Prof. Richard J Wurtman

Professor of Neuropharmacology, Emeritus

Primary DLC

Department of Brain and Cognitive Sciences

MIT Room: 46-5009

Areas of Interest and Expertise

Neural and Endocrine Regulation
Control of Glandular Functions and Bodily Metabolism of the Brain
Effects of Light, Food, and Other Environmental Factors on Mammalian Regulatory Systems
Brain Neurotransmitters and Behavior: Their Responses to Drugs, Nutrients, and Hormones
Melatonin and the Pineal Gland
Weight Loss
Obesity
Binge Eating
Alzheimer’s Disease
Sleep
Depression
Molecular and Cellular Neuroscience
Chemical Pathology of Alzheimer's Disease
Interactions of Brain Dopamine and Serotonin Membrane Synthesis
Neurochemistry
Pharmacology

Research Summary

Effects of Drugs, Foods and Diseases on Brain Neurotransmitters and Behavior
The goal is to discover safe and effective treatments for brain diseases. I do this by (1) doing fundamental research to identify a previously-unsuspected control mechanism involving brain chemistry; (2) confirming that this mechanism also works in the human brain; 3) identifying a disease in which this mechanism seems not to be operating properly; and 4) doing pilot studies to see whether a possible new treatment, based on these discoveries, actually works. Examples of fundamental principles we have discovered are the facts that (1) certain food constituents affect the chemistry of the brain, and (2) melatonin is a hormone, which is secreted at nighttime, and which promotes sleep. New treatments that have been based on this "translational research" include: (1) melatonin to promote sleep; (2) REDUX (dexfenfluramine) to treat obesity; (3) PROZAC (fluoxetine) to treat the premenstrual syndrome; (4) Citicoline- which is currently in large-scale, Phase III testing, to treat strokes; and 5) a protein/carbohydrate mixture to enhance the efficacy of L-dopa in treating Parkinson's Disease.

Melatonin
It is now recognized that melatonin, the hormone secreted by the pineal gland, has the important role of telling us when to fall asleep, and helping us to remain asleep. This recognition- as well as the knowledge that giving people low doses of melatonin can be used to treat insomnia -have their origins in research done over the past several decades in our laboratories.

Initially in studies on rats, we showed that a) melatonin is a true hormone; b) that it is normally produced at nighttime; and c) this daily rhythm in melatonin synthesis normally is generated by the environmental light cycle: light, acting via the eyes, inhibits melatonin synthesis. Subsequent studies in the MIT Clinical Research Center showed that in humans, like rats, the hormone is produced at nighttime but not during the daytime. Moreover, in humans, nighttime melatonin production was found to decrease markedly with age, such that in most people over the age of 50, instead of having blood levels rise from 10 to 100 (picograms/ml) at 10 PM -midnight, they rise only to 20 or 30.

We suspected that the nighttime rise in blood melatonin levels might allow this rhythm to serve as a time signal to the brain, and that this signal might be used in turning on and maintaining sleep. Finally, in 1993-1994, we showed that if young people received tiny doses (0.3 mg orally) of the hormone in daytime- when blood melatonin levels are very low -they became sleepy and fell asleep. (The sleep thus produced is normal, electroencephalo-graphically. And the effect of the melatonin in producing sleep is independent of its ability to shift rhythms.) The correct dose of melatonin for this purpose, 0.3 mg, is just sufficient to raise blood melatonin levels to their nocturnal range, but very much lower than the dose sold for various unproved purposes in many health-food stores.

Older people often complain of insomnia, particularly difficulty in staying asleep, and in falling back to sleep after they awaken at night. Doses of melatonin which give them "youthful" blood melatonin levels correct this insomnia.

Alzheimer's Disease
A generally-held if unproved view of Alzheimer's Disease is that the brain changes and dementia result from toxic effects of an abnormal protein, called amyloid, which is a polymer of a small fragment (A-beta) of a protein (APP) that is produced normally in all cells. Hence a major goal of researchers hoping to treat this disease is to find drugs that will decrease the formation of A-beta from APP, and increase the production of APP's other major metabolite APPs ("soluble APP"). We have shown that the synthesis of APP, and the proportions of this protein that are broken down to A-beta or to soluble APP, are under the control of particular neurotransmitters and the "second messengers" they generate. For example, the neurotransmitters acetylcholine, serotonin, and glutamate act via particular receptors, and the second messenger diacylglycerol, to promote the breakdown of APP to soluble APP, and to suppress its breakdown to A-beta. In contrast norepinephrine and prostaglandins, acting by some of their receptors and the second messenger cyclic AMP, promote the synthesis of the APP molecule. Thus, using drugs that act on these receptors, it should be possible to block the formation of APP and all its metabolite, or promote the formation of soluble APP and suppress that of A-beta (and amyloid). This has now been demonstrated in tissue culture, and is in the process of being demonstrated in animal models of Alzheimer's Disease. The next step will involve transferring these technologies to come up with an effective treatment for diminishing the amount of amyloid in the Alzheimer's Disease brain. Conceivably, this may ameliorate the dementia of the disease.

Precursor Control of Brain Phospholipid Synthesis
Over the years we have found that the rates at which brain cells produce a number of important compounds, for example the neurotransmitters serotonin, dopamine, and acetylcholine - normally depend on brain concentrations of their precursors (tryptophan, tyrosine, and choline). It now appears that the syntheses of phosphatidylcholine and certain other membrane phospholipids also depend on precursor availability. The main precursor is cytidine, a compound that is not present in the final phospholipid product, but which, when phosphorylated to CTP, controls a key step in phospholipid synthesis (i.e., the combining of phosphocholine and CTP to form endogenous cytidyldiphosphocholine [CDP-choline]). When neurons are stimulated to produce neurites, for example by exposing them, in culture, to Nerve Growth Factor, another precursor- diacylglycerol-can also become limiting in phosphatide synthesis.

These observations have led to a possible new drug for strokes and brain injury. Goals of treating these conditions include a) diminishing the ultimate size of the damaged area (which usually expands during the initial week after the stroke, because of the release of toxic compounds, like arachidonic acid oxidation products from nearly dying cells), and b) facilitating the regrowth of damaged axons and synapses by surviving neurons. Both can be obtained by giving a drug, Citicoline, that breaks down to choline and cytidine, and thereby increases CTP and phosphocholine levels in the brain. Current studies show that Citicoline-again acting via choline and cytidine-also increases the production of soluble APP, which is believed to enhance neurite outgrowth. Citicoline is currently in what may be the final phases of testing to become a recognized treatment for stroke.

Neurochemical Mechanisms Underlying Cocaine Dependence
The actions of cocaine, and the development of dependence on this drug, have generally been thought to be mediated by increased intrasynaptic levels of brain dopamine. We suspect that a relative serotonin deficiency may also be involved, particularly in the depression that often develops following cocaine withdrawal. We now find that cocaine-withdrawn rats exhibit a "carbohydrate-craving" (i.e., they chose to eat relatively large quantifies of carbohydrates - which, in turn, are known to raise brain serotonin levels); moreover drugs that selectively enhance serotonin-mediated neurotransmission diminish the depressive manifestations of cocaine withdrawal.

Recent Work