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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.
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