Researchers have identified a causal link between binge drinking and circadian clock genes in a brain region previously implicated in hazardous alcohol use. Binge drinking is a common and harmful pattern of alcohol use, responsible for more than half of alcohol-related deaths. There is already robust evidence that genes involved in controlling circadian rhythm — the body’s natural processes that follow a 24 hour light/dark cycle — are associated with hazardous drinking and alcohol abuse. However, it is not known which areas of the brain mediate the clock genes’ effects on drinking. A brain region known as the nucleus accumbens shell (NAcSh) is already noted for its role in risky drinking; the region forms part of the brain’s ‘reward system’, reinforcing the use of alcohol and other addictive substances by release of dopamine. In the new study, reported in Alcoholism: Clinical and Experimental Research, scientists investigated whether clock genes in the NAcSh are involved in regulating binge drinking.
Experiments were performed in laboratory-bred mice according to strict animal welfare guidelines. Mice were exposed to alcohol in an established procedure that mimics human binge drinking and provides a valuable tool for studying its underlying neurobiology. The method involves daily access to alcohol for a limited duration during the dark (active) circadian phase, when mice will voluntarily consume a large quantity of alcohol. First, mice were provided with 20% alcohol or sucrose solution (as a control) for a 2-hour period over 3 consecutive days, with access to water at all other times. On day 4, the alcohol/sucrose exposure was continued for 4 hours, after which the mouse brains were examined for clock gene activity in the NAcSh and in a brain region concerned with regulating circadian rhythms (known as the suprachiasmatic nucleus; SCN). A second group of mice were exposed to alcohol or sucrose, or water, in the same way. However, on day 4, they were treated with small pieces of DNA specifically designed to block the activity of three major clock genes; these DNA sequences, or non-specific sequences as a control, were carefully infused into the NAcSh region of the mice brains one hour before onset of alcohol exposure. Fluid consumption was then measured for 4 hours.
The researchers found that following exposure on day 4, clock gene activity in the NAcSh (but not in the SCN) was greater in mice that had binged on alcohol than in those exposed to sucrose. Further, knocking out clock gene activity in the NAcSh resulted in significantly less alcohol consumption on day 4, compared to that consumed after infusion of control sequences. Of note, knocking out clock gene activity did not reduce fluid intake in mice exposed to sucrose or water.
It is increasingly evident that alcohol consumption in both humans and laboratory rodents may be regulated by clock genes. The current finding, that binge drinking was significantly reduced by knock-down of clock gene activity in the NAcSh, suggests that there is a causal relationship between circadian genes in the NAcSh and binge drinking in laboratory mice. Circadian clock genes in the NAcSh may also play a crucial role in binge drinking in humans.
Antisense-induced downregulation of clock genes in the shell region of the nucleus accumbens reduces binge drinking in mice
R. Sharma, H. Puckett, M. Kemerling, M. Parikh, P. Sahota, M. Thakkar (pages xxx).
ACER-20-4687.R2
