The researchers looked at the role of the natural substance cholecystokinin (CCK) in modulating communication between cells in the brain. CCK, originally isolated from the digestive tract, is one of the most abundant small proteins, or peptides, in the brain, and it is linked to psychiatric disorders such as anxiety, depression, and schizophrenia.
The study appears as an Advanced Online Publication in Nature Neuroscience.
Using sophisticated electrophysiological measurements, the UC Irvine team showed that CCK functions in the brain as an extremely specific switch with a highly unusual, dual action. On the one hand, CCK enhances the synthesis and release of natural marijuana-like (endocannabinoid) substances from a particular class of nerve cells known to modulate neuronal excitability in brain circuits critical for cognition and mood. On the other hand, CCK robustly increases electrical activity in a different class of nerve cells that play critical roles in learning and memory.
"These results reveal a new mechanism for CCK to regulate nerve cell activity in a highly specific manner," said Csaba Foldy, postdoctoral researcher in anatomy and neurobiology and lead author of the study.
The study looked at the hippocampus, the region of the brain involved in learning, memory and emotion. Damage or alterations to the hippocampus can cause cognitive disorders, epilepsy, and mental illness.
"By linking CCK actions to endocannabinoids, the study provides novel possibilities for the future development of therapies for a number of neurological diseases," said Ivan Soltesz, professor and chair of the Department of Anatomy and Neurobiology and senior author of the study. "Cannabinoid compounds are interesting because they act through special receptors on nerve cells to modulate these cells behavior."
"This discovery offers the potential for new drug therapies because the link between CCK and cannabinoids can now be further investigated to determine how its modulation by either pharmacological or genetic means alters excitability in the hippocampus," he added.
???We didn't monitor the estrous cycle in the female mice, so it's likely we sampled from different estrous phases in different animals,??? Charles said. ???Yet we still found a consistent difference in the CSD threshold between males and females. Our results suggest that the female brain has an intrinsic excitability that predisposes them to migraine that may not be simply linked to a specific phase of the menstrual cycle.???
These results are exciting, Charles said, because they may represent a model for understanding the mechanisms underlying the increased prevalence of migraine in women. In addition, they add to growing evidence that CSD is a key target for the development of new migraine treatments.
In a separate study, the researchers identified what they hope will eventually be a new treatment option for migraine. They found that a medication called memantine (brand name Namenda), which is currently approved for the treatment of Alzheimer's disease, inhibits CSD and appears to be a highly effective treatment for some patients with frequent migraine. In the retrospective study, 54 patients who were treated with memantine for at least two months were asked to fill out a survey describing their experience with the medication. The majority, 36, reported a substantial reduction in estimated headache frequency. These were all patients who had previously tried other treatments without success.
While Charles cautioned that these results need to be confirmed with a larger study, the encouraging results are an example of how new insights into the basic mechanisms of migraine are leading to novel approaches for therapy for the hundreds of millions of individuals worldwide who suffer from this disabling condition.