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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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