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TAKING A CLOSE LOOK AT BRAIN CHEMISTRY Analytical chemists are developing techniques for investigating neurotransmitters CELIA M. HENRY, C&EN WASHINGTON Analytical chemistry is starting to shine light on the workings of brain chemistry. At a symposium at Pittcon earlier this month, analytical chemists described their work to increase the understanding of this complex system. "Analytical chemistry in the brain is very challenging," symposium co-organizer R. Mark Wightman, the W. R. Kenan Jr. Professor of Chemistry at the University of North Carolina, Chapel Hill, told C&EN. "There are a million compounds, and you want to pick out and look at one or two. Once you're able to identify them, you want to understand what they're doing." Christian Amatore, professor of chemistry at Ecole Normale Superieure, Paris, described electrochemical monitoring of exocytosis, the process of releasing materials such as neurotransmitters from cells, using carbon fiber microelectrodes. Five independent physicochemical stages govern exocytosis, Amatore said. In his presentation, he focused on the stages in which the vesicle docks to the cell membrane, forming a fusion pore, and in which the vesicle and cell membranes fully fuse. These stages affect the shape of the spikes observed during electrochemical monitoring of neurotransmitters. When the fusion pore forms, a small amount of the vesicle contents is released, with a large spike of released material following full fusion. Amatore pointed out that in electrochemical monitoring there is not always a sharp transition between the fusion pore and full fusion. Wightman uses the electrochemical technique cyclic voltammetry to monitor the release of dopamine, which is thought to be part of the brain's reward system, on a subsecond timescale. He also uses microelectrodes fabricated from carbon fibers. Wightman was a pioneer in the development of the carbon microelectrodes that many chemists use to monitor neurochemistry. One of the challenges is making sure that he's really looking at dopamine. The cyclic voltammetric signature of dopamine is similar to that of another neurotransmitter, norepinephrine. However, Wightman can distinguish dopamine by measuring in the region of the brain known as the nucleus accumbens, where there is no interference from norepinephrine. Dopamine neurons can undergo "tonic firing" or "phasic firing," Wightman said. Tonic firing occurs at a frequency of about 5 to 10 Hz, and it represents the basal firing rate. In contrast, phasic firing occurs in short, fast bursts that last less than half a second. "Before the development of these carbon fiber electrodes, there was never a way to follow these changes on subsecond timescales," Wightman told C&EN. "People didn't know what dopamine was doing on a fast timescale." BRAIN PROBE Capillary electrophoresis coupled with ultraviolet detection shows that hungry snails release more serotonin than satiated snails. COURTESY OF JONATHAN SWEEDLER BY TRAINING RATS to respond to audiovisual cues that are associated with a reward, in this case the self-administration of cocaine, Wightman's research is showing that dopamine can be elevated in anticipation of receiving a reward. When a rat is placed in a chamber with a lever that dispenses cocaine, the rat first presses the lever frequently to load up with cocaine and thereafter presses the lever at regular intervals. After the rat presses the lever, the amount of dopamine increases. However, an interesting thing happens when the rats learn to associate the cues with the administration of the cocaine. They experience an increase in dopamine when they approach the lever but before they press it. This dopamine increase during "approach behavior" doesn't happen with untrained animals, so it's not caused by just the cues. "Before, people thought that dopamine being elevated was a reward in itself," he said. "We're looking at these real fast things, which deal with the anticipation or the alerting of the animal that something is going to happen." |
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