BioWorld International Correspondent

LONDON - The brain receptors to which the active ingredients of marijuana bind play an important role in maintaining the brain's normal functions of learning and memory, a new study has shown. Mice that lacked those receptors suffered early memory loss and had fewer cells in the part of the brain that controls learning and memory.

Andreas Zimmer, who was professor of molecular neurobiology at the University of Bonn in Germany when he conducted the study, told BioWorld International: "We now have in our hands a system that seems to be naturally involved in slowing down the aging of the brain. This is tremendously important because if we can understand more about how that works, we can capitalize on it and perhaps find out ways of improving memory."

The work is reported in the Oct. 10, 2005, issue of Proceedings of the National Academy of Sciences in a paper titled "Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors."

The main active ingredient of marijuana is a cannabinoid derivative called delta-9-tetrahydrocannabinol (THC). It binds to two types of receptors, CB1 and CB2. CB1 is found mainly in the brain, while CB2 is present mostly on cells outside the nervous system. The cannabinoid receptors, and the signalling molecules that bind to them, are together known as the endocannabinoid system.

In the light of conflicting and controversial results on the impact of cannabinoids on learning and memory, and of blocking the CB1 receptor, Zimmer and his colleagues decided to investigate the role of the CB1 receptor more closely. In particular, they examined the long-term effects of removing CB1 receptors, with the help of a genetically modified mouse that lacks a functional gene for CB1.

Using a range of tests, they evaluated the ability of mice of different ages to learn tasks or remember other mice. They categorized the mice as "young" (6 weeks to 8 weeks old), "mature" (3 months to 5 months) or "old" (14 months to 17 months).

One test assessed the animals' ability to learn how to balance on a rotating rod for 90 seconds. Young and mature wild-type animals learned how to do this easily, while old wild-type mice found it much more difficult.

Among mice without CB1 receptors, only young animals could learn how to stay on the rod for the full 90 seconds, and they learned it significantly faster than wild-type animals. But the performance of mature mice that lacked CB1 was almost indistinguishable from old knockout mice.

The researchers also tested whether the mice could remember each other. The mice being evaluated were exposed to an unknown young male. Young and mature wild-type mice could still recognize that partner one hour, four hours and eight hours after presentation. Old wild-type mice failed to recognize the partner even after four hours.

When young mice lacking CB1 performed that test, they recognized the partner after 16 hours, but not after 24 hours. Mature knockout mice, however, could recognize the partner after one hour, but not after four hours. Old knockout mice could not recognize the partner after even one hour.

A further experiment showed a statistically significant reduction in the density of nerve cells in parts of the hippocampus of the brain - a region known to mediate learning and memory - in knockout animals.

Overall, the results suggest that the learning and memory of the knockout animals is improved in young individuals but declines rapidly as they grow older.

Writing in PNAS, Zimmer and colleagues suggested that "[this decline] is related to the documented neuroprotective effects of endocannabinoids, which are mediated by CB1 receptors." Their results, they add, "strongly suggest that the endocannabinoid system has a neuroprotective function in wild-type mice that depends on CB1 receptors."

The authors also said their results have "important medical implications" for drugs that block CB1 receptors. They wrote: "To the best of our knowledge, long-term effects of CB1 receptor antagonist treatments on learning and memory, age-related decline of cognitive functions, and neurodegenerative processes have not yet been studied. Those experiments should be performed, in view of the anticipated long-term use of rimonabant (SR141716A) by patients with eating and addiction disorders."

The group also is keen to investigate whether lack of the CB1 receptor will affect the progression of Alzheimer's disease in a mouse model. Zimmer said, "It seems perfectly reasonable that if the endocannabinoid system is neuroprotective, it may also regulate the progression of Alzheimer's disease."