deltafosb.html

As scientists continue to decode the human genome and proteome, they have realized that almost everything about human beings from behavior to appearance is determined at least in part by genetic code. In September of 1999, researchers uncovered that repeated use of cocaine led to the production of a new gene, D-FosB, which remains in the brain after cocaine use has ceased. Recognizing the presence of this gene is the first step towards treating addiction for all sorts of drug users. D -FosB is also produced in the brain when substances including heroin, PCP, nicotine, and alcohol are used repeatedly.

In theory, if geneticists can isolate this gene and eventually find a way to render it inactive in drug addicts, they will be able to increase the likelihood of these people remaining clean from drugs. Many people who try and give up addictive substances find it almost impossible, partially because of the action of this gene. Although this does not provide a solution to drug use in general, it potentially provides people with greater control over their decisions.

According to ABC News, through a Reuters wire, in their article 'Key to Addiction ', "U.S. scientists have come a little closer to understanding cocaine addiction, throwing a lifeline to addicts who fear that even if they do kick the habit a relapse is inevitable"(Reuters 1999) Researchers at Yale University of Medicine found that cocaine addicts accumulate a large enough amount of D-FosB, making it a biological factor in addiction. According to Eric Nestler, professor of psychiatry and neurobiology at Yale, "There has been the sense that there is perhaps some kind of switching of the brain. We think D-FosB may be one part of the switch"(Reuters 1999). Using genetically engineered mice, the Yale team found the responsiveness to cocaine rose significantly when the D-FosB gene was turned on in addiction-forming regions of the brain. When D-FosB accumulates in this particular nerve cell type, sensitivity to cocaine is substantially increased. Habitual cocaine users have high levels of buildup in one area of their brain.

The article stresses the importance of the discovery in providing drug addicts with a possible release from the strangle-hold drugs have on their lives. The gene effectively makes drugs feel even better to addicts. The more the chemical builds up in their brain, the more they experience the positive effects of the drug. Furthermore, "Understanding the role of D-FosB in turning a casual user of cocaine into a chronic addict is a step on the way to understanding the biological processes of addiction" (Reuters, 1999). Eventually, by understanding this interaction, it may be possible to stop the neurobiological changes accompanying drug addiction.

"Expression of the transcription foactor D -FosB in the brain controls sensitivity to cocaine."

According to Dr. Kelz et al., random exposure to cocaine "transiently induces several Fos family transcription factors in the nucleus accumbens (NAc), a region of the brain that is important for addiction. In contrast, chronic exposure to cocaine does not induce these proteins, but instead causes the persistent expression of highly stable isoforms of D-FosB" (Kelz et al., 1999). This accumulation of D-FosB suggests that it may influence the neural and behavioral "plasticity that accompanies chronic drug exposure" (Kelz et al, 1999). Using transgenic mice, the doctors were able to show that D-FosB expression heightens the rewarding and locomotor-activing effects of cocaine. The doctors found that D-FosB enhances sensitivity to cocaine by altering gene expression, in turn contributing to cocaine addiction (Kelz et al., 1999).

Through experimentation, the Yale group found that D-FosB expression greatly increased locomoter responses of mice given cocaine up to 50% above the levels caused by initial exposure. The doctors went on to show that the rewarding properties of cocaine also were increased with the gene's presence. By using place-conditioning, where a particular environment is associated with repeated cocaine exposure, doctors found that D-FosB produced a "marked enhancement in sensitivity to the rewarding properties of cocaine, with maximal place conditioning observed at the lowest dose of cocaine used" (Kelz et al., 1999).

Figure 1 FosB expression in NAc of bitransgenic NSE-tTA TetOp–fosB (N++) mice. a ,
Immunohistochemistry showing FosB induction in bitransgenic but not single transgenic NSE-tTA (N+-),
mice (original magnification 200). ac, anterior commissure. b, Colocalization of FosB with dynorphin,
but not enkephalin, in N++ mice. Left: green arrows, FosB-positive, dynorphin-positive NAc neurons.
Right: red arrows, enkephalin-positive, FosB-negative NAc neurons; blue arrows, FosB-positive,
enkephalin-negative NAC neurons. c, Single-cell RT-PCR confirming FosB expression exclusively in
substance-P-positive neurons. Top, representative gel. Bottom, number of neurons double-positive for
neuropeptide and FosB. d , Bar graph and western blot (e) showing FosB induction in N++, but not
N+-, mice switched to water (asterisk: t = 5.27, P < 0.0005, Student's t-test). f, Gel shift showing
induction of AP-1 binding activity in FosB-expressing mice. non spec., non-specific band. Dox,
doxycycline. (Kelz et al., 1999).

Reprinted with Permission from Nature.

D-FosB, as a transcription factor, acts by altering gene expression (Kelz et al., 1999). Although the results are not definite, it is thought that glutamate receptor subunits including GluR2 are the targets of D-FosB for many reasons. The researchers found that sustained cocaine use leads to an accumulation of D-FosB in the NAc region of the brain resulting in increased GluR2 receptor subunits. It is also thought that GluR2 is one of many receptors regulated by the D-FosB in this region of the brain. With this understanding, researchers can now try to find out how this presence of increased GluR2 in the brain leads to an enhanced reward mechanism. The doctors went on to say that the results of the experiment indicate that D-FosB may alter gene expression in at least the medium term that increase an individual's sensitivity to cocaine, and in turn the development of an addiction (Kelzet al., 1999). Weather or not researchers are able to come up with a mechanism to stop this build up and in turn reduce cocaine addiction is probably a matter of time and effort. However, it is also likely that continued research will lead to more factors that genetically influence cocaine addiction.

Comparison:
Interestingly, the two articles seem to stress different elements of the discovery. The ABC article focuses on the human impact of the discovery. It stresses the possible savior effects it could have on drug addicts on avoiding relapses, and leans towards the gene's discovery providing an end to addiction for cocaine users. On the other hand, the journal article is more careful to explain that the discovery has been made in mice, and although it is thought to have similar effects in humans, the testing has not been carried on to that level yet. Furthermore, the journal article more carefully explains the process in which the study was undertaken, and further explains the biological pathway which leads to the increased sensitivity to the drug. Before reading the journal article, it was unclear what process the gene had in influencing addiction, nor what area of the brain was affected. Although popular press can provide an outlet to genetic information to the masses, it is important to recognize the sensational biases it often contains.

Reuters. 1999. 'Key to Addiction' . 8/29/01.
Kelz, Max B. et al. 1999. "Expression of the transcription factor Delta-FosB in the brain controls sensitivity to cocaine." Nature. 16 September, 1999. <http://www.nature.com/nature> 8/28/01.