Brain Chemical Linked to Illness Duplicated in Lab

Oregon neuroscientists have duplicated a key component of the brain’s chemical system thought to play a critical role in a number of major illnesses involving the brain, which they say represents a major step forward in research on the causes and treatment of schizophrenia, Parkinson’s disease and drug addiction.

A team headed by Olivier Civelli of the Oregon Health Sciences University in Portland reports in today’s Nature that they used genetic engineering techniques to produce large quantities of the protein to which the neural transmitter dopamine binds in the brain of rats. The rat protein, called the D-2 dopamine receptor, is thought to be virtually identical to the human version.

Cloning of the receptor has been one of the key goals of neuroscientists because it should lead to new understanding of illnesses that involve defects in dopamine utilization. This, in turn, could lead to improved drugs that are geared more specifically to fight schizophrenia and other dopamine-related conditions.

A report issued by the National Institutes of Mental Health this June, referring to the need to clone the D-2 dopamine receptor, said, “There are few areas of basic research that are as critical for schizophrenia research at the present time.”

Added NIMH Director Lewis L. Judd on Wednesday: “The cloning of the dopamine receptor is a vital step in the study of the causes of schizophrenia and is likely to prove important to the development of more effective and better targeted treatments for this disease.”

In fact, Cambridge NeuroScience Research Inc. in Massachusetts, which partially sponsored the Oregon research, is already using the cloned receptor to screen for potential new anti-psychotic drugs, according to Mark Lampert, the company’s business development manager. The company is also using the gene from the cloned receptor as a probe to look for defective receptor genes in the blood cells of individuals with various types of mental illness.

The cloning “will undoubtedly lead to better understanding of neurotransmission (communication between brain cells) . . . and may contribute to a clearer understanding of the role of that receptor in mental illness,” said NIMH geneticist Elliot S. Gershon.

Dopamine is one of the key neurotransmitters, chemicals that are used to send messages from one brain cell to another. At their destination, the neurotransmitters bind to special receptor proteins in the membrane of the nerve cells, like a key in a lock, and thereby trigger a chemical reaction within the cell.

Imbalances in dopamine production and use have been implicated in a variety of mental disorders. Insufficient production of dopamine, for example, causes Parkinson’s disease, which affects more than a million Americans. Its symptoms include tremors and rigidity of limbs, and treatment involves replacing the dopamine, either in drugs or by implanting dopamine-secreting tissues into the brain.

An excess production of dopamine, in contrast, is thought to be one of the major factors in the development of schizophrenia, which is characterized by disordered thought, hallucinations, and inappropriate emotional responses. An estimated 3 million Americans suffer from schizophrenia, including 40% of all patients in mental hospitals.

Anti-psychotic drugs such as chlorpromazine and haloperidol, which halt hallucinations and delusions, are used to treat schizophrenia because they bind to the D-2 dopamine receptors, preventing the excess dopamine from overstimulating them. But use of these drugs is limited because of their serious side effects. The most severe side effect is tardive dyskinesia, an untreatable movement disorder that affects 20% of people using the drugs.

Neurologists speculate that the side effects are caused by binding of the drugs to other receptors in the brain, thereby interfering with other mental pathways. By using the D-2 receptor to screen potential drugs, researchers hope to find agents that bind only to that receptor and that therefore have fewer side effects.

Dopamine is also thought to play a role in addiction to cocaine and amphetamines, and understanding of the receptor is expected to give new insights into that process.

The cloning of the D-2 dopamine receptor is the latest of a series of discoveries made by molecular biologists using genetic engineering techniques to study the brain. In February, 1987, Boston researchers identified a genetic defect associated with Alzheimer’s disease and Florida scientists found a gene associated with manic-depressive illness.

Last month, British researchers found a defective gene associated with schizophrenia. The protein produced by that gene has not yet been identified, however, and the defective gene may represent one of many defects that can cause schizophrenia.

Researchers are confident that other forms of mental illness will also yield their secrets to genetic engineers.