BETHESDA, MD (NIH) -- In research employing fruit flies, scientists at the University of Arizona have provided new insights into how molecules may control addiction, memory formation, and brain plasticity. Their research has provided the first evidence that the molecule AP1, which helps to regulate changes in the manufacture of certain proteins in brain cells, also is required for long-term changes in the function of synapses (the connections between brain cells).

The study, funded by the National Institute on Drug Abuse (NIDA), is published in the April 25, 2002 issue of Nature. NIDA Acting Director Dr. Glen R. Hanson says that "understanding addiction at the molecular level will help in the search for new pharmacologic agents to treat or interrupt the biological processes that result in addiction."

It has been known that long-term behavioral changes, such as drug addiction, are associated with changes in the manufacture of certain proteins in brain cells. Animal studies have identified a few key molecules such as CREB and AP1 that regulate these changes. For example, a variant form of AP1, called deltaFosB, is produced in the brain after multiple exposures to cocaine and controls long-term sensitization to the drug.

The prevailing view is that production of AP1 is activated by CREB. Once produced, AP1 helps CREB direct the manufacture of a subset of proteins required to modify the function of brain cells that control behavior.

Lead investigator Dr. Mani Ramaswami says that although it had been believed that AP1 helps generate changes in synapses, direct evidence has been lacking until now.

The Arizona researchers analyzed the role of AP1 in synaptic change. A surprise finding, says Dr. Ramaswami, is that the synaptic changes controlled by AP1 are more extensive than those controlled by CREB, and more closely resemble synaptic changes induced by real experience. Also unexpected was the observation that the activity of AP1 was increased by a protein called JNK which was not previously known to function in synaptic change.

Dr. Ramaswami says, "Although these observations and conclusions were made from analysis of a synapse in the fruit fly Drosophila melanogaster, several molecules that affect plasticity at this synapse have a similar function in mammalian brain cells." These findings, he explains, " suggest that pharmacological drugs that activate or inhibit JNK or AP1 could have profound effects on brain plasticity processes that are involved in drug addiction, memory formation and even recovery from brain injury."