Memory, Pain, Depression, and Peptides... Putting the Pieces Together

By Jason Socrates Bardi

Sometimes the greatest moments in one's professional career are those in which one's accomplishments are not recognized.

Such a moment occurred for Tamas Bartfai in 1983, when he wrote a paper together with Tomas Hokfelt and Jan Lundberg claiming that he had identified a neuron that used not just one, but two neurotransmitters. They had discovered, in these neurons, the coexistence of the acetylcholine (ACH) and vasoactive intestinal polypeptide (VIP), two molecules that are released into synapses and transmit nerve impulses—a coexistence that was not thought possible at the time.

His manuscript was less than well received.

"We were rejected from every major journal," says Bartfai, who is professor of neuropharmacology and director of the Harold L. Dorris Neurological Research Center at The Scripps Research Institute (TSRI). "'It is well known that a neuron can have only one transmitter or we would have cacophony in the brain,' wrote one Nobel laurate referee."

Today there are over 40 well-documented examples of neurons with coexisting neutotransmitters. These examples have been described in thousands of papers, and more are discovered every year.

"I am quite pleased when I look at that paper rejected by Nature," he says.

What's in a Brain

Bartfai describes himself as a molecular neurobiologist—someone who attempts to associate cellular and molecular mechanisms to the phenomenon of cognition. Bartfai's own interests involve specifically identifying the molecular correlates of changes in long-term memory and in emotional states.

These attempts are, by Bartfai's own admission, mere starting points. Cognition is a complicated subject from a molecular perspective due to the number of neurons, neurotransmitters, and interconnections. There are emotional components, attentional components, sensory inputs, the creation and retention of short- and long-term memory, and the molecular interactions between these disparate events. There are stimuli and signals to be sorted out, and different regions of the brain that are involved in the different types of memory.

"We think in terms of very few transmitters and very few neurons and very few connectivities when we imagine how all of this works as compared to the trillions of nerve cells that actually participate," says Bartfai. "Where are these proteins formed, and are they specific to memory or to a circuit? What are the rules for reading them out when you recall a memory?"

"These are things that we don't really know much about," he says.

Understanding the connection between cellular and molecular interactions and cognition is one of Bartfai's key goals, but he also wants to find ways of turning these basic observations into useful therapeutics—therapeutics to counter degenerative diseases like Alzheimer's disease, which is characterized by a loss of memory.

Long-term memory involves the synthesis of new proteins, a characteristic that makes it amenable to someone like Bartfai, who is a biochemist by training. Because new proteins are formed as memories are formed, proteins and memories could, in theory, be alternatively blocked by synthesis inhibitors or enhanced by regulating the production of those inhibitors.

But, says Bartfai, at the moment, we are only really good at identifying non-specific ways of impairing memory, such as through alcohol. There are no drugs proven to enhance human cognitive ability or to help bring damaged cognition back to a more normal state.

"To stop the decline of memory," says Bartfai. "That is what we are really talking about—not making super IQ's, because there are enough of those already."

Unveiling the Effects of Peptides

One of the systems on which Bartfai is working is neurons that, like those he identified in 1983, use two distinct neurotransmitters. These are the cholinergic neurons that project to the hippocampus, and he is actively pursuing them because they are concentrated in a locus—called the Nucleus Basalis—which provides acetylcholine input to the hippocampus, is important for cognition, and which is severely damaged in Alzheimer's disease.

The hippocampus is a ridge of tissue along the lateral ventrals of the brain sandwiched between the cerebral cortex and the thalamus. This is where we think many of the chemical processes take place that are important for forming and retaining memories, the basic processes of cognition.

Cholinergic inputs to the hippocampus contain both the neurotransmitter acetylcholine (ACh) and the neuropeptide galanin. These two chemicals coexist specifically in those hippocampus neurons, and both chemicals are released into the gaps, or synapses, between two neurons during the signaling from one neuron to another that takes place during cognitive processes.

Acetylcholine is a well characterized neurotransmitter and one with which Bartfai is very familiar. In the early 1970s, simultaneous with S.H. Snyder and Sir Arnold Burgen, he made the first identification of muscarinic ACh receptors in the brain, which are one type of neuronal receptors for acetylcholine, and his research in this area has continued since then.

"In the end," says Bartfai, "everything we do in my laboratory turns out to have to do with modifying the cholinergic activity in the brain."

Galanin is interesting to Bartfai because this unassuming peptide appears to be one way in which ACh levels are regulated in the body. Galanin seems to have a local feedback in ACh release, regulating the neuronal excitability in that part of the brain, the hippocampus, and, in turn, influencing cognition. "It is clear that [galanin has] quite a large effect on cognition," he says.

