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NIDA researchers have found that, when it comes to brain cells, "speed"
actually does kill. "Speed" is a street name for methamphetamine, a
powerfully addictive stimulant. Previous research had shown that
methamphetamine damages but does not kill certain nerve cells in brain
structures that control movement. The new research, conducted in mice,
indicates that methamphetamine-induced damage prompts other nerve cells in
brain regions involved in cognition as well as movement to self-destruct.
The new findings raise concerns that methamphetamine may have
significantly more harmful long-term consequences than previously thought,
the researchers say.
| Neurotoxic Effects of
Methamphetamine |
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Previous research showed that methamphetamine damages the nerve endings
of brain cells containing dopamine, a chemical messenger that plays a role
in movement and pleasure. Animal studies indicate that a gradual, partial
recovery occurs in the dopamine system when methamphetamine exposure is
stopped. For example, a recent imaging and postmortem study of the brains
of monkeys found substantial recovery in dopamine function over an
18-month period following the animals' last e xposure to the drug.
However, human brain imaging studies suggest that significant damage to
nerve endings of dopamine-containing cells persists in the brains of
chronic methamphetamine abusers for at least 3 years after they have
stopped using the drug. The damage, which affects dopamine nerve endings
located in the brain structures that make up the striatum, is similar to
but less extensive than that caused by Parkinson's disease.
| Human Brain Areas Corresponding to
the Mouse Brain Areas Damaged by Methamphetamine |
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Methamphetamine-induced damage to nerve terminals of dopamine-producing
cells occurs primarily in a brain region called the striatum.
Methamphetamine-induced apoptosis killed off different types of
nerve cells in the frontal cortex, the hippocampus, and the striatum
in mice.
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"People used to think that the most serious methamphetamine-induced
damage was to dopamine nerve terminals because it put people at risk for
developing Parkinson's disease as they got older," says Dr. Jean Lud
Cadet, clinical director of NIDA's Intramural Research Program (IRP).
"We've now shown in our lab that methamphetamine is much more toxic than
previously thought. It does not just destroy the endings of
dopamine-containing nerve cells, it also kills other nerve cells that
produce other neurotransmitters in additional brain pathways," he
says.
IRP researchers led by Dr. Cadet first linked this widespread loss of
brain cells to a natural mechanism called apoptosis, through which the
body programs unhealthy cells to kill themselves. In a study in cell
cultures, they showed that treating rat brain cells with methamphetamine
caused cell death marked by apoptotic patterns, such as DNA fragmentation
and disintegration of cell bodies. Subsequent studies in genetically
engineered mice that lacked specific genes known to promote or suppress
programmed cell death suggested that at least part of the nerve damage
caused by methamphetamine may result from activation of the molecular
machinery that is involved in apoptosis. The strongest evidence that
methamphetamine unleashes widespread apoptosis in animals came in a recent
study that showed the drug caused DNA fragmentation and loss of nerve cell
bodies in the striatum, the hippocampus, and the frontal cortex of mice
brains.
"Although these findings are in mice, if methamphetamine kills nerve
cells in the same brain regions of humans who abuse the drug, the
functional consequences could be significant," Dr. Cadet says. Loss of
cells in the hippocampus and cortex could damage memory, cognitive
function, and decision-making capacity, he says. Loss of striatal cells
could lead to serious movement disorders that resemble tardive dyskinesia
and Huntington's chorea.
Recent brain imaging studies in former methamphetamine abusers
conducted by Dr. Richard Ernst and Dr. Linda Chang at the Harbor-UCLA
Medical Center in Torrance, California, provide additional support for the
finding that methamphetamine abuse causes brain cell death, says Dr.
Cadet. The California researchers found alterations in brain chemistry in
long-term methamphetamine abusers indicative of nerve cell loss or damage
similar to that found in people suffering from strokes or Alzheimer's
disease (see "Brain
Imaging Studies Show Long-Term Damage From Methamphetamine
Abuse").
If methamphetamine kills brain cells in humans, it may cause cognitive
impairments that will have to be addressed when treating methamphetamine
abusers, Dr. Cadet says. Although impaired people can do well in
treatment, it is possible that developing medications to repair the brain
could help such patients to do even better, he says. (See "NIDA
Pursues Many Approaches to Reversing Methamphetamine's Neurotoxic
Effects")
Sources
Cadet, J.L.; Ordonez, S.V.; and Ordonez, J.V. Methamphetamine induces
apoptosis in immortalized neural cells: Protection by the proto-oncogene,
bcl-2. Synapse 25:176-184, 1997.
Deng, X; Ladenheim,B.; Tsao, L.I.; and Cadet, J.L. Null mutation of
c-fos exacerbation of methamphetamine-induced neurotoxicity. Journal of
Neuroscience 19(22):10107-10115, 1999.
Melega, W.P. Recovery from methamphetamine induced long-term
nigrostriatal dopaminergic deficits without substantia nigra cell loss,
Brain Research, in press.
McCann, U.D.; Wong, D.F.; Yokoi, F.; Villemagne, V.; Dannals, R.F.; and
Ricaurte, G.A. Reduced striatal dopamine transporter density in abstinent
methamphetamine and methcathinone users: Evidence from positron emission
tomography studies with [11C]WIN-35,428. Journal of Neuroscience
18(20):8417-8422, 1998.
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