinking in mice. This suggests CRY activators as a potential new target for alcohol use disorder treatments.
Area of Science:
- Neuroscience
- Pharmacology
- Chronobiology
Background:
- Disruptions in circadian rhythm and clock genes are linked to metabolic, mood, anxiety, and substance use disorders.
- While alcohol's effects on clock genes are known in rodents, targeting clock gene function for alcohol drinking behaviors is unexplored.
- Cryptochromes (CRY1/2) are key circadian clock components implicated in various physiological processes.
Purpose of the Study:
- To investigate the effects of a cryptochrome (CRY1/2) activator, KL001, on alcohol intake in mouse models of excessive and relapse-like drinking.
- To determine if pharmacological modulation of CRY1/2 influences alcohol consumption patterns.
Main Methods:
- Mice underwent chronic intermittent alcohol drinking (IAD) for 3 weeks, establishing excessive intake and preference.
- The effects of KL001 were assessed after acute (1-day) and chronic (1-week) alcohol withdrawal using the alcohol deprivation effect (ADE) model.
- KL001 was administered at doses of 1-4 mg/kg prior to withdrawal assessments.
Main Results:
- KL001 administration significantly reduced alcohol intake and preference in a dose-dependent manner after acute withdrawal.
- The observed reduction in alcohol consumption was specific to alcohol, as KL001 did not affect intake of sucrose or saccharin.
- Both single and multiple doses of KL001 prevented the alcohol deprivation effect after chronic withdrawal, indicating no tolerance development.
Conclusions:
- Pharmacological activation of CRY1/2 with KL001 effectively reduces excessive and relapse-like alcohol drinking in mice.
- These findings highlight CRY activators as a potential novel therapeutic target for alcohol use disorder.
- In vivo evidence supports targeting the circadian clock machinery for alcohol addiction interventions.
