On why we do what we do. I've always been very interested in mechanisms, in how things work. Late in my pre-med studies I discovered an area of science called behavioral neuroscience that allowed me to address both of my loves - learning about the biological mechanisms of the nervous system, and about psychopathologies and other behavioral abnormalities. So I didn t gotomedical school sometimes I kick myself for t h a t I went to Johns Hopkins University and began studying behavioral neuroscience in the department of psychology where I was awarded a PhD. in 1980.
time and time again, is that even though these drugs do what we think they should do, they have no positive effect on cognition. We think it is not simply that more acetylcholine would be better, but rather that what we have to recreate is the "when" part of it. Acetylcholine release has to be tightly orchestrated with other events in the cortex. Otherwise, you don't restore cholinergic function at all, just cholinergic levels. So what my colleague Dr. Martin Sarter and I do is look at animals which have damage to the cortex to see if they have cognitive disorders like the kinds one would predict in an Alzheimer's patient; then we insert microdialysis probes in them to see if our drugs reduce the behavioral
On aging and disease. Basically, my research involves two areas. The first is the recovery of brain function after trauma. The second
Of time, and the river of cognition. involves degenerative diseases, specifically Parkinson's and Alzheimer's diseases. The problem with these diseases, of course, is that they are enormously debilitating. But if behavioral neuroscience can help us understand what the neurochemical mediation of normal motor behavior, normal attention and normal memory is, we might then be able to develop new pharmacological agents to treat Parkinson's and Alzheimer's.
On where microdialysisfitsin. This is where the use of in vivo microdialysis comes in. Microdialysis in the hands of a behavioral neuroscientist is different than microdialysis in the hands of, say, a neuropharmacologist. It's a heck of a lot easiertodo microdialysis in anesthetized preparations, for instance, but with that ease comes Dr. John Bruno, Ohio State U.
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of microdialysis is that it allows us to correlate neurotransmitter efflux with ongoing behavior. For that, we need awake and alert subjects, in our case rodents. We do a lot of work looking at drugs, for instance, that might be used to enhance cortical acetylcholine efflux transsynaptically in animal models of Alzheimer's disease. Both direct agonists and cholinesterase inhibitors represent strategies for treating Alzheimer's disease by enhancing cortical acetylcholine function. What people have found,
deficits while at the same time enhancing cortical acetylcholine efflux. So far, inrespectto the benzodiazepine selective inverse agonists we are currently studying, the answer appearstobe yes. In our work, we use the complete BAS microdialysis package including the liquid chromatographs with immobilized enzyme reactors. We want to conduct experiments repeatedly in the same animal, a process called repeated session microdialysis. This allows us to look at the effects of various experiences on dialysis efflux before, during, and after the experience. An added advantage of repeated session microdialysis is that we can use the animal as its own control. So you can always express your manipulation as a percentage, for example, of what that animal's nonstimulated efflux is. That's a statistical argument, but it happens to be a very potent one. Sometimes you hear that "timing is everything." Certainly we are convinced that it's a key to the Alzheimer's puzzle. And, when I think about it, my exposure to behavioral neuroscience came at a critical time as well. Hopefully, the flow of events since then will result in more medical benefit than I could have ever effected if I had followed a different course. Serious sciencefor serious scientists.
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Analytical Chemistry News & Features, December 1, 1996
