These receptors are among the most sensitive signaling proteins to alcohol. Thus, GABA A receptors are important sites of alcohol's actions on the brain. A variety of data indicates that there are different subtypes of GABA A receptors in different brain areas and that this translates to differential brain region responses to alcohol. Differential development of tolerance to the various actions of alcohol has been known for some time. These studies clearly identify one of the more important molecular mechanisms of tolerance and dependence upon alcohol.
Alcoholics have unique and different responses to alcohol.
Low responses to alcohol may be related to genetic differences in GABA A receptor subunits expressed in individuals at risk for alcoholism. Nora Volkow's group at Brookhaven National Laboratory has shown that alcoholics, and individuals with a family history of alcoholism, have reduced brain metabolic responses to lorazepam, a drug that selectively acts on GABA A receptors. David Goldman, of the National Institute on Alcohol Abuse and Alcoholism, has found markers on human chromosome 4 that include a cluster of GABA A subunit genes in families with a history of alcoholism. This region of the chromosome encodes a variant of the GABA A receptor alpha6 subunit that is particularly common in the cerebellum, an area of the brain involved in movement and posture. Morrow has shown that alpha6 subunit expression is altered during the development of tolerance.