Through the Times With Solomon Snyder, M.D.

Psychiatric Times

July 2005

Vol. XXII

Issue 8

Although he hated science in high school, Solomon Snyder, M.D., received the nation's highest science honor this year, the National Medal of Science. In the intervening 40+ years, Snyder found that he loved the discovery and creativity of scientific research. In fact, his lab at Johns Hopkins University pioneered the identification of opiate receptors and was the first to identify several novel neurotransmitters.

Ironically, it was Snyder's love of music that facilitated his entry into scientific research.

"When I was in high school, one thing I did really well was play the classical guitar. I gave concerts and played for Andres Segovia, the great classical guitarist," Snyder told Psychiatric Times.

Snyder considered taking master classes with Segovia after high school and then attending a music conservatory. Instead, "after a lot of soul searching," the Washington, D.C., native chose to attend Georgetown University.

"In high school, I liked reading about philosophy. My other friends were considering going into engineering or pre-med. I got this idea that psychiatry might be a little like philosophy. Though I hated science, I thought I could stomach it and be pre-med, which I was at Georgetown," he said.

He worked his way through college giving guitar lessons and helping to run a guitar store. One of Snyder's guitar students was among the first group of research associates at the National Institutes of Health, and he invited Snyder to spend a summer working at his NIH lab before entering the Georgetown University School of Medicine.

"So I went to work in the lab, and I found that it wasn't like science we learned in school. It was very creative, and I loved it. I spent all of my summers and elective periods at NIH," he said.

During medical school, he did psychological studies of patients with schizophrenia on the NIH research ward. After graduating at age 23 and interning at Kaiser Foundation Hospital in San Francisco, Snyder obtained a position as a research associate at the National Institute of Mental Health and simultaneously fulfilled a military service requirement.

At the time, male medical school graduates were subject to the Doctors' Draft Law and were being conscripted into the Army and often sent to combat zones. Since the NIH was part of the U.S. Public Health Service, work there counted for military service. It was also "the pre-eminent research facility on earth," said Snyder.

"I got a position with Julius Axelrod [Ph.D.], who subsequently won the Nobel Prize for his research on drugs and neurotransmitters," Snyder said.

For Snyder, the two years (1963 to 1965) working with Axelrod "were very defining in the sense I realized that I was really good at it [doing the research] and that I loved it. It was a very creative thing."

But Snyder still wanted to be a psychiatrist. In 1965, he went to Johns Hopkins University for his psychiatry residency.

"An arrangement was worked out so I could be on the faculty while I was a resident. So I set up a laboratory and have never left," he said. Presently, he is director of the department of neuroscience and distinguished service professor of neuroscience, pharmacology and psychiatry.

The Institute for Scientific Information cites Snyder as one of the 10 most-often cited biologists in the scientific literature. Snyder has authored more than 1,000 journal articles and many books, including Drugs and the Brain (Scientific American Library Series, 1986; revised edition, W.H. Freeman & Company, 1996) and Brainstorming (Harvard University Press, 1989).

He serves on several editorial boards, including Proceedings of the National Academy of Science, Journal of Molecular Neuroscience, Molecular Psychiatry, and Journal of Nervous and Mental Diseases. Snyder has been on the editorial board for PT since it was first published in 1985. He also was a frequent presenter at the U.S. Psychiatric & Mental Health Congress.

"Way back when John Schwartz [M.D.] first decided to do continuing medical education for psychiatrists, I was one of the first people he worked with. He would set up small groups of psychiatrists (15 to 20) for a weekend in New York or some other city, and I would literally spend two days, full-time, with these people in informal settings, teaching them psychopharmacology," Snyder said.

Molecular Neuroscience

Many advances in molecular neuroscience have come from Snyder's and colleagues' identification of receptors for neurotransmitters and drugs and elucidation of the actions of psychotropic agents. His team pioneered the labeling of receptors by reversible ligand binding in the identification of opiate receptors.

"It was very exciting in 1973 when we discovered the opiate receptor," he said. "And of course, man was not born with morphine in him, so the existence of the opiate receptor suggested that there must be a morphine-like neurotransmitter. We were fortunate in being one of the groups that helped identify endorphins [endogenous morphine-like neurotransmitters]. That was all very exciting."

