Researchers get a grip on marijuana

From the munchies to the giggles to paranoia, smoking marijuana causes widespread changes in the brain. Now researchers at Stanford University School of Medicine are a step closer to understanding how the drug's active ingredients - tetrahydrocannabinol and related compounds, called cannabinoids - may exert their effects.

David Prince, MD, the Edward F. and Irene Thiele Pimley Professor of Neurology and Neurological Sciences, and his colleagues found that a group of neurons that act as information gatekeepers in the brain's major information processing center, called the cerebral cortex, release cannabinoids that quiet their own activity. This form of self-inhibition is a novel way for neurons to regulate their own ability to send messages to their neighbors. Tetrahydrocannabinol from marijuana may work its brain-altering magic by binding to these same cells.

"Marijuana is a major drug of abuse with actions in the brain that aren't entirely known. Now we understand one piece of the puzzle," Prince said. The work of Prince and his colleagues John R. Huguenard, PhD, associate professor of neurology and neurological sciences, and Alberto Bacci, PhD, staff research associate, is published in the Sept. 16 issue of Nature.

The cells under scrutiny lie in the cerebral cortex. This region processes information from the eyes, ears, skin and other sense organs, regulates movement and performs complex functions such as those involved in thinking, learning and emotions. The cortex contains two major types of nerve cells: pyramidal neurons that excite both local and more distant neighbors, and inhibitory interneurons that act as local dimming switches, shutting down the activity of nearby brain cells. The inhibitory interneurons prevent the brain from taking in and responding to every thought, sight or sound it encounters. They also protect against runaway excitation such as that seen in epilepsy.

In previous work, other researchers had found that pyramidal cells manufacture and release cannabinoids that bind to a receptor on the membrane of interneurons. In this process, called retrograde signaling, the pyramidal cell does the equivalent of slipping its guardian interneuron some sleeping pills. It frees itself from inhibition by releasing cannabinoids that briefly decrease the interneuron's ability to release inhibitory molecules.

In contrast, Bacci and his colleagues found that interneurons can drug themselves when they get repetitively excited, triggering a self-inhibition process. The class of interneurons the researchers studied, the so-called "LTS cells" of the cerebral cortex, manufacture and release cannabinoids that bind to their own cannabinoid receptors and shut down their ability to signal other neurons. By shutting themselves off, the interneurons block their quieting action on the excitatory pyramidal cells - an effect that can last as long as 35 minutes, much longer than what had been seen with retrograde inhibition. Without the quieting effect, pyramidal cells signal more intensely, triggering a higher level of activity in circuits of the cortex.

Prince said it's too early to know exactly how marijuana binding to the cannabinoid receptor exerts its behavioral effects. However, because the interneurons inhibit cells that have such wide-ranging effects, it's no surprise that the drug alters how people perceive the world around them. "A loss of inhibition in pyramidal cells could produce changes in perception, in motor function and in everything the cerebral cortex does," he said.

The Stanford team hopes that by studying how these receptors work, researchers may learn how to make drugs that selectively bind and block subtypes of cannabinoid receptors on one type of cell but not another. This may be one way to harness the medically useful aspect of marijuana without causing brain-altering side effects.

According to Prince, such drugs could also be useful in treating epilepsy. Pyramidal cells are among those that fire out of control during a seizure. One reason these cells fire so rapidly may be that interneurons get shut down. A drug that blocks cannabinoid receptors on some types of inhibitory interneurons might allow them to continue quieting the pyramidal cells during periods of intense activity.