Brain’s Marijuana ‘Receptor’ Is Identified : Medicine: Researchers say the discovery should help ‘fulfill the promise’ of the substance as medicine.

After two decades of searching, government researchers have finally identified the specific site on the surface of brain cells where marijuana binds to induce its mood-altering effects.

Identification of this so-called cannabinoid receptor, reported today in the British journal Nature, should provide a major step forward for researchers who are trying to produce drugs that have the positive medical effects of marijuana without its accompanying intoxicated feeling, disorientation and impaired perception and memory.

Marijuana has been found to have therapeutic effects on epilepsy, glaucoma, asthma, nausea, pain and hypertension. It is now used to only a limited extent in treating nausea in cancer patients, however, because of both the moral issues associated with its mood-altering effects and the severe restrictions the government has placed on the growth and sale of marijuana.

The existence of a receptor means that the brain almost certainly produces its own chemicals, similar to those found in marijuana, that are used in communication between brain cells. Moreover, the location of the cells involved suggests the chemicals may be involved in memory and intelligence, as well as having therapeutic properties.

“The receptor’s not there just so people can go out and smoke pot and get high,” said pharmacologist Tom I. Bonner of the National Institute of Mental Health in Bethesda, Md., a co-author of the paper.

Those naturally occurring compounds or synthetically produced derivatives could be the foundation of a whole new family of drugs.

The identification of the cannabinoid receptor should “vastly accelerate drug development, fulfilling the . . . promise of marijuana as medicine,” said neuroscientist Solomon H. Snyder of the Johns Hopkins University School of Medicine. “I’d say it’s one of the most important discoveries in marijuana research.”

Pharmacologist Lisa A. Matsuda and her colleagues at the institute sifted through genetic material in the brain cells of rats until they found a gene that looked like a good candidate for the cannabinoid receptor.

They then inserted the gene into cells from the ovaries of Chinese hamsters. These cells, which are widely used in research, do not normally respond to marijuana. But when Matsuda exposed the genetically altered cells to delta-9-tetrahydrocannabinol, the primary ingredient of marijuana, they exhibited a biochemical response that could only have been stimulated by the receptor.

Although the Nature paper reports only on the rat brain receptor, Matsuda said in an interview that her group has found a similar gene in human brain tissues.

The researchers also determined where in the rat brains the receptor was being produced. They found that is was most common in the cerebral cortex, which is the seat of all conscious sensations and actions, memory, will and intelligence. The concentration of cannabinoid receptors is also high in the hippocampus, which plays a crucial role in short-term memory.

In addition to new forms of disease therapy, identification of the cannabinoid receptor could lead to development of new compounds to ease the craving of people who have become habituated to marijuana.

Matsuda also speculated that some mental disorders whose causes are currently unknown may be the result of defects in the cannabinoid receptor. Because of the discovery of the receptor, she concluded, “we can learn a lot more about how the brain works.”

The discovery also provides a definitive solution to a dispute that has been roiling the drug abuse research community for years.

Many researchers did not believe that a cannabinoid receptor actually existed. Because delta-9-tetrahydrocannabinol is a molecule that dissolves readily in fats, researchers long assumed that it exerted its effects by dissolving in the membrane of brain cells and disrupting normal activities.

That is the mechanism, for example, by which most anesthetics work.

Two years ago, Allyn C. Howlett, a pharmacologist at the St. Louis University School of Medicine, reported experiments that strongly indicated that a cannabinoid receptor did exist and that predicted many of its properties. The work suggested that the receptor was found primarily in parts of the brain involved in thought, learning and memory.

“Her work . . . was probably not accepted by a large group of people because of a lot of evidence that argued against a receptor theory,” Matsuda said.

“Our results show that there is a gene present that produces the protein that she described,” thereby confirming Howlett’s work and vindicating her arguments, Matsuda said.

In a telephone interview Wednesday, Howlett said that she and her colleagues have isolated a chemical that they believe is the brain’s naturally occurring cannabinoid, but that the work is too preliminary to discuss.