Unfreeze Your Memory with Galantamine

Evidence for Galantamine Continues to Mount

Unfreeze Your Memory
with Galantamine

In fear-conditioned mice, galantamine reversed a
certain type of age-related memory impairment
By Will Block

No passion so effectually robs the mind of all its powers of acting and reasoning as fear.
— Edmund Burke

reeze!" If you hear that in real life, you’re in trouble, because it’s probably a cop or a robber talking (and aiming a gun at you for emphasis). Either way, it’s not good, and chances are, you will freeze—in fear. Fear is a useful emotion, because it can help protect you from harm, such as getting shot. All the fears that you acquired in your youth, such as the fear of robbers and drunk drivers and hungry lions, will probably stay with you forever.

What if, however, in your later years, you learned a new fear—a legitimate one, such as the fear of a newly discovered communicable disease (SARS, for example) that was spreading across the globe? You would probably also learn what steps you could take to help protect yourself from this disease. But what if, because of a loss of memory function due to mild cognitive impairment (or worse), you subsequently forgot what you had learned? You would then be at greater risk of contracting the disease, and your statistically calculated life expectancy would be shortened a bit. That is definitely not life enhancement.

But let’s get back to freezing. Although it’s a perfectly natural response to a sudden, unexpected threat, it can paralyze you at precisely the moment when decisive action, based on your instinct for survival (or perhaps your ability to reason, depending on the nature of the threat) is most needed. This is a tall order, as Edmund Burke observed.* It’s a challenge for mice as well as men—not that mice are known for their great reasoning ability, but they sure are useful in medical research, as we’ll see below. (And in some ways, actually, mice are pretty smart: see “Galantamine Can Modify Alzheimer’s Disease” in the October 2005 issue.)


*He was talking about the fear of consequences in the political and social arenas, but the principle is the same. You probably know Burke, a brilliant political philosopher, as the author of the maxim, “All that is necessary for the triumph of evil is that good men do nothing.” (Iraq comes to mind.) The only trouble is, Burke never said that, despite the thousands of Web pages that quote him on it. It appears to be a modern paraphrase of something that Burke did say, but its true origin remains unknown.


Can Galantamine Restore Fear Memory?

Researchers at Temple University in Philadelphia were interested in gaining new insight into the neural mechanisms by which short-term memories are acquired and subsequently retained as long-term memories. Such knowledge is valuable not only for its own sake, but also because it may point toward better ways in which to treat memory-impairing neurodegenerative diseases, such as Alzheimer’s. Probably the most effective agent against Alzheimer’s is the plant alkaloid galantamine, a nutritional supplement that is also sold as a prescription drug called Razadyne™ (formerly Reminyl®).

One objective of a new study published by the Temple researchers was to see whether galantamine could alleviate a specific type of memory loss—the loss of a fear memory—in aged mice.1 Previous research had suggested that different parts of the brain are involved in different types of learning and memory, and the researchers had reason to believe that two distinct aspects of fear conditioning might allow these differences to be exploited in trying to distinguish between the neural mechanisms for the acquisition of memory and those for the retention of memory. The two aspects of fear conditioning in question are called contextual conditioning and cued conditioning. The difference is easy to understand if you know how the experiment is designed, so let’s look at that now.

How to Frighten a Mouse

The basic idea is to determine how well laboratory mice can learn to fear a certain conditioned stimulus and how long they can remember what they learned, as measured by their conditioned response to the stimulus. (For a refresher on conditioned stimuli and responses, see the sidebar.)

Pavlov’s Drooling Dog

When your dog Buster salivates (and perhaps goes a little nuts) at the sight or smell of food, it’s not because he decided to salivate. He can’t help it—it’s dictated by the nervous system he was born with. Now, if you ring a bell every time you start preparing Buster’s dinner, it won’t take long before he starts drooling and carrying on whenever he hears that bell, even if there’s no food in sight. Buster has learned that the bell means food, and his response is still automatic, not under his control.


Ivan Pavlov (center) with his assistants and The Dog.
In technical jargon, the first scenario is unconditioned, i.e., not learned. The food is the unconditioned stimulus, and Buster’s salivation is the unconditioned response. The second scenario, however, is conditioned, i.e., learned through training. The bell is the conditioned stimulus, and Buster’s salivation at the mere sound of it is the conditioned response—he has been conditioned to associate the bell with food. (It doesn’t have to be a bell—it could be any kind of stimulus, including, of course, the lovely sound of a can opener.)

This phenomenon also occurs in cats (surprise!) and, indeed, in virtually all living creatures. The man who discovered it and explored it in depth was the Russian physiologist Ivan Pavlov, whose name became a household word as a result. Pavlov’s work in this arena is celebrated because it led to the insight that a good part of learning and of the development of human behavior is the result of all sorts of conditioned responses picked up in the course of living our lives. This provided the foundation for the school of psychology called behaviorism.

