to alcohol affected by genes active in neurons
you blame your genes if you can't handle your liquor?
A new study conducted at Washington University School
of Medicine in St. Louis may pave the way to finding
out. Researchers found that the brain's response to
alcohol is partially under the influence of two genes.
The genes, studied in both adult and newborn mice, were
found to affect sensitivity to alcohol intoxication,
interest in alcohol consumption and risk of developmental
brain damage from alcohol.
that we understand that these genes are involved in
neural processes affected by alcohol, we think they
will be good candidates to look at in the human population,"
says Louis Muglia, M.D., Ph.D., associate professor
of pediatrics, of molecular biology and pharmacology
and of obstetrics and gynecology. "It will be interesting
to see if there are human variants of the genes associated
with either fetal alcohol syndrome or addictive behaviors
uncover the genes' effect, the research team — led by
Muglia, also a pediatric endocrinologist at St. Louis
Children's Hospital — inactivated the two genes in mice.
In newborn mice with the genetic inactivation, ethanol
(the alcohol used in beer, wine and spirits) caused
significantly more neurodegeneration than it did in
normal newborn mice. In adult mice with the genetic
inactivation, the sedative effect of ethanol lasted
up to twice as long. Further, when ethanol was freely
available, adult mice with the inactivation drank much
less ethanol than normal animals.
researchers report their findings in two articles appearing
in the March 2 and April 20 issues of the Journal of
Neuroscience. James W. Maas, predoctoral trainee, is
first author on both studies. The genes studied make
enzymes called adenylyl cyclases (AC), which support
neural function and contribute to learning and memory.
These enzymes are so essential that they exist in ten
similar forms, and some type of AC is found in every
cell of the body.
forms, AC1 and AC8, are found mainly in neurons. The
researchers eliminated AC1 and AC8 from the brains of
the mice by inactivating the genes that code for the
enzymes. "We wanted to test how the lack of AC1
and AC8 would influence ethanol-induced neurodegeneration
in the brains of newborn mice—as a model for what happens
in fetal alcohol syndrome in humans—and also how it
would affect adult mice that consumed ethanol,"
alcohol exposure is regarded as the leading cause of
mental and physical birth defects and is the most common
preventable cause of birth defects in the United States.
During the first week after birth, the brains of mice
are in a stage of development similar to that of human
fetuses during the last trimester of pregnancy. The
research team found that in the newborn mice, the lack
of AC1 and AC8 increased neuronal sensitivity to ethanol's
destructive effects. Newborn mice missing either of
the AC enzymes and given ethanol had much greater neuronal
damage, even at low ethanol doses, than normal mice.
you look at children who were exposed to alcohol during
gestation, you'll see that not all develop fetal alcohol
syndrome," Maas says. "We think the levels
of AC1 and AC8 enzymes may predispose a fetus to being
more or less sensitive to alcohol consumption by the
mother." Theorizing that the enzymes modulating
ethanol's effect during brain development might be the
same ones involved in ethanol actions later in life,
the researchers looked at the effects of the same genetic
inactivations in adult mice.
adult mice, ethanol does not damage neurons in the brain,
but it does have a marked sedative effect. The studies
showed that adult mice lacking AC1 slept 1.5 to 2 times
longer for a given ethanol dose than normal mice. The
researchers did not see that effect in mice lacking
AC8. Previous studies have shown that the more sensitive
an animal is to sedation by ethanol, the less ethanol
it seeks to drink. Mice lacking AC8, but not those lacking
AC1, displayed significantly lower preference for ethanol
and cut their voluntary ethanol consumption compared
to normal mice.
contrast, mice lacking the enzymes suffered the same
amount of ataxia, or loss of muscle coordination, after
ethanol consumption as normal mice. "Our results
confirm that ethanol affects various parts of the adult
brain via different mechanisms," Muglia says. "Ataxia
deficits are thought to be mediated primarily by the
cerebellum. Because ataxia after ethanol consumption
was the same in both altered and normal mice, AC1 and
AC8 probably are not critical to ethanol's effects in
the cerebellum. But, the effects on sedation and ethanol
preference suggest that each AC gene has a role in influencing
ethanol's effects in the cerebral cortex."
studies demonstrated that the response to ethanol is
very different in newborn compared to adult mice. "During
development, the brain makes more neurons than it needs
and weeds out unnecessary neurons by killing the inactive
ones. In adults, however, the brain wants to protect
all its neurons," Muglia says. "By blocking
neuronal receptors, ethanol exaggerates the normal destruction
of neurons in the developing brain, but it only temporarily
turns off neurons in the adult brain. AC1 and AC8 help
mediate these processes."
JW Jr, Vogt SK, Chan GCK, Pineda VV, Storm DR, Muglia
LJ. Calcium-stimulated adenylyl cyclases are critical
modulators of neuronal ethanol sensitivity. Journal
of Neuroscience, 2005 April 20;25(16):4118-4126.
JW Jr, Indacochea RA, Muglia LM, Tran TT, Vogt SK, West
T, Benz A, Shute AA, Holtzman DM, Mennerick S, Olney
JW, Muglia LJ. Calcium-stimulated adenylyl cyclases
modulate ethanol-induced neurodegeneration in the neonatal
brain. Journal of Neuroscience, 2005 March 2;25(9):2376-2185.
from the National Institutes of Health and the Washington
University Medical Scientist Training Program supported