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.
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.
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.
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."
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.
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."
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.
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."
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."
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.
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."
The researchers include Arvind Kumar, Kwang-Ho Choi, William Renthal, Nadia M. Tsankova, David E. H. Theobald, Hoang-Trang Truong, Scott J. Russo, Quincey LaPlant, Teresa S. Sasaki, Kimberly N. Whistler, David W. Self, and Eric J. Nestler of The University of Texas Southwestern Medical Center; and Rachael L. Neve of Harvard Medical School and McLean Hospital. This work was supported by grants from the NIDA and NIMH.
Kumar et al.: "Chromatin Remodeling is a Key Mechanism Underlying Cocaine-Induced Plasticity in Striatum." Publishing in Neuron, Vol. 48, 303-314, October 20, 2005, DOI 10.1016/j.neuron.2005.09.023, www.neuron.org
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