When exposed to large amounts of alcohol, neurons in the hippocampus produce steroids (shown in bright green, at left), which inhibit the formation of memory. Pictured at right, neurons in the same region of the brain that have not been exposed to alcohol. Image: Kazuhiro Tokuda |
A person who drinks too much alcohol may be able to perform complicated
tasks, such as dancing, carrying on a conversation, or even driving a car, but
later have no memory of those escapades. These periods of amnesia, commonly
known as “blackouts,” can last from a few minutes to several hours.
Now, at Washington University School of Medicine in St. Louis, neuroscientists have identified
the brain cells involved in blackouts and the molecular mechanism that appears
to underlie them. They report, in The Journal of Neuroscience, that
exposure to large amounts of alcohol does not necessarily kill brain cells as
once was thought. Rather, alcohol interferes with key receptors in the brain,
which in turn manufacture steroids that inhibit long-term potentiation (LTP), a
process that strengthens the connections between neurons and is crucial to
learning and memory.
Better understanding of what occurs when memory formation is inhibited by
alcohol exposure could lead to strategies to improve memory.
“The mechanism involves NMDA receptors that transmit glutamate, which
carries signals between neurons,” says Yukitoshi Izumi, MD, PhD, research
professor of psychiatry at Washington University School of Medicine in St. Louis. “An NMDA
receptor is like a double-edged sword because too much activity and too little
can be toxic. We’ve found that exposure to alcohol inhibits some receptors and
later activates others, causing neurons to manufacture steroids that inhibit
LTP and memory formation.”
Izumi says the various receptors involved in the cascade interfere with
synaptic plasticity in the brain’s hippocampus, which is known to be important
in cognitive function. Just as plastic bends and can be molded into different
shapes, synaptic plasticity is a term scientists use to describe the changeable
properties of synapses, the sites where nerve cells connect and communicate.
LTP is the synaptic mechanism that underlies memory formation.
The brain cells affected by alcohol are found in the hippocampus and other
brain structures involved in advanced cognitive functions. Izumi and first
author Kazuhiro Tokuda, MD, research instructor of psychiatry, studied slices
of the hippocampus from the rat brain.
When they treated hippocampal cells with moderate amounts of alcohol, LTP
was unaffected, but exposing the cells to large amounts of alcohol inhibited
the memory formation mechanism.
“It takes a lot of alcohol to block LTP and memory,” says senior
investigator Charles F. Zorumski, MD, the Samuel B. Guze Professor and head of
the department of psychiatry. “But the mechanism isn’t straightforward. The
alcohol triggers these receptors to behave in seemingly contradictory ways, and
that’s what actually blocks the neural signals that create memories. It also
may explain why individuals who get highly intoxicated don’t remember what they
did the night before.”
But not all NMDA receptors are blocked by alcohol. Instead, their activity
is cut roughly in half.
“The exposure to alcohol blocks some NMDA receptors and activates others,
which then trigger the neuron to manufacture these steroids,” Zorumski says.
The scientists point out that alcohol isn’t causing blackouts by killing
neurons. Instead, the steroids interfere with synaptic plasticity to impair LTP
and memory formation.
“Alcohol isn’t damaging the cells in any way that we can detect,” Zorumski
says. “As a matter of fact, even at the high levels we used here, we don’t see
any changes in how the brain cells communicate. You still process information.
You’re not anesthetized. You haven’t passed out. But you’re not forming new
memories.”
Stress on the hippocampal cells also can block memory formation. So can
consumption of other drugs. When combined, alcohol and certain other drugs are
much more likely to cause blackouts than either substance alone.
The researchers found that if they could block the manufacture of steroids
by neurons, they also could preserve LTP in the rat hippocampus. And they did
that with drugs called 5-alpha-reductase inhibitors. These include finasteride
and dutasteride, which are commonly prescribed to reduce a man’s enlarged
prostate gland. In the brain, however, those substances seem to preserve
memory.
“We would expect there may be some differences in the effects of alcohol on
patients taking these drugs,” Izumi says. “Perhaps men taking the drugs would
be less likely to experience intoxication blackouts.”
The researchers plan to study 5-alpha-reductase inhibitors to see how easily
they get into the brain and to determine whether those drugs, or similar
substances, might someday play a role in preserving memory.
