By David N. Leff
Late yesterday afternoon, a symposium in Washington learned, in words and pictures, how a novel brain drug reversed schizophrenia symptoms in rats and in patients.
Neuroscientist Gary Lynch told the 55th Annual Scientific Convention of the Society of Biological Psychiatry how an oral ampakine compound he discovered acted to increase the strength of connections between neurons in the brain. Lynch, a professor of neurophysiology at the University of California Irvine (UCI), is scientific director of Irvine, Calif.-based Cortex Pharmaceuticals Inc. He founded the company a decade ago to develop the ampakine family of drugs. (See BioWorld Today, April 15, 1998, p. 1.)
¿Ampakines,¿ Lynch told BioWorld Today, ¿are positive modulators of brain function. So, when the powerful glutamate neurotransmitter is released by one neuron, it crosses the cleft between synapses and lands on the ampakine-programmed glutamate receptor. This now begins to open and close its channels, meaning that little pulses of sodium-mediated current go through. That¿s the normal thing that¿s happening, billions of times a second.
¿Now imagine,¿ Lynch continued, ¿that you have an ampakine compound that comes into the brain. It lands on its docking site on the glutamate receptor. But in contrast to the way most drugs work, the ampakine sits on that receptor and does nothing. The receptor is neither activated nor blocked. However, when the glutamate transmitter itself now arrives, it lands on its waiting receptor, which opens and passes a pulse of current. And the presence of the ampakine prolongs that pulse.
¿Our work up to this point,¿ Lynch said, ¿described ampakines at the level of synapses and receptors and behavior. Now we have a new whole-brain in vitro system that monitors the known electroencephalogram [EEG] rhythms of sample rat-brain sections. That allows us to take all this synaptic pharmacology that we¿ve accumulated and, in terms of small networks of cells, go to macro phenomena and literally see what the neuronal connections are.¿
Lynch then described animal work done by two UCI researchers, Ursula Hess with Christine Gall.
¿Their experiment with rats,¿ Lynch told his audience, ¿began by knocking out the dopamine-secreting neurons on one of their brains¿ two cerebral cortices. Then they injected the animals with methamphetamine ¿ known to drug-abusers on the street as speed.¿
¿If you give a rat methamphetamine,¿ he said, ¿that will cause a marked increase in dopamine activity, and you will get all these strange behavioral abnormalities. So, now what they had were rats that had a huge dopaminergic response, but on only one side of the brain. The animals started to rotate ¿ but only in one direction. They just rotated and rotated like crazy ¿ literally. So, the researchers asked whether an ampakine could stop, or at least reduce, that repetitive kind of behavior. And ampakines in fact proved very effective at offsetting those effects.
¿We would have predicted,¿ Lynch said, ¿that what was happening to those rats was that the ampakine allowed them to assemble a cortical network that suppressed their rotational behavior. And in this instance we could actually name the cortical network we wanted.¿
He continued: ¿We had the dopamine-secreting neurons on one side, giving a massive dopaminergic activation of the striatum, the caudate, and then the cortex. But it was only on one side. So the rats, so to speak, had only one oar rowing and so were going in circles. What we really wanted to have happen now was to have the other oar start moving ¿ [to have] the other motor cortex become active. That would be one obvious solution to the animals¿ problem, to start pushing with their other foot.
¿We would say that by giving an ampakine what we should see happen is the contralateral motor cortex, which would be relatively silent, now gets lit up like a Christmas tree, which would help the animal stop spinning,¿ Lynch said. ¿And that¿s exactly what happened. In the control animals, the motor cortex on the contralateral side of the lesion was very quiet compared to the methamphetamine side. And in the case of the animals that got the ampakine compound, that same cortex was intensely active.
¿With that rat outcome in mind,¿ Lynch said, ¿we recalled the hypothesis that schizophrenia involves an inadequate glutamatergic response. Thus, ampakines became a rather obvious candidate, particularly on the basis of these animal results.¿
This brought Lynch to the climax of his symposium presentation.
¿About two weeks ago,¿ he said, ¿Don Goff, a professor at Harvard who has a lab at Mass General Hospital, reported the first study of ampakines in human schizophrenia. His double-blinded, randomized, controlled trial involved only 18 patients, all long-term schizophrenics. They were on clozapine, which is the gold standard for antischizophrenia drugs.
¿But these subjects have the disease long-term, and were resistant to treatment,¿ Lynch said. ¿Because ampakine was going to be administered for a month on top of clozapine, they weren¿t taken off their medication. So, Goff wound up with 12 patients who¿d got the ampakine on top of their clozapine, and six control subjects who went through the whole thing on clozapine alone.
¿The easier comparison to make,¿ Lynch said, ¿was their pre-experiment baseline across a series of psychiatric indices. These fall into three schizophrenic camps, the so-called positive and negative symptoms. Positive symptoms include active hallucinosis, anhedonia and delusions. The negative sets deal with social withdrawal and loss of emotional responsiveness. Both positive and negative symptoms are improved by clozapine. However, the cognitive aspects of the disease ¿ memory disorders, verbal problems, disordered thoughts and attention deficits ¿ generally are not improved by any available drug.
¿What that patient trial reported,¿ Lynch noted, ¿was a statistical improvement in the ampakine patient group, and remarkably enough, given the small size of the sample, the first point we wanted to make is that the ampakine was added to the clozapine and there were no problems.
¿The second piece of news,¿ he said, ¿is that in several of the cognitive tests, the ampakine-treated subjects showed significant improvements. And this was not restricted to the cognitive effect. The third aspect, if you take the data overall, is a statistical difference between the ampakine and placebo groups with regard to the degree of improvement.
¿We¿ve had two more weeks of time to analyze this data,¿ Lynch said. ¿These are clinical studies, with massive amounts of data that have not in any sense been sanitized or audited. What we really reported here, just because of the obvious interest of the subject,¿ he concluded, ¿was the unwashed version of the data.¿ n