A new laser-based process to study the regulation of signal transmission between cells of the nervous system has led to the discovery of several compounds that could become the basis for a cocaine-poisoning treatment.

The discovery was made using "laser-pulse photolysis," a technique under development in the laboratory of George P. Hess, professor of biochemistry at Cornell University. The technique might have other uses in illuminating nerve cell reactions in such diseases as epilepsy and Parkinsonism. The discovery was reported in the Dec. 5 issue of Proceedings of the National Academy of Sciences (Vol. 97, No. 25, pp. 13895-13900), and described by Hess at the American Chemical Society's Pacifichem International Congress in Honolulu on Dec. 18, 2000.

The compounds identified by Hess and his colleagues involve RNA (ribonucleic acid), the chemical found in the nucleus and cytoplasm of cells that plays an important role in protein synthesis and other chemical activities of the cell. Students in the Hess laboratory synthesized artificial RNA compounds that prevent cocaine from blocking proteins that are essential for normal functioning of the nervous system.

One of these proteins is the nicotinic acetylcholine receptor (nAChR), an integral protein of nerve and muscle cell membranes to which the substance released at some nerve endings – acetylcholine – binds. At the neuromuscular junction, nAChRs initiate muscle contraction.

During the last two decades, many unsuccessful attempts have been made to find compounds that would prevent cocaine from blocking proteins that are essential to brain function. A major difficulty in investigating these proteins is that once activated, they remain in their active form for just a few milliseconds. The techniques developed at Cornell are allowing scientists to examine the electrochemical activity of the proteins in this critical microseconds-to-milliseconds period. The identification of the RNA compounds, Hess said, will enable the design of other smaller and more stable compounds for treating cocaine poisoning. Cocaine is a powerful central nervous system stimulant that Clinical Toxicology Review has called "one of the most commonly abused drugs in the United States, exacting an enormous toll in terms of human suffering." The publication has estimated that 5 million Americans use the drug

regularly. Cocaine use can result in cardiovascular collapse, coma and death. The cost to society each year of dealing with this problem is estimated to be many billion dollars in the United States alone.

"Laser-pulse photolysis lets us look at an ensemble of molecules -- not just a single channel or a single molecule -- during the split-second reactions that relay electrical signals through the nervous system," Hess says. He notes that the unique ability of laser-pulse photolysis to characterize reactions during the milliseconds they occur on the surface of nerve cells suggests numerous applications of the technique:

• It could lead to a better understanding of the effect of disease-causing mutations of the receptors that control signal transmission between nerve cells.
• The design of mechanism-based drugs could proceed more rationally through knowledge of the exact roles and timing of all the chemical players at the junctions between neurons and muscle cells or between neurons and other neurons.
• Neurobiologists could greatly expand their basic understanding of how neurons respond to the two kinds of neurotransmitters -- excitatory and inhibitory.
• Cells that contain specific neurotransmitter receptors could be identified.

The studies were supported, in part, by grants from the National Institutes of Health.