For release: Thursday, December 6, 1990
Animal studies have revealed new knowledge of brain chemistry in Parkinson's disease and suggest new treatment approaches, according to results published in the December 7, 1990 issue of Science .*
People with Parkinson's disease have reduced levels of dopamine — a substance important to the transmission of signals between nerve cells, or neurons — in the brain region responsible for movement control. This loss is particularly severe in an area known as the substantia nigra, which in turn effects the striatum.
"For years, the major treatments for Parkinson's disease have concentrated on supplementing the deficient supply of dopamine in the substantia nigra. But intermittent doses of dopa-generating drugs do not always result in complete symptomatic relief," said Thomas N. Chase, M.D., chief of the National Institute of Neurological Disorders and Stroke's Experimental Therapeutics branch and an author of the paper. "These new results tell us that dopamine significantly affects the striatum and other brain systems as well. Learning about these effects should offer new avenues for treating Parkinson's disease."
In healthy people and animals, dopamine regulates two major pathways originating within the striatum, maintaining the delicate balance of brain chemicals that allows normal, coordinated movements. In the current study, scientists at the NINDS and the National Institute of Mental Health (NIMH) examined how low dopamine levels in Parkinsonian rats alter the striatopallidal and striatonigral neurons that comprise these two pathways.
The study, performed in the NIMH's Laboratory of Cell Biology, found that dopamine depletion affected striatopallidal neurons by elevating levels of certain dopamine receptors — known as D2 — and of a brain chemical called enkephalin. Lack of dopamine also affected striatonigral neurons: they showed lowered levels of D1 receptors and of two other brain chemicals, substance P and dynorphin. "In other words," said NIMH investigator Charles R. Gerfen, Ph.D., "the effect of lost dopamine on the D1 receptor is completely opposite its effect on the D2 receptor."
By using medications that selectively stimulated D1 or D2 receptors, the scientists were able to reverse some of these effects of dopamine depletion. When the scientists treated Parkinsonian rats with a drug that stimulated the D2 receptors (which inhibit enkephalin) the rodent's elevated levels of enkephalin fell. Conversely, stimulating the D1 receptors (which have an excitatory effect on the brain chemicals they influence) raised the animal's levels of both substance P and dynorphin.
They also found that the way these drugs were delivered to the rats affected treatment effectiveness: D1 receptors responded to intermittent injections, while D2 receptors needed continuous treatment provided by a small pump.
These studies are already having an impact on research to treat people with Parkinson's disease; although is is too early to predict results, several trials are now beginning to test drugs that affect enkephalin, substance P, and dynorphin levels.
"This work is a fine example of the value — in fact, the necessity — basic research has for clinical progress," said NINDS director Dr. Murray Goldstein. "Only through such fundamental studies can we gain the knowledge necessary to make reasoned, and reasonable, clinical judgments."
The National Institute of Neurological Disorders and Stroke, one of the 13 National Institutes of Health in Bethesda, Maryland, is the primary supporter of brain and nervous system research in the United States. The National Institute of Mental Health is a component of the Alcohol, Drug Abuse, and Mental Health Administration and supports research nationwide on the brain, mental illnesses, and mental health.
* "D1 and D2 Dopamine Receptor-Regulated Gene Expression of Striatonigral and Striatopallidal Neurons," by C. R. Gerfen, T. M. Engber, L. C. Mahan, Z. Susel, T. N. Chase, F. J. Monsma, Jr., and D. R. Sibley, Science, December 7, 1990.
Last Modified August 7, 2009