Delving deeper into the machinery of cocaine addiction
October 20, 2005
Laptop Battery Researchers are now understanding in greater detail the
molecular machinery underlying the short-term brain changes that
produce the high of cocaine, as well as the longer-term changes
behind addiction. Their findings
offer hope for targeted drugs
that can short-circuit that addiction machinery.
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Thinkpad In the October 20, 2005, issue of Neuron, researchers led by
Eric J. Nestler and Arvind Kumar of The University of Texas
Southwestern Medical Center have pinpointed a key molecular
mechanism by which genes are switched on in the brain that govern
both short-term and long-term effects of cocaine. Such activation
is called transcriptional activation because it induces the gene to
begin making copies of itself into messenger RNA that trigger
protein production.
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Microsoft In their experiments, the researchers studied a process called
"chromatin remodeling"-in which the histone proteins enfolding
genes are chemically altered to render the genes active. They
administered to rats both short-term, acute cocaine doses and
long-term, chronic cocaine and analyzed the alteration of the
histones affecting specific genes involved in cocaine response in
the brain.
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Laptop Computers In their studies, they used an analytical technique called
"chromatin immunoprecipitation assays" to measure the effects of
cocaine on histone proteins. This technique, they emphasized, makes
it possible "to study such transcriptional mechanisms in the brain
in vivo and understand, with increasing complexity, how chronic
cocaine administration leads to the long-term regulation of its
target genes."
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Laptop Computer The researchers found that giving the rats acute doses of
cocaine induced histone modifications that activated a gene called
cFos, which is an important regulator of many other genes. However,
this gene was desensitized by chronic cocaine.
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Desktop Computer In contrast, they found, histone modifications activated two
other genes, BDNF and Cdk5, only during chronic cocaine
administration. Their findings, they wrote, "directly implicate
these mechanisms in cocaine-induced neural and behavioral
plasticity."
Notebooks The Cdk5 gene is particularly interesting, they wrote, because
it has been implicated in the long-term rewiring of brain circuitry
in the striatum, a brain region known to be important in cocaine's
behavioral effects.
Lenovo The researchers found that the histone modifications affecting
BDNF and Cdk5 persisted for long periods. The researchers commented
that "To our knowledge, these are the most long-lived examples of
drug-induced chromatin remodeling in brain published to
date."
Hard Drive They also wrote that "Such long-lived changes in chromatin
remodeling might be one of the crucial mechanisms for
cocaine-induced neuroadaptations in striatum, which mediate the
neural and behavioral plasticity that underlies cocaine
addiction."
Travelstar The researchers also performed behavioral studies on the rats,
to demonstrate the central role of histone modifications in
cocaine's effects. They found that, when given drugs that enhance
the histone modification, rats showed a greater reward response
from cocaine. In contrast, when histone modification was damped
using drugs, the animals showed decreased rewarding effects.
Gateway Of their findings, the researchers concluded that "Such
regulation provides a new layer of complexity, at the molecular
level, through which cocaine produces neural and behavioral
plasticity, and reveals mechanisms for the treatment of cocaine
addiction that involve interfering with this plasticity."
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