Cannabinoids' Role In Retinal Function Described

The UCSD researchers, in collaboration with colleagues from The Neurosciences Institute in San Diego and the University of Washington in Seattle, have described for the first time the specific distribution and effects on retinal function of the cellular receptor proteins activated by cannabinoids.

These findings, published in the December 7 issue of the Proceedings of the National Academy of Sciences (PNAS), may provide a missing link in efforts to unravel the complicated and fascinating machinery by which the retina turns light into meaningful information in the brain. The work also provides greater understanding of the effects of marijuana and hashish, drugs which have been used by man for millennia.

“The retina is incredibly complex, highly sensitive to shifts in light levels, and responsive to contrasts, colors and lines,” said Alex Straiker, principal author of the PNAS paper and a graduate student in UCSD's neuroscience program. “We understand very little about how the retina works. By demonstrating that this receptor system is present, we add another piece to the puzzle, opening one more window into how the eye works. It also suggests that marijuana affects vision because it plugs into an existing signaling system that is abundant in the retina.”

Cannabinoids are naturally occurring compounds in vertebrates, and are known to play an important role in intercellular signaling. The chemical THC found in marijuana is a cannabinoid, though different from the ones produced by the body. Two cannabinoid receptors, CB1 and CB2, were discovered only the last ten years. CB1 exists primarily in the central nervous system, while CB2 is found primarily in the peripheral nervous system.

The PNAS paper reports that the retinal cells of rhesus monkeys, chicks, salamanders, goldfish, mice and rats, all similar in many respects to the human eye, contain high levels of CB1. The researchers also found CB1 receptors localized in both rod and cone photoreceptors, the retinal structures that respond to light, processing colors and black and white images. The extensive and consistent localization of these receptors in the retinas of a variety of species suggests that they play a fundamental role in modulating the transmission of signals critical for visual perception.

“The fact that this system is so highly conserved in species separated by hundreds of millions of years of evolution suggests that it's important,” said Straiker. “Nature likes to tinker, so any time you see something this consistent, it raises eyebrows.” The paper also points to a functional role of cannabinoids in the inhibition of calcium channels involved in visual signaling.

“Two key players in the processing of light information in the retina are photoreceptors, which catch light and turn it into a signal that can be interpreted by other cells, and bipolar cells, which are next in line in the flow of information,” said Straiker. “Communication between the cells requires the release of a neurotransmitter called glutamate, triggered by calcium currents passing through a specific calcium channel. Cannabinoids are known to inhibit calcium channels. If you shut down the channel, you shut down the release of glutamate, and profoundly alter the cell's ability to signal.”

Some of the reported effects of the use of marijuana and hashish include the perception of a snowy visual field, increased light intensity and altered vision. In fact, Straiker said his interest in seeking CB1 receptors in the retina was sparked in part by accounts of dramatic alterations in visual perception following marijuana use.

These findings suggest that at least some of the visual effects of marijuana and hashish use occur at the earliest stage of visual processing, as the calcium channels critical for the normal processing of visual information are inhibited.

Co-authors of the paper are Harvey Karten, professor of neurosciences, and Greg Maguire, formerly assistant adjunct professor of ophthalmology, both of the UCSD School of Medicine; Nephi Stella and Daniele Piomelli, formerly at The Neurosciences Institute, and Ken Mackie of the University of Washington.

The research was supported by the National Institutes of Health, The Glaucoma Foundation, and the Neurosciences Institute, which receives major support from Novartis.

Straiker is a graduate student in the UCSD Graduate Program in Neurosciences, ranked as the premier neuroscience graduate program in the country by a National Research Council survey of the National Academy of Sciences. Straiker is presently continuing his work as a graduate student and researcher in the Molecular Neurobiology Laboratory at The Salk Institute, a participating institution.