Pharmacology

The following are bits of writing from many sources such as personal correspondence, posts to on-line discussion groups, notes, and occasionally even some journaling. All of this is informal in nature, but contains some interesting and/or useful information.

Welcome to the Monkey House
[Posted to the neuroscience group on MySpace.com]
>please make a drug that permanently makes people less angry, so that I can distribute it in the water supplies everywhere kthx
As for the original question, the "heightened alertness" of this post 9/11/01 era made people look more closely at this idea of drugging the water supply. My lab was funded to research the idea of using cultured neuronal networks as broad band biosensors with which to sample the water for neuroactive compounds, so I tended to watch the reports on such a threat relatively closely.
However, the experts almost universally doubted the possibility based on the typically tremendous volume of reservoirs that supply our drinking water. The amount of any drug that would have to be dumped into such a body in order for it to achieve an effective concentration at your tap would be inconceivable, especially since everyone drinks bottled water or soft drinks anyway.
Now, if you want to have a significant effect on the population, get a job at Starbucks and switch the coffee for decaf and see if the world doesn't chill out a bit.
On a more serious note, Kurt Vonnegut famously tackled a question to this effect in his short story "Welcome to the Monkey House" (found in the story collection of the same name and probably in most freshman English short story anthologies). I won't spoil it for anyone, but I will say it's worth reading if you're interested in pharmacology, free will, and ethics.

Pharmacology
An interesting effect of SSRIs (and a good lesson on brain anatomy) is that you will be aware of certain feelings, but no longer act on them or be affected by them while on medication in the same manner as you were while unmedicated. My plethora of OCD and other symptoms demonstrate this all the time. I have a compulsion, but I just think I'm going to do it, and I don't. My frontal cortex is unaffected (as I understand it there are no serotonin receptors in the FC), but my limbic system is on track. The habits are present as memories, but not the impetus for action.

More neuroscience
[Posted to the neuroscience group on MySpace.com]
Chocolate doesn't have much of an effect on men. In fact, one of the differential effects of the stuff was accidentally demonstrated during an fMRI study a year or two ago. The study was designed to map the mental processes involved in taste the way we have for other modalities such as hearing and vision, so the subjects were given various foods while they were being scanned. As you already guessed, one of these was chocolate. One of the "incidental findings" of the study was that the male participants eventually reached a satiation point beyond which they really couldn't eat any additional chocolate without feeling sick. By contrast, the women in the study *never* reached that point. So now we understand Valentine's Day... and maybe have a little more insight into what happened to Anna Nicole Smith!
Incidentally, I think Jon's original post was about people being less angry, not necessarily that they had to be happy. There are a lot of cases of mental dysfunction in which individuals engage in rages without any clinical depression (although I should point out that anger/rages are somewhat typical of "low-grade" depression in males whereas the expected lethargy is almost the norm in females). Many in the population also suffer from lack of prefrontal control, which results in impulsive (read: "thoughtless") outbursts in which they act on their first thought and respond negatively. Conversely, a person *with* control would still have the thought but would be better able to mitigate the response such that it would come out more diplomatically, if at all (e.g., some are great at holding their tongues; others are just crass).
There's an excellent lay article on the most extreme cases of such lack of control and the science behind it by New Yorker magazine writer Malcolm Gladwell at:
http://gladwell.com/1997/1997_02_24_a_damaged.htm

Self-medication
This is a fairly well-studied phenomenon among people with abnormal brain chemistries. Although it sounds like some sort of holistic healing or anti-physician approach, it isn’t. What people tend to do when they aren’t “right” is to find a pharmacological treatment that brings them back to balance. People with ADD, for example, tend to go for stimulants: everything from caffeine to cocaine; anything with an amphetamine-like effect. Schizophrenics are smokers in far greater numbers than the general population, largely because of several chemical agents with anti-psychotic properties found among the other 4,000 compounds in tobacco. Alcohol works on depression ironically because it is a depressant. However, what it depresses is the inhibitory components of the brain. Thus, people become “disinhibited,” the complete opposite of when depressed. There are other examples (e.g. chocolate for jilted women), but I’m not as familiar with their mechanisms.

