Alcohol's legendary sedative effects may be caused by a brain steroid derived from progesterone that damps down anxiety. This could help explain why alcohol makes people feel so relaxed, and why men and women react to alcohol differently.

It only takes a few drinking sessions for revellers to get acquainted with alcohol's effects. Scientists, though, have had a harder time figuring out exactly how the drug works on the brain. Alcohol appears to interact with two brain receptors, one of which, the GABA receptor, is exploited by tranquilizers such as Valium. But it is not clear exactly how alcohol interacts with this receptor.

Animal studies show that stress increases levels of the brain steroid allopregnanolone, which acts on the GABA receptor to reduce anxiety. Because alcohol triggers the release of stress hormones like corticosterone, and progesterone, from which allopregnanolone is derived, Morrow's team suspected that drinking might also increase levels of the steroid.

To find out, the researchers gave rats moderate doses of ethanol roughly equivalent to the amount of alcohol someone might consume at a cocktail party. When they removed each animal's cerebral cortex after 20 minutes, the rats given alcohol showed dramatic rises in allopregnanolone levels compared to rats given saline.

Was the steroid responsible for alcohol's sedative effect? Investigators then treated rats with a drug called finasteride, which blocks the formation of allopregnanolone from progesterone, before giving them another drink. Alcohol usually lowers electrical activity in a number of areas in the brain, but finasteride prevented this, indicating that allopregnanolone does play a role in the relaxing effects of alcohol.

The investigators believe that allopregnanolone is very important for the anticonvulsant and sedative effects of alcohol. Perhaps women need to drink less to get the rewarding effects of alcohol because they naturally have higher levels of the steroid. That could explain why women are less likely to become alcoholics than men. Investigators have previously shown that female rats drink more ethanol during the phase in their reproductive cycle when progesterone levels are low.

The Journal of Neuroscience March 2000 (vol 20, p 1982)