By David N. Leff

On the streets of New Haven, Conn., and in that city's disco clubs, the latest drug fix is called an "illy."

This intelligence comes from molecular psychiatrist John Krystal, a professor of psychiatry at Yale University School of Medicine, in New Haven. "My understanding," he told BioWorld Today, "is that angel dust and ketamine have become part of an extraordinarily toxic cocktail. To make the illy, users soak marijuana in formaldehyde and add phencyclidine (PCP) or ketamine."

Krystal's research focuses on drug addiction and schizophrenia. PCP — also known as "angel dust" — is a hallucinogenic drug of abuse that evokes certain cognitive and behavioral symptoms similar to those of schizophrenia. In real life, PCP is used as a veterinary anesthetic, and for turning rats into laboratory models of human schizophrenic behavior. (See BioWorld Today, March 20, 1997, p. 1.)

Ketamine, a PCP derivative, "has very similar properties in animal models," Krystal said, "but with shorter-acting, less potent cognitive and behavioral effects than PCP."

Schizophrenia itself is slippery to diagnose or describe. Its hallmark traits include disordered perception and thought, marked by hallucinations and delusions, social dysfunction, disinterest in other people and the world, aberrant behavior that is sometimes violent.

It besets both genders, and is usually diagnosed in late adolescence. Schizophrenia afflicts 1 percent of the world's population. In the U.S., schizophrenics occupy one-fourth of all available hospital beds. Little is known of the disorder's inheritance pattern, but as neuroscientist Bita Moghaddam observed, "Albert Einstein's brother had schizophrenia."

With one exception, she pointed out, all of the antipsychotic drugs used to treat schizophrenia act by blocking the brain's dopamine receptor. Schizophrenia is the reverse Parkinson's disease (PD), of which the cause is a dearth of dopamine. "And that's why one of the side effects of treating schizophrenics with these drugs," Moghaddam added, "is that they get Parkinsonian-like tremors. The therapeutics produce that condition by blocking the PD patients' dopamine neurotransmission."

Moghaddam is an associate professor of psychiatry and neurobiology at Yale. She and Krystal are colleagues but not collaborators.

Today's edition of Science carries a paper titled "Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats." Moghaddam is its senior author.

"In clinical trials as a model for schizophrenia," she explained, "PCP and drugs such as ketamine that are analagous to PCP, increase glutamate neurotransmision. This suggests that these drugs may exert their behavioral effects by activating glutamate transmission, as opposed to inhibiting it, which has been the standard thinking.

"The main finding we reported," she told BioWorld Today, "was targeting in a normal class of glutamate receptors, a subclass of their metabotropic [modulatory] receptors. These drugs reduced in rats the behavioral effects of PCP that may be relevant to schizophrenic symptomatology."

Unlike Current Antipsychotics, No Side Effects

"The interesting aspect of these new drugs," Moghaddam continued, "is that, seen by themselves, they are not producing any side effects. So in a way they are normalizing the disrupted system. This is very different from the current drugs that are used to treat schizophrenia, which work by blocking the dopamine receptor."

One such new drug is under development by Eli Lilly and Co., of Indianapolis, which identifies it only as LY354740. "The Lilly drug acts systemically and selectively on one of the eight known metabotropic glutamate receptors," Moghaddam pointed out.

"The reason I had this drug," she recalled, "is that I heard Lilly present data describing it in a scientific conference. We had been looking for an activator of this particular glutamate receptor, based on our previous work. So when I heard that Lilly had actually synthesized this drug, I asked them to give us some. They provided me with a limited supply."

She and her co-author injected the Lilly molecule into laboratory rats under the influence of PCP, which turned the animals into schizophrenic act-alikes. They ran around frantically, rolled their heads non-stop, and showed disturbances of memory and attention — all thought to mimic the human symptoms. The Lilly drug lowered excess glutamate levels in the PCP-treated animals by stimulating the subgroup receptors. The rats recovered working memory, and cut down on their intense locomotion and head-rolling, with no adverse side effects.

Interpreting this result, Moghaddam observed that dopamine "has beeen implicated in schizophrenia, of course, the main reason being that drugs have blocked the dopamine receptor, and have antipsychotic effects.

"We had hypothesized," she recounted, "that activation of dopamine plays a role in psychosis. It was actually found many years ago that PCP and other psychotic mimetic drugs increase dopamine release. So, everyone put two and two together, and concluded that this activation of dopamine is what is causing these behavioral effects in animals and in humans.

Blocking Glutamate, Not Dopamine

"A very surprising — and in our opinion the most interesting — aspect of our finding was that this Lilly drug, even though it inhibited the behavior and blocked the glutamate, did not block dopamine activation," Moghaddam went on. "Had that activation been responsible for these behaviors, they would actually have been blocked as well. It seems as if it is reducing these behaviors without going through the dopamine system. And this may account for the absence of side effects."

Asked about possible human studies of the drug in future, Moghaddam rejoined: "When you talk about clinical trials, it's like opening a new can of worms. But Lilly has announced that they have this drug in clinical trials, and that it has passed the toxicity phase. They are now looking at its effects on anxiety and addiction. So far, it seems to be tolerated very well. I don't know if it has shown efficacy. It's still in early stages."

Moghaddam emphasized that her rodent experiments have a built-in uncertainty factor.

"The caution is that we are basically assuming — based on indirect evidence — that some of these behaviors parallel human schizophrenia," she said. "Even in human diseases such as cancer, when you actually induce the disease in the rat, the drug that works in that animal model may not work in humans.

"In our report," she concluded, "we are making a number of assumptions that the cognitive or other deficits are paralleling a complex human disorder, and that may not be the case."

Krystal commented: "The point is that [the Lilly drug], as far as it has been shared in public, appears to be a very safe, well-tolerated medication in its experimental trials, with a mechanism of action of reducing glutamate release in this very specific way. The fact that it attenuates PCP effects in animals suggests that there may be some utility in evaluating this drug in schizophrenia patients." *