Almost lost in the excitement over the work for which Pavlov became so famous is the fact that most of it was carried out after he had already won the Nobel Prize in medicine or physiology (in 1904). The award was for his work on the physiology of digestion—he discovered the neurological mechanisms involved and established the importance of the autonomic nervous system. Crucial to the success of these studies was that Pavlov was also a brilliant experimental surgeon whose great skill enabled him to succeed where others had failed.

Pavlov, by the way, had quit the seminary to attend medical school instead, after reading Charles Darwin’s masterwork, On the Origin of Species. Ironically, Darwin had quit medical school (in part because he couldn’t stand the gore) and decided to make a career in the church! He found that he had no aptitude for that either, though, and he eventually shipped out on HMS Beagle as a naturalist. Thus was launched one of the greatest and most fruitful intellectual adventures in human history. It has inspired thousands of young people to pursue careers in biology or medicine, and dozens of them have, like Pavlov, won the Nobel Prize for their discoveries.

The mice chosen for this study were of a strain with demonstrated proficiency in fear conditioning. Two age groups were used: young (2–3 months) and old (19–20 months). The technique used was to train the mice to fear an electric shock—which is not hard to do. The device used was a chamber, about the size of a shoebox, with Plexiglas end panels, stainless steel side panels, and a floor consisting of a stainless steel grid through which a painful but harmless electric shock could be delivered to the feet of the mouse standing on it.

An electric shock constitutes an unconditioned stimulus, to which the unconditioned response is that the mouse will jump. It doesn’t take too many such incidents for the mouse to realize that the chamber is a bad place to be. This experiment, however, entailed a conditioned stimulus (a 30-second burst of loud white noise), which was followed immediately by a 2-second foot shock.*


*White noise is noise of equal intensity at all frequencies within a broad band (the term arose by analogy with white light); it sounds like a hiss. For you techies, the noise intensity was 85 dB, and the foot-shock current was 0.57 mA.


Noise/shock (wait 2 minutes) noise/shock (wait 2 minutes) noise/shock … before long, the mouse gets the idea that that noise causes a shock. He has learned that the noise is the cue to the shock, so he will subsequently fear the noise, even if the shock never comes—that’s cued conditioning. But there is a catch: the noise and shock occur in the context of being in that chamber, so the mouse will learn to fear the chamber itself, even if there’s no noise. That’s contextual conditioning. The crucial question is: will the noise cue trigger the mouse’s fear out of the context of the familiar, dreaded chamber, i.e., will the cue still work elsewhere?

Different Chambers, Different Perceptions, Same Fear

Answering that question is easy, and it enables one to evaluate the two forms of conditioning separately. To assess contextual conditioning, you put the mouse back in the original chamber a day later—with no noise and no shock—and see whether he freezes in fear just from being there; you repeat this on subsequent days to see how long the fear persists. To assess cued conditioning, you put the mouse in an unfamiliar and very different chamber that he has no reason to fear, then give him a burst of noise (but no shock) and see if he freezes in fear from the noise cue alone; again, you repeat this procedure daily.

In this experiment, the new chamber differed from the original chamber in size, shape, materials of construction, and color. Instead of a stainless steel grid, the floor was a solid plastic. For a nice touch of olfactory novelty, the researchers placed vanilla extract under the chamber to intrigue the mice.

From Cool to Frozen in a Flash

Mouse to self, after looking and sniffing around the new chamber: “Hey, this is more like it—cool!” But then comes that darned noise. “Oh, no, not again!” Mouse freezes in fear—the conditioned response. For experimental purposes, freezing is defined as remaining completely motionless except for breathing. The researchers record how long the mouse remains frozen within a given time span; they then compare that with previously recorded data on normal mouse activity, which, of course, entails “frozen” periods when the mouse happens to be standing still (perhaps thinking about the origin of the universe, or just daydreaming about cheese—who knows?). The statistical difference between the durations of normal freezing and fear freezing is a measure of the mouse’s fear (the Fear Factor, to borrow a phrase from perhaps the stupidest TV show ever).

Age Makes a Difference in One Domain

Now that we understand how the experiment was designed, what were the results? Better yet, what conclusions did the researchers draw from the results? (Having to read the details would probably rot your brain, and the whole idea of using galantamine is to prevent that.) There were four main conclusions:

  1. The aged mice acquired fear conditioning—both contextual and cued—as well as the young mice. That is, they readily acquired a short-term memory of the Bad Things (the original chamber and the noise).
  2. The aged mice were not memory-impaired, compared with the young mice, in terms of contextual fear conditioning. That is, they were just as able as the young mice to retain a long-term memory of the original chamber as being a Bad Thing.
  3. The aged mice were memory-impaired, compared with the young mice, in terms of cued fear conditioning. That is, they were not as able as the young mice to retain a long-term memory of the noise as being a Bad Thing. But:
  4. Galantamine, injected intraperitoneally 20 minutes before training or testing sessions, reversed the age-related memory impairment in cued fear conditioning. Injections of placebo (saline solution) had no such effect.

