Milk of amnesia, no more

There is a common sedative called Propofol. It is strong, fast-acting, and allows a clear-headed recovery from its effects. It plays nicely with pain killers and is nonaddictive. Propofol d has an opaque whiteness that earned it the monicker “milk of amnesia” because it is widely used as a sedative and anesthetic. Yet when it’s given to people to maintain sedation for surgery, there’s a high incidence of traumatic memories. Seemingly paradoxically, while Propofol knocks people out it also enhances certain memories.
This is due to the fact that Propofol is a “dirty” drug. When it goes into the body and up into the brain, it doesn’t work with one brain area, or system, or even chemical. It has an entire cast of mechanisms, though with two leading actors:  the GABA system and the endocannabinoid system. GABA is the brain’s break pedal; it’s an inhibitory chemical messenger in the brain that balances out excitement. The endocannabinoid system (without which, marijuana would not be nearly as exciting) is another group of chemical messengers in the brain, though not as well understood. It was only discovered a decade ago and breaks all the rules of traditional chemical messengers in the brain. One of its well-defined and major roles, however, is to inhibit GABA – putting a break on the brain’s break pedal.
Propofol increases activity for both these systems – GABA and endocannabinoid alike. In theory, the two systems should cancel the other out, like eating a salad for lunch but having a cheesecake dessert. But reality is rarely like theory.
For one, there’s Propofol’s effect on memory. People tend to be remember more traumatic experiences during surgery when they’re sedated with Propofol than with other drugs. And that has to do with those complicated little endocannabinoids.
“but wait! When I smoke…I mean, I’ve heard that when you smoke marijuana, it’s harder to remember things!”
That is true. And it’s also true that in some circumstances, activation of the endocannabinoid system* can improve a memory. Remembering something and improving a memory are two different things.  This is because “memory” isn’t a one-step process. It is a multipart, dynamic process that is constantly churning.
It’s generally accepted that there are three stages to the act of memory:  encoding, consolidation, and retrieval.
The first step is encoding, in which the thing to be remembered makes a physical imprint in the brain. Imagine building a sandcastle on a beach. That sandcastle is that specific memory. The tidal ocean, lapping at the shores of the beach and your new sandcastle is like your brain. Both are constantly changing, and if left alone, will erase the sandcastle/memory. To make sure the sandcastle lasts, you have to reinforce it, strengthening its walls and reconstructing it after it takes some damage. That is the process known as consolidation; it reinforces a fleeting memory to give it a chance to survive in the neural sea of activity. And finally, there’s retrieval. Gazing down at the majestic beauty of your sandcastle, whenever you want to, as long as it exists.
The metaphorical memory castle

The metaphorical memory castle

If cannabinoids enter the picture before the memory process starts, then there’s difficulty in even building the sandcastle, or encoding the memory. But, if their effects come into play soon after the memory is encoded, then it can strengthen the memory, possibly due to an inhibitory effect on activity near the memory; meaning it doesn’t strengthen the sandcastle but calms the tidal waves that would otherwise wear it down, the net effect of which is preserving the sandcastle.
Tying all this together is a recent experiment that looked at memory, endocannabinoids, and the “mlik of amnesia” – propofol.
In this experiment, rats were put into a passive avoidance chamber – a two chamber box, one side light, one side dark, with a retractable door separating the two and an electrical grid on the floor. It looks a little something like this:
Yamagata Y, et al, (2009) Kinase activity of Ca2+/calmodulin-dependent protein kinase IIα is essential for hippocampal synaptic plasticity and behavioral learningJournal of Neuroscience, 29: 7607-7618

Yamagata Y, et al, (2009) Kinase activity of Ca2+/calmodulin-dependent protein kinase IIα is essential for hippocampal synaptic plasticity and behavioral learningJournal of Neuroscience, 29: 7607-7618

Rodents like dark spaces. Being in an open, light space causes them anxiety, which is why you see them in sewers and garages, not in the park or the windowsill. The test uses this instinct to test memory. When the rat moves from the light side to the dark side (much like Anakin Skywalker in Episode III), it receives a mild electric shock form the floor. In doing this, the experimenters try to create an association in the rat’s brain between the dark chamber and a shock. Later, if the rat hesitates to go back into the dark chamber, that’s taken as evidence that it remembers the shock. The length of time the rat stays in the light chamber is a measure of how strong the memory is.
After the rat is shocked in the dark chamber, it’s given Propofol: either immediately, 30 minutes, 90 minutes, or 180 minutes after the shock. Two days later, the rat is put back into the same cage and tested.
The results found that rats given the Propofol immediately or 30 minutes after the shock stayed away from the dark chamber longer, indicating they had stronger memories than those not given Propofol or those given Propofol past 30 minutes.
This suggests two things: 1) Propofol, somehow, helps solidify memories that are currently in place and 2) there’s a time limit that this effect can take place. The experimenter’s suspected that the endocannabinoids were involved with the memory effect, so they looked at the interaction between the two. In different rats, they gave Propofol and then removed the brain for analysis after 8 or 40 minutes.  After 8, but not 40 minutes, there was increase in one of the major endocannabinoids, anandamide. This time course fits – increasing endocannabinoids around 8 minutes but losing that increase after 40 minutes – fits in nicely with the memory retention data. Furthermore, when rats were given a drug that blocked any activity of the endocannabinoid system, the memory-supporting effects of Propofol disappeared.
Propofol, by increasing anandamide, helps fledgling memories stay alive! And while this doesn’t mean you should get high after studying, it does inform how this common surgery drug should be used on patients, and more importantly, creates a basis to investigate how the endocannabinoid system can be used to block traumatic memories or facilitate positive memories.

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