Mount Sinai Study Identifies Genetic Changes in the Brain That Occur with Chronic Cocaine Use
Mount Sinai researchers reveal the significant effect that repeated exposure to cocaine has on the brain — specifically on a protein identified as G9a, which regulates gene expression in cells.
Mount Sinai researchers have identified that chronic cocaine exposure significantly reduced the expression of a protein known as G9a, which functions to modify chromatin through an event referred to as histone methylation in order to maintain basic patterns of gene expression in cells. These new findings, titled Essential Role of the Histone Methyltransferase G9a in Cocaine-Induced Plasticity, will appear in Science on January 8, 2010.
The protein G9a functions within the normal nervous system to block the ability of environmental perturbations to aberrantly induce gene expression in the brain’s reward circuitry. Following chronic cocaine, G9a activity is reduced, leading to the activation of many genes that contribute to enhanced behavioral sensitivity and heightened synaptic connectivity between neurons, thus strengthening associations between the drug experience and the neural reward circuitry leading to addiction.
"Identifying how drugs of abuse alter the molecular biology of the brain to promote addiction-related behavioral syndromes is key to the development of future treatments," said Eric Nestler, M.D. Ph.D., Professor and Chair of the Department of Neuroscience and Director of the Brain Institute at Mount Sinai School of Medicine. "Chronic exposure to the highly addictive substance cocaine has previously been shown to result in long lasting alterations in the ways in which our genes are expressed in the brain, particularly in brain reward regions, which play a crucial role in regulating responses to natural rewards such as food, sex, and social interactions. These regions are corrupted by drugs of abuse to cause addiction."
Drug addiction is a very serious psychiatric illness, for which there are currently no definitive treatments or cures. Chronic drug use results in persistent behavioral syndromes characterized by compulsive behaviors, negative withdrawal symptoms and a life long susceptibility to relapse.
Chronic cocaine administration dramatically alters gene expression in the nucleus accumbens, a key component of the brain’s reward circuitry, in part, through regulation of chromatin modifications at specific genes. G9a repression following chronic cocaine administration leads to increased expression of many genes known to serve aberrant functions in response to drugs of abuse.
"We identified that G9a repression following chronic cocaine exposure was mediated by the drug-induced transcription factor DFosB [pronounced delta-Fos-B], which has previously been shown by the Nestler laboratory to promote addictive-like behavioral syndromes in response to cocaine," said Ian Maze, a Ph.D. student in the Department of Neuroscience and lead author of the study.
"Using genetically engineered viruses, we were able to over express G9a in the nucleus accumbens," said Maze. "We demonstrated that increasing G9a activity in this brain region, thus opposing the effects of chronic cocaine exposure, blocked cocaine reward. On the other hand, using viruses to genetically knockout G9a expression in this brain region, thus mimicking the effects of chronic cocaine exposure, enhanced cocaine reward. These data suggest that G9a functions to block cocaine reward by repressing aberrant gene expression in response to chronic cocaine administration."
One hallmark of chronic cocaine exposure is enhanced synaptic connectivity between nucleus accumbens neurons and other neurons projecting into this brain region. Such enhanced connectivity is heavily correlated with increased behavioral sensitivity to cocaine.
"We discovered that G9a acts to block sensitivity to cocaine by repressing the expression of genes necessary for enhanced synaptic connectivity following chronic cocaine exposure, an effect mediated by DFosB, which is itself necessary for cocaine-induced neuronal plasticity," said Dr Nestler.
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