Galantamine Preserves and Protects Memory …

Aha! Yet again, as in many previous studies in both animals and human beings, galantamine has proved to be a compound with remarkable memory-preserving and memory-protecting properties. In this case, it enabled the aged mice to preserve the useful (in principle, anyway) memory of a previously learned fear. There is survival value in that, or at least the value of being less likely to come to some form of harm than would otherwise be true.

What if, e.g., you were to forget your healthy fear of the flu virus and you therefore forgot that it’s important to wash your hands frequently during flu season (because that’s one of the best ways to avoid catching it)? This is not just a theoretical example—forgetfulness in matters of personal hygiene is a common symptom of Alzheimer’s disease.

… By Boosting Cholinergic Function

The two brain regions most intimately involved in fear conditioning are believed to be the hippocampus, which plays a central role in memory processes, and the nearby amygdala, which plays an important role in the emotions (particularly fear and aggression), but also in memory. It has been known for over a decade that both contextual fear conditioning and cued fear conditioning require the amygdala, but that only contextual fear conditioning critically requires the hippocampus.

Thus, since cued fear conditioning requires the amygdala but not the hippocampus, the fact that the aged mice were as able as the young mice to acquire cued fear conditioning suggests that, during aging, the amygdala maintains its ability to support the acquisition of associative memories of this particular kind. This ability did not, however, extend to the retention of such memories in the aged mice for more than one day. That type of deficit resembles the symptoms of age-related memory decline that have been observed in both rodents and humans.2

Based on numerous lines of evidence and reasoning, the Temple researchers believe (but cannot be certain) that the inability of the aged mice to retain their memory of cued conditioning was due to a decline in cholinergic function in their brains (i.e., neural activity for which the principal neurotransmitter is acetylcholine). This might explain why galantamine was able to reverse the effect—it is a potent effector of cholinergic function in the brain. (For more on this, see, e.g., “Galantamine Helps Save Memory, and Money Too” in the December 2001 issue.)

Fear Not—Galantamine Is Available

Being afraid from time to time is normal and natural—it acts as a brake on foolish or reckless behavior and can help steer us clear of harm’s way. Of course, no one wants to be scared to death, even figuratively, let alone literally (the latter can happen, by the way), and fortunately, that seldom occurs in our mostly safe, sanitary, comfortable existence. Unlike our distant ancestors on the African savannah, we’re not stalked by predators, but we are haunted by the specter of neurodegenerative disease, which can rob us of our lives as surely as a lion could—it just takes longer.

Be glad—be very glad—that galantamine came to be on this earth and that it’s readily available to anyone who wants it. As the evidence of its effectiveness in combating age-related cognitive impairment continues to mount, we will continue, unafraid, to champion its cause.

References

  1. Gould TJ, Feiro OR. Age-related deficits in the retention of memories for cued fear conditioning are reversed by galantamine treatment. Behav Brain Res 2005 [online preprint].
  2. Winocur G. A neuropsychological analysis of memory loss with age. Neurobiol Aging 1988;9:487-94.

Dual-Action Galantamine

Galantamine provides a heralded dual-mode action for boosting cholinergic function: it inhibits the enzyme acetylcholinesterase, thereby boosting brain levels of acetylcholine, and it modulates the brain's nicotinic receptors so as to maintain their function. The recommended daily serving ranges from a low of 4 to 8 mg of galantamine to begin with to a maximum of 24 mg, depending on the individual's response.

For an added measure of benefit, it is a good idea to take choline, the precursor molecule to acetylcholine, as well as pantothenic acid (vitamin B5), an important cofactor for choline. Thus it is possible to cover all bases in providing the means to enhance the levels and effectiveness of your acetylcholine.

It’s also a good idea to take the following:

  • Green tea polyphenols, a class of antioxidants, operating together as a system, that can also fight amyloid-beta toxicity
  • Vitamin C and Vitamin E, which have been shown to work together to help protect your brain's hotbeds of free radical activity
  • Turmeric curcuminoids, a system of antioxidants that helps protect your neurons from damage or death caused by amyloid-beta
  • Folic acid, vitamin B6, and vitamin B12, important vitamins that help prevent damage to mitochondria (where they help repair DNA damage), cofactor the production of nitric oxide, and reduce levels of homocysteine (a neurotoxin)
  • Lithium, an important brain food that is found in the bottled waters of American and European health spas ... that also lowers the toxicity of amyloid-beta while causing an increase in neurotrophic factors that help induce neurons to repair themselves when under stress ... that helps cause an increase in gray matter and helps enhance neurogenesis of hippocampal neurons


Will Block is the publisher and editorial director of Life Enhancement magazine.

Ingredients in this Article

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