Gene Transfer Modifies Response to Addictive Drugs

A recent study describes how researchers used viral-mediated gene transfer to deliver and overexpress the binding protein CREB locally, thus mimicking the CREB hyperactivity seen after the delivery of drugs of abuse or exposure to stress. The study was published in the August 20, 2002, issue of the Proceedings of the National Academy of Sciences.

It had been found previously that drugs of abuse activate CREB, a specific binding protein known for playing a role in the plasticity and adaptation of nerves in the nucleus accumbens area of the brain. In the current study, using CRE-LacZ reporter mice, investigators found that not only rewarding stimuli such as morphine but also aversive stimuli such as stress can activate CREB in the nucleus accumbens shell.

Then, using viral-mediated gene transfer to locally alter the activity of CREB, the investigators found that this manipulation affected morphine reward, as well as the preference for sucrose, a more natural reward. Local changes in CREB activity also induced a more general syndrome, by altering reactions to both rewarding and aversive stimuli.

"In the paper we show that inducing local CREB hyperactivity decreases the emotional response of an animal in different ways, including those that are rewarding, aversive, anxiety-provoking or hurtful,” explained first author Dr. Michel Barrot, assistant professor of psychiatry at the University of Texas Southwestern Medical Center (Dallas, USA). "On the other hand, a decrease in activity in the CREB site causes the opposite reaction. These data suggest the CREB activity in the shell of the nucleus accumbens controls the behavioral responses to emotional stimuli.”

Dr. Eric Nestler, the report's senior author, concluded, "This work supports the view that brain-reward regions important for addiction may also be involved in symptoms of depression and implicates the critical role of CREB in controlling the activity of these brain regions.”




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