Galanin also controls the pain threshold at the spinal cord level through the same neuronal action in the spinal cord that morphine uses—hyperpolarizing primary sensory neurons. Transgenic models with no galanin receptors, for instance, have different pain thresholds. One possible application for this is to develop a class of galanin receptor agonists—non-opiate pain relievers that could be taken with morphine, for instance, to lower the required dose of morphine eight-fold or more as suggested by animal experiments.

Galanin is also a growth-promoting, or trophic, molecule, and its local expression is required for the growth of certain neurons. In Alzheimer's disease, galanin is overexpressed in the basal forebrain. Moreover, as Alzheimer's disease wipes out many of the cholinergic neurons of the hippocampus, those that survive in the nucleus show elevated expression of galanin.

"We don't know how to use this observation, but it is clear that galanin, as a modulator of cholinergic activity, is important for the survival and function of the cholinergic nucleus," says Bartfai. "And the function of the cholinergic nucleus is what we want to restore in [Alzheimer's] patients, because that is the best replicated way of ensuring cognitive improvement." For instance, the only approved Alzheimer drugs, Arisept and Excellon, enhance cholinergic activity."

Despite everything that is known, however, Bartfai admits he doesn't fully understand the mechanism of galanin's action or how to use it. This is one of the things he aims to accomplish at TSRI.

Bartfai's work has led to three galanin receptors becoming the target of more than 20 projects in the pharmaceutical industry. At the moment, Bartfai and his colleagues in the Harold L. Dorris Neurological Research Center are looking to establish combinatorial libraries that he hopes will eventually lead to the creation of more effective galanin receptor antagonists for antidepressant and cognition-enhancing therapies.

Coming Home to TSRI

Bartfai joined TSRI as a professor of neuropharmacology in 1999, and was appointed director of the Harold L. Dorris Neurological Research Center a few months later. The center was founded with a remarkable $10 million endowment from Helen L. Dorris of San Diego—the largest TSRI had ever received for research in the neurosciences.

Bartfai came to TSRI after serving as senior vice president in charge of central nervous system (CNS) research at Hoffman-LaRoche, a department most famous for the drug Valium, and for its Parkinson's disease drugs. He was brought there to develop a major human genetics effort to aid discovery of new treatments for schizophrenia and Alzheimer's disease. Prior to working at Hoffman-LaRoche he was involved in the development of Zimelidine, the first selective serotonin reuptake inhibitor (SSRI) and two anti-psychotic agents used in the treatment of schizophrenia as a consultant for ASTRA (now ASTRA–Zeneca).

"I reorganized and refocused [the research group at Hoffman-LaRoche]," says Bartfai. "Once that was done, the job became very administrative, and I came here."

After his appointment as director, he decided to focus on the center to maximize the synergy between the researchers. To do this, he recruited two associate and two assistant professors, who, in addition to their own research agendas, had research interests in common with Bartfai. These shared areas of interest include developing new models for schizophrenia, finding faster-acting anti depressants, addressing basic questions involving fever and sleep as they tie into depression, and examining the role of cytokines in inflammation and pain.

Bartfai sees the Harold L. Dorris Neurological Research Center as the link between the chemistry at TSRI and the whole-organism behavioral studies of the Neuropharmacology Department—with the aim and the tools for doing nothing short of understanding the brain's function in biochemical terms. He points to the department's work on antidepressants as an example.

Depression is a widespread and often debilitating psychiatric condition marked by persistent feelings of sadness or hopelessness, inactivity, changes to sleep and eating patterns, and suicidal tendencies. The National Institute of Mental Health estimates that in any given year, about one out of every ten American adults suffer through some major form of depression. And about two percent of all Americans will use antidepressants at some point in their lives.

Normal antidepressants take two or three weeks to take effect, and as many as a third of patients do not respond to the drugs. This is problematic because the core symptom of serious depression is suicidal tendencies. In 1997, for instance, 30,535 Americans committed suicide, making it the eighth leading cause of death in the United States that year. One of Bartfai's longstanding goals is to develop a quick-acting compound for the treatment of depression. "We just don't know how to make such a tablet yet," he says.

Electroconvulsive therapy and sleep deprivation are the two known methods of bringing on a rapid antidepressive response, but, while effective, neither method produces longlasting effects. The antidepressant effect of sleep deprivation, for example, only lasts about 48 hours. (Clinical sleep deprivation, says Bartfai, must be monitored by professionals and is not the same thing as staying up late. "That just makes people irritated," he says).

Bartfai predicts that in the next three to four years, his department should have identified some drug targets that, when manipulated, will lead to a fast-acting antidepressant.

"That would be great," he says, because [in my lifetime] there have been more young people [who have died] from suicide than who died in World War II."

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Tamas Bartfai is professor of neuropharmacology and director of the Harold L. Dorris Neurological Research Center.