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The reefer connection: Brain's "internal marijuana" signaling system implicated in very early stages of Alzheimer's pathology

funny brain cactusIt's axiomatic that every psychoactive drug works by mimicking some naturally occurring, evolutionarily adaptive, brain-produced substance. Cocaine and amphetamines mimic some aspects of a signaling chemical in the brain called dopamine. Heroine, morphine, and codeine all mimic neuropeptides called endorphins.

Tetrahydrocannabinol, the active component in mariuana and hashish, is likewise a doppleganger for a set of molecules in the brain called endocannabinoids. The latter evolved not to get us high but to perform numerous important signaling functions known and unknown. One of those is, as Stanford neuroscientist Dan Madison, PhD, puts it, to "open up the learning gate."

In a key mammalian brain structure called the hippocampus,  which serves as (among other things) a combination GPS system and memory-filing assistant, endocannabinoids act as signal boosters for a key nerve tract - akin to transformers spaced along a high-voltage electrical transmission cable.

But the endocannabinoid system is highly selective in regard to which signals it boosts. Its overall effect in the hippocampus is to separate the wheat from the chaff (or in this case, would it be appropriate to say "the leaves from the seeds and stems"?). This ensures that real information (e.g., "that looks like some food!" or "I remember being here before") gets passed down the line to the next relay station in the brain's information-processing assembly line.

A new study in Neuron by Madison and his colleagues shows a likely link between the brain's endocannabinoid system and a substance long suspected of playing a major, if mysterious, role in initiating Alzheimer's disease. As I wrote in a release accompanying the study's publication:

A-beta — strongly suspected to play a key role in Alzheimer’s because it’s the chief constituent of the hallmark clumps dotting the brains of people with Alzheimer’s — may, in the disease’s earliest stages, impair learning and memory by blocking the natural, beneficial action of endocannabinoids in the brain.

This interference with the "learning gate" occurs when A-beta is traveling in tiny, soluble clusters of just a few molecules, long before it aggregates into those textbook clumps. So does it follow that we should all start smoking pot to prevent Alzheimer's disease?

Hardly. Again, from my release:

Madison said it would be wildly off the mark to assume that, just because A-beta interferes with a valuable neurophysiological process mediated by endocannabinoids, smoking pot would be a great way to counter or prevent A-beta’s nefarious effects on memory and learning ability... “Endocannabinoids in the brain are very transient and act only when important inputs come in," said Madison ... "Exposure to marijuana over minutes or hours is different: more like enhancing everything indiscriminately, so you lose the filtering effect. It’s like listening to five radio stations at once.”

It may even be that A-beta (ubiquitously produced by all the body's cells), in the right amounts at the right times, is itself performing a crucial if still obscure service: fine-tuning a process that fine-tunes another process that tweaks the circuitry of learning and remembering.

Previously: The brain makes its own Valium: Built-in seizure brake?, How villainous substance starts wrecking synapses long before clumping into Alzheimer's plaques and Black hat in Alzheimer's, white hat in multiple sclerosis?
Photo by Phing

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