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Scientific Report 2005




The Harold L. Dorris Neurological Research Institute


Schizophrenia is a devastating psychiatric disorder that affects 1% of the world’s population. At the Harold L. Dorris Neurological Research Institute, M. Margarita Behrens and her group work on new approaches for the treatment of this disease. Their research is based on the understanding that the cognitive aspects of the disease are as important as the hallucinations and other, so-called positive symptoms, addressed by current antipsychotic treatments. The investigations are based on the theory that many symptoms of schizophrenia arise from lowered glutametergic signaling in certain parts of the brain, including the frontal cortex. The scientists are defining mechanisms and agents to enhance the effects of glutamate at the N-methyl-D-aspartate receptors that induce interneurons containing γ-aminobutyric acid.

Major depression is widespread in our society, and it exacts a heavy toll. According to estimates from the National Institute of Mental Health, about 1 of every 10 American adults has some major form of depression. Bruno Conti and his group at the Harold L. Dorris Neurological Research Institute are searching for an antidepressant that is faster acting than the currently used fluoxetine (Prozac) and its competitor drugs. They are also comparing the clinically well-proven effects of sleep deprivation and electroconvulsive shock on depression. These drastic treatments are rarely used, but they are fast acting and effective when the risk of suicide is high. In collaboration with scientists at Novartis Pharma AG, Basel, Switzerland, Dr. Conti and his colleagues mapped transcriptional changes caused in different brain regions by these treatments. Now they are validating some of the findings for development of new treatments.

Many scientists at the institute study galanin signaling in the brain and the effects of the serotonergic and noradrenergic systems, the current main targets of antidepressant drugs. Galanin affects depressive-like behavior and performance in memory tasks in brain preparations and in animals. Results of this research include development of the first galanin receptor agonist that can be given systemically and that reaches the brain. The agonist changes the seizure threshold, thus slowing epileptic seizures, and also affects learning and memory. Recently, scientists at the institute showed that galanin, acting at the type 2 receptor, exerts a neuroprotective effect. Thus, agonists of this galanin receptor are candidates for treatment of depression and cognitive decline. Within the new project at Scripps Research funded by the National Institutes of Health

Roadmap Initiative, development of galanin receptor agonists will involve several experienced researchers who have decades of pharmaceutical experience, including Hugh Rosen, Department of Immunology; Ed Roberts, Department of Chemistry; Julius Rebek, the Skaggs Institute for Chemical Biology; and Jan Lundstrom and Tomas Bartfai, Molecular and Integrative Neurosciences Department.

Another area of active research at the institute involves determining which proteins in the warm-sensitive neurons of the hypothalamus are involved in thermoregulation. Thermoregulation is intimately connected with the sleep-wake cycle, eating behavior, and aging. We have produced animals that mimic the effects of energy (calorie) restriction, the only well-documented method for prolonging life span in humans and other mammals. We seek also to answer questions such as, What makes a person hot and feverish when he or she is sick? Although fever is one of the most common conditions since the origin of humans, the pathways involved and the mechanisms that underlie fever and thermoregulation are still not completely understood. However, understanding these pathways and mechanisms is important for understanding inflammatory mechanisms. Research in this area will have an impact on the treatment of “hot flashes” that occur during menopause or during prostate cancer.

Treatment for these conditions requires an understanding of their underpinnings, and this need is addressed by the Harold L. Dorris Neurological Research Institute. Founded in 1999 as the result of a $10 million long-term commitment by Helen L. Dorris through the Harold L. Dorris Foundation, named in her brother’s honor, the institute has attracted an international cadre of scientists from France, Switzerland, Sweden, Mexico, and Italy from such disciplines as neurology, immunology, chemistry, molecular biology, and endocrinology to study neurologic disorders.

 


Tamas Bartfai, Ph.D.
Director

Dorris Center Web Site