Monday, August 31, 2009

First the rhythms

Over at his blog at The Atlantic, Hua Hsu posts this sick amateur rap video

Thought it would be a good second post for a blog with this name.

Let's talk pot.

THC, and its botanical vehicle, marijuana are all over the press this week. The LA Times has produced a story describing the cultural landscape surrounding the normalization of pot.
At fashion-insider parties, joints are passed nearly as freely as hors d'oeuvres. Traces of the acrid smoke waft from restaurant patios, car windows and passing pedestrians on the city streets -- in broad daylight. Even the art of name-dropping in casual conversation -- once limited to celebrity sightings and designer shoe purchases -- now includes the occasional boast of recently discovered weed strains such as "Strawberry Cough" and "Purple Kush."

Public sentiment is more than anecdotal; earlier this year, a California Field Poll found that 56% of California voters supported legalizing and taxing marijuana. Last month, voters in Oakland overwhelmingly approved a tax increase on medical marijuana sales, the first of its kind in the country, and Los Angeles Councilwoman Janice Hahn has proposed something similar for the City of Angels. "In this current economic crisis, we need to get creative about how we raise funds," Hahn said in a statement.

Smoking pot used to be the kind of personal conduct that could sink a U.S. Supreme Court nomination (Douglas H. Ginsburg in 1987) and embarrass a presidential candidate (Bill Clinton in 1992). Today, it seems to be a non-issue for the current inhabitant of the Oval Office; Barack Obama issued his marijuana mea culpa in a 1995 memoir.

This, I believe is an irreversible process and actually a GOOD thing. Study after study has shown that marijuana's neuroactive components, cannabinoids are far less toxic than other recreational drugs. Also recently it has been shown that cannabinoids may have a neuroprotective effect. To me it is a sign of greater cultural sanity for a society to really come to its senses with regards to marijuana.

That being said, our current state of knowledge of the neurobiological mechanisms underlying marijuana's obvious behavioral effects is far from complete, which makes the report by Puighermanal et. al in this month's issue of Nature Neuroscience so important. For the first time, researchers have been able to provide an explanation for THC-induced amnesia at the cellular level. THC activates CB1 receptors leading to an increase in mTOR activity, a protein kinase that is highly involved in cell growth, proliferation, and protein synthesis. Using first an inhibitor of mTOR, rapamycin (the reason mTOR is called what it is-- Mammalian Target Of Rapamycin) and later an inhibitor of protein synthesis, anisomycin, the researchers found that the cognitive deficits accompanying THC dosing were abolished. Protein synthesis is highly energy intensive for cells and an imbalance of protein synthesis has been reported in cases of mental retardation, including genetic disorders related to autism.

This imbalance in protein translation is the end result of a network wide imbalance of excitation and inhibition. GABA is the dominant inhibitory neurotransmitter in the brain. CB1 receptors lead to inhibition of neurotransmitter release from which ever cell they are found on. Importantly CB1 receptors are found on GABAergic hippocampal neurons in numbers nearly 40 times as large as glutamatergic neurons. Widespread hippocampal activation of GABAergic CB1 receptor-positive neurons leads to a decrease in inhibitory tone, producing a relative increase in excitatory glutamatergic tone. Increased glumatergic activity leads to increased protein synthesis mediated by the all important NMDA receptor.

The paper gets pretty complicated and they used many different mice knockouts to get at their data, but the end result is that THC-induced amnesia in mice, and its human analog, "weed memory", is due to the temporary imbalance of protein synthesis due to a temporary imbalance of excitatory and inhibitory activity in the hippocampus.


Puighermanal, E., Marsicano, G., Busquets-Garcia, A., Lutz, B., Maldonado, R., & Ozaita, A. (2009). Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling Nature Neuroscience, 12 (9), 1152-1158