Dissection of the inebriated brain.

The brain is the seat of alcohol's euphoric, intoxicating influence, as well as many of its long-term toxic consequences. But the mechanisms underlying alcohol's effects have been elusive, and no overall brain change has been observed that can explain all the striking effects of low doses of alcohol.

Recently developed methods are allowing scientists to examine alcohol's effects on individual groups of cells in the brains of laboratory animals. These effects are "highly specific to certain nerve pathways," reported Floyd E. Bloom of Scripps Clinic and Research Foundation in La Jolla, Calif., at the AAAS meeting. They comprise the first elements in what scientists expect eventually to add up to a biochemical scenario of intoxication.

The brain area that coordinates nerve cell activity to produce fine motor control, balance and muscle tone is currently spot-lighted in such research. This area, the cerebellum, uses "Purkinje" cells with complex, branched structures to gather information from incoming cells and carry output to the rest of the brain.

In one line of research, these cells were examined in mice that had been inbred at the University of Colorado in Boulder about 25 mouse generations to be extremely sensitive or extremely insensitive to alcohol. The Purkinje cells react differently to alcohol in the sensitive and insensitive mice. In the most sensitive mice, alcohol depresses the activity of the Purkinje cells more markedly and for a longer period than in the least sensitive mice. This differential activity is not seen with depressant drugs other than alcohols, and it is not seen in the hippocampus, the other brain area examined.

Alcohol sensitivity is a property of the cerebellar tissue, says Barry Hoffer of the University of Colorado Alcohol Research Center in Denver. In recent research he has transplanted pieces of cerebellum into the eyes of mice of the donor strain and those of different strains. The alcohol sensitivity of the Purkinje cells always reflects the donor, rather than the recipient, strain. Therefore, the cell itself, rather than its input, determines at least in part the response to alcohol.

But Bloom and his colleagues report that some of the cells that carry signals into the cerebellum also play a role in alcohol's effects. The Scripps group finds that in normal rats an intoxicating dose of alcohol increases the activity of one major source of input to Purkinje cells, the nerve processes called climbing fibers. This is a particularly important input, explains Bloom's co-worker Steven Henrisken, because it preempts the Purkinje cell, interrupting the cell's other activities. Thus, in the presence of alcohol, the climbing fiber activity overwhelms the cerebellum's normal output.

The climbing fibers arise from cells in the area of the brain stem called the inferior olive complex. This area gathers information from other areas of the brain to send on to the cerebellum. Bloom speculates that ethanol may activate the cells of the inferior olive by reacting chemically with a normal neurotransmitter to create an unnatural, stimulatory compound.

A laboratory study of long-term exposure to ethanol has revealed another specific site of alcohol's action, Bloom reports. He and his colleagues acclimatized rats to alcohol vapors that produce a blood alcohol level associated with intoxication. They used this procedure to avoid a frustrating problem of animal research on alcoholism: Animals generally refuse to drink a solution containing alcohol unless it is the only liquid available and they are quite dehydrated; thus the animals are generally in poor health. In contrast, animals exposed to alcohol vapor remain healthy and continue to gain weight, Bloom says. And they become tolerant to the alcohol, so that after three weeks of exposure, cells of the inferior olive no longer show increased activity. But all is not normal. If the flow of alcohol vapor is interrupted, there is a "profound shift" in activity. Bloom has traced this postwithdrawal change to another set of brain cells, the locus ceruleus.

The locus ceruleus offers a tempting explanation of the clumsiness of an intoxicated person. This brain stem area, which sends processes to the cerebellum as well as to other brain regions, normally shows a response with a fixed latency to novel events in an animal's environment. But in the presence of alcohol, the latency becomes variable. Thus, the nerve cell signal loses its time relationship with the triggering event. This discrepancy may make the difference between catching or missing a dropped plate, for example, bloom speculates. "This may be the start of a biochemical description of the alcohol effect."