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Fraser Trevor Fraser Trevor Author
Title: Cocaine affects the expression of numerous genes
Author: Fraser Trevor
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Genes determine the shape and function of every cell. Every individual is born with a unique combination of roughly 30,000 genes. Every c...
Genes determine the shape and function of every cell. Every individual is born with a unique combination of roughly 30,000 genes. Every cell in the body contains all 30,000. One cell differs from another—a liver cell looks and acts differently from a brain cell, for example—because, in each, certain genes are turned on, while others are turned off.
The popular notion that our genes never change is incorrect. It is true that the fundamental pattern of gene activation that gives each of our cells its essential properties is fixed once and for all during development. For example, once a cell develops into a liver cell, it remains a liver cell for life and cannot be converted into a brain cell. However, every cell retains the capacity to change the level of activity (expression) of a portion of its genes in response to the demands we place upon it. An example is weightlifting: Muscle cells respond to repeated exercise by increasing the expression of certain genes, leading to growth and strengthening of the individual cells and, collectively, of the entire muscle. So it is with brain cells: As we use them, they respond with changes in gene expression that, overall, increase their capacity to meet the demands we make upon them. For example, our brains register and store memories by altering gene expression in cells in the hippocampus and amygdala.
Cocaine affects the expression of numerous genes within the NAc, including some that influence the important neurotransmitter chemical glutamate and the brain’s natural opioid-like compounds produced by the body (Kalivas and McFarland, 2003; Nestler, 2001). In the author’s University of Texas laboratory, investigators have been studying cocaine’s effect on one particular genetic component, a protein called ΔFosB.

ΔFosB

Like dopamine, ΔFosB is a pace-setting chemical. However, instead of leaving the cell that produces it and stimulating neighboring cells as dopamine does, ΔFosB remains in its original cell and stimulates certain genes. Chemicals that act this way are called genetic transcription factors. While cocaine affects several transcription factors, its effects on ΔFosB are the most long-lasting.
ΔFosB is naturally present in small quantities in the cells of the NAc, but chronic cocaine exposure causes it to accumulate to high levels (Nestler, Barrot, and Self, 2001). Researchers believe ΔFosB may constitute an important molecular “switch” in the transition from drug abuse to addiction, mainly for three reasons:
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FROM THE RUSH TO THE ADDICTION, COCAINE'S EFFECTS IN THE BRAIN
(Brain inset) Cocaine causes euphoria in the short term and addiction in the long term via its effects on the brain’s limbic system, which consists of numerous regions, including the ventral tegmental area (VTA) and nucleus accumbens (NAc), centers for pleasure and feelings of reward; the amygdala and hippocampus, centers for memory; and the frontal cortex, a center for weighing options and restraint.
(Main panel) Cocaine causes the neurotransmitter dopamine to build up at the interface between VTA cells and NAc cells, triggering pleasurable feelings and NAc cellular activities that sensitize the brain to future exposures to the drug. Among the activities are increased production of genetic transcription factors, including ΔFosB; altered gene activity; altered production of potentially many proteins; and sprouting of new dendrites and dendritic spines.
(Graph inset) The time courses of cocaine-induced buildup of ΔFosB and cocaine-related structural changes (dendrite sprouting) suggest that these neurobiological effects may underlie some of the drug’s short-term, medium-term, and long-term behavioral effects.
  • Once created, a molecule of ΔFosB lasts for 6 to 8 weeks before breaking apart chemically (Nestler, Barrot, and Self, 2001). Therefore, each new episode of cocaine abuse exacerbates the buildup of ΔFosB that has accumulated from all previous episodes during roughly 2 months. If someone is abusing cocaine daily, the levels of ΔFosB will be extremely elevated all the time.
  • Mice with elevated ΔFosB exhibit a set of behaviors that correspond to human addictive behaviors, while mice with normal levels do not. Conversely, blocking the buildup of ΔFosB in mice during a regimen of cocaine exposure reduces these behaviors.
  • ΔFosB plays a role in the genetic machinery that determines very basic properties of a cell, including very long-term or permanent ones such as its structure and interface with other cells.
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