Very soon after the identification of opiate receptors, Snyder and his team were able to utilize ligand binding techniques with various modifications to identify and characterize receptors for the major neurotransmitters in the brain, including glycine receptors, cholinergic receptors, serotonin receptors, γ-aminobutyric acid (GABA) receptors, dopamine receptors, α-adrenergic receptors and calcium antagonist drug receptors, as well as receptors for adenosine, cholecystokinin, bradykinin, histamine H₁, neurotensin and angiotensin II.

Those same techniques, Snyder said, also helped revolutionize the drug industry. The isolation and subsequent cloning of receptor proteins was facilitated by the ability to label, and thus monitor, receptors using the ligand binding techniques. No longer did chemists have to synthesize large amounts of chemicals and screen drugs in intact rats, where they "didn't know what the drug was doing," he explained. With the ability to measure receptors in a test tube, chemists could make tiny bits of chemicals and study their effects on receptors.

Challenging Dogma

When Snyder started researching neurotransmitters, just a handful had been identified: acetylcholine, norepinephrine, dopamine and serotonin. Now, he said, there are anywhere from 50 to 100, depending upon who you ask, and the neurotransmitters serve different kinds of functions.

"Some of them are very atypical compared to the classical neurotransmitters like acetylcholine ... A lot of our research is covering novel neurotransmitters which change the entire concept of what neurotransmission is," Snyder said. "All of the novel neurotransmitters provide new ways of developing drugs that can be more selective and effective in all sorts of diseases."

In detailing the changing concept of what a neurotransmitter is, Snyder first pointed to acetylcholine, found in the 1920s to transmit messages between nerves.

"The dogma about what criteria a chemical must satisfy to be called a neurotransmitter was always based on what was known. So when acetylcholine was the only known neurotransmitter, its properties were set up as the criteria that must be satisfied," he said.

The criteria at that time was that a neurotransmitter must be a small molecule; must be an amine; must be stored in synaptic vesicles; must be released in a particular fashion and act at specific receptors; and must be inactivated by an enzyme that degrades it.

Then the catecholamines (e.g., dopamine and norepinephrine) came along in the 1950s. By the 1960s, the criteria for what constitutes a neurotransmitter began to change. The change, Snyder said, was due in part to the work of his mentor, Axelrod.

"One of the things for which he received the Nobel Prize was his discovery that most neurotransmitters are not inactivated by an enzyme, but are pumped back into the nerve that released them," Snyder said.

Snyder's own lab has changed much of the dogma surrounding neurotransmitters. For example, Snyder's group established gases as a new class of neurotransmitters. In 1987, some researchers reported that the gas nitric oxide (NO) played a major role in blood vessel relaxation. A number of the properties of NO suggested to Snyder and his team that NO might have a role in brain function, conceivably as a neurotransmitter (Neuropharmacology 2004;47[suppl 1]:274-285).

On the Johns Hopkins' neuroscience Web site (<neuroscience.jhu.edu/peopledetail.asp?ID=1>), Snyder further explained:

We discovered that NO satisfies the major criteria of a neurotransmitter, as NO synthase is localized to specific neuronal populations and inhibitors of the enzyme block neurotransmission in certain systems. Yet NO is a gas which cannot be stored in synaptic vesicles, released by exocytosis or act at receptor proteins on cell membranes.

He explained that in vascular stroke, excess release of the excitatory amino acid neurotransmitter glutamate activates NO synthase to form NO that mediates neurotoxicity. Evidence for this includes the blockade of stroke damage by inhibitors of NO synthase and a lesser amount of stroke damage in the brains of mice lacking the neuronal form of NO synthase.

In mice in which the gene for the nueronal NO sythase has been knocked out, Snyder and his team observed dramatic alterations in social and sexual behavior indicating a prominent role for NO in agression and sexual attraction.

At least one other gas, carbon monoxide (CO), may be a neurotransmitter, according to Snyder and his team. Carbon monoxide is formed by the action of the enzyme heme oxygenase (HO), which cleaves the heme ring liberating CO and forming biliverdin, which is converted to bilirubin.

"We found that a neuronal form of heme oxygenase occurs in discrete neuronal populations in the brain, and CO formed from it may be involved in regulating levels of cyclic GMP," Snyder said on the neuroscience Web site.

Besides forming CO, heme oxygenase action gives rise to ferrous iron and biliverdin, which is rapidly reduced to bilirubin. Snyder's team has shown that bilirubin is a key neuronal antioxidant neuroprotectant.

Low nanomolar concentrations of bilirubin reverse the oxidant effects of 10,000-times higher concentrations of oxidants, an amplification mediated by a unique bilverdin reductase cycle. When bilirubin acts as an antioxidant, it is oxidized to biliverdin. Biliverdin reductase rapidly reforms bilirubin. Deletion of biliverdin reductase from cells leads to excess oxidation and cell death.

Even more rules about what is a neurotransmitter were overturned with Snyder's and colleagues' discovery that the amino acid D-serine is a neurotransmitter.

"Now, all chemicals in the body come in mirror image forms: either the D-form or the L-form ... Sugars are always the D-form and amino acids, the constituents of protein, are the L-form ... But lo and behold, D-serine exists [as an amino acid] and was discovered not that many years ago in high concentrations in the brain, but nobody knew what it was doing," Snyder told PT.

"What was even remarkable is that it [D-serine] isn't in neurons at all. It is in glia, the supportive cells of the brain. Eighty-five percent of the cells in the brain are glia and have been thought of as just holding things in place while the neurons did all the work. Yet, in fact, glia have a neurotransmitter, D-serine."

Immunohistochemical maps reveal D-serine in a unique population of glia that ensheathe nerve terminals selectively in regions of the brain enriched in the subtype of glutamate receptor referred to as the N-methyl-D-aspartate (NMDA) receptor. This research on D-serine has implications for drug development, according to Snyder.

"D-serine acts together with glutamate, well known as a major excitatory neurotransmitter in the brain. Excess release of glutamate occurs during strokes, and plays a role probably in most neurodegenerative diseases. So if you could stop excess glutamate transmission, especially at the NMDA subtype glutamate receptor, you could relieve strokes, and you might have therapeutic agents in neurodegenerative diseases like Alzheimer's and Parkinson's disease," Snyder said.

Massive efforts, Snyder added, have been directed toward developing drugs that block these NMDA receptors, but most of them have adverse side effects.

"Well, we discovered that D-serine acts together with glutamate in activating these receptors, and we discovered that it is made by a very specific enzyme that converts L-serine to D-serine, so we call it serine racemase," Snyder said. "We have made drugs that inhibit that enzyme, and you reduce the activation of the NMDA receptors with potential therapeutic consequences.

"The elegance of this approach is that glutamate is one of the most abundant amino acids in the body. It is found in such enormous concentrations, and it does so many things, that attempts to manipulate it produce many nonspecific side effects," Snyder explained. In contrast, D-serine is unique in that it exists only as a neurotransmitter, only in the area of NMDA receptors, and can only be formed by the enzyme serine racemase.

"So if you have a drug that inhibits that enzyme selectively, you have a much more specific therapeutic agent," Snyder said, adding that animal studies are underway on the drug.

Snyder has been at the forefront of molecular neuroscience and his efforts have been acknowledged by numerous organizations. For his early research, he received the Albert Lasker Award for Basic Biomedical Research in 1978. At the 1997 U.S. Psychiatric & Mental Health Congress, he was named "Teacher of the Decade."

In more recent years, the American Psychiatric Association awarded him the Judd Marmor Prize; the Society for Neuroscience gave him the Ralph Gerard Prize; the National Alliance for Research on Schizophrenia and Depression gave him the Lieber Prize and Goldman-Rakic Award; and the National Academy of Sciences gave him the Sarnat Award. In March, he was one of eight recipients chosen by the National Science Foundation to receive the National Medal of Science.

"It was a great honor, and it honors all of my students, graduate students and postdoctoral fellows, who have been making discoveries over all of these years," Snyder said.

Asked if he is still playing his guitar, Snyder responded, "At Johns Hopkins, there is a big program to encourage chamber music concerts so as to promote interaction of faculty and students. I have performed with a guitar quintet and done guitar duets with medical students. And now I write and perform songs for my grandchildren for their birthdays."