Neuroscience
[Posted to the neuroscience group on MySpace.com]
>>What do u think are going to be the greatest advancements in this area of neuro?
>the greatest developments will come from research discovering new receptors and their natural ligands.
While new compounds are constantly being discovered, they are only extending our ability to influence things at the synaptic level. Essentially, we are compensating for excesses and/or shortages in neurotransmitters when, in fact, the problem is almost always more systemic (hence the effect on behavior that created the need for the individual to seek aid in the first place).
The paradigm-shifting developments in neuroscience and psychiatry will more likely come from gene manipulations that will address the issues that lead to the problems we presently "bandage" with pills. By that, I mean that medication is a temporary treatment that only lasts until the next dosage whereas changes at the genetic level would continually exert an influence. I don't claim to know how this will be accomplished or I would be at the patent office right now, but the end result will be larger and more permanent changes at the cellular level (e.g., to up/down-regulate transmitter function as necessary) as well as at higher levels where more global pathologies (schizophrenia being the stand-out example) are the problem.
Note that it is possible that we are already addressing this issue without our knowledge. For example, after being on the market for more than a decade by this point SSRIs (specifically, I believe it was Prozac) were recently found to promote the growth of new neurons in the brain (I wish I could be more specific here, but I couldn't find the article to fact-check myself). It is possible that other drugs may have similar secondary effects that are responsible for their positive influence. Indeed, maybe these should be regarded as primary effects from the theraputic perspective.
While no one can refute the notion that *nurture* has a strong influence on the ultimate design of the brain, nature can hardly be discounted where any biological phenomenon is concerned. While some disorders are inherited outright, other genetic components only confer a *predisposition* toward an unhealthy outcome. Either way, the move "beyond pharmacology" will have to address the genetic components that result in faulty wiring in the first place.

Headphones as L-DOPA
What helped me get around to doing the mundane chores was having a part of cordless headphones connected to either my computer or tv. Lately, I've been using the mp3 player to the same end.  It helps me keep my mind occupied while I'm doing things like, for example, (from today) filling my car's tires, the bike tires, hanging up the bird house, and trimming bushes, all of which take me away from the computer or tv or anything else I would rather be doing.

Part of this may also be that the "pleasurable" effect of experiencing books on tape (or whatever) stimulates dopamine pathways.  This transmitter is also the involved in movement (the lack of it results in Parkinson's and Parkinsonian symptoms in other conditions).  If you recall the movie Awakenings with Robin Williams, one of the treatments that worked was to expose the patients to things they enjoyed.  This brought them out of their catatonic states and got them up and moving again.  And it wasn't just playing *any* music that would do it.  In one case, they had to play Jimi Hendrix to motivate a particular patient.  Interesting.


Pharmacology
[Posted to the neuroscience group on MySpace.com]
>Could someone please explain to me how a new generation drug like strattera evidently differs so substantially in its chemistry compared to classic ADHD drugs (e.g., ritalin and adderall) that it can be considered a "non-stimulant"?
Stimulants tend to also dump out neurotransmitter vesicles, so there is an abundance of NTs in the synapse. I'm going to stick to that generalization without going any deeper because, otherwise I will reveal my ignorance.
However, there are sometimes secondary effects via the circuitry. For example, Analytic [another member of the forum] pointed out in the Amphetamines thread in this group that "Amphetamine... binds directly to beta-NE receptors causing increased dopamine release." Again, you've got DA release, but because you've activated something "upstream" (as opposed to directly activating DA receptors and/or blocking DA reuptake).
>...why aren't other drugs such as Wellbutrin and Provigil--which act almost exclusively on dopamine to my knowledge-- classified as stimulants?
Actually Wellbutrin (aka bupropion) also acts on norepinephrine reuptake (i.e., it inhibits both). I've read that it also has an effect as an SSRI as well, but not great enough to be regarded on the level of, say, Prozac (aka fluoxetine). As a result, most sources seem to avoid saying they know its actual mechanism of action. (I read a bunch about it back when a friend started it and asked me how it worked; I hit dead ends in most sources I tried.)
I don't know much at all about Provigil, but I read that it does not work directly on dopamine receptors. For those outside the field, this is relatively easy to test by making (cloning/expressing) copies of all the known dopamine receptors and seeing whether a given drug binds (i.e., sticks) to them. There are more involved approaches than that, of course. These are usually tried as well, just in case someone can get a publication out of it.
>Is there any truly definitive medical definition of “stimulant”; or is it more of a colloquial term?
I don't know the answer to this one or any of the rest. (Didn't want you to think I just missed them though.) Anyone?
A final point for anyone interested in this topic: Don't just focus on the NT involved. You also have to consider the mode of action (e.g., inhibitory vs. excitatory effects on the receptor, reuptake inhibitor, or transporter overloader... or whatever they call this last category) as well as the brain area(s) involved.
At this stage of the game, we're taking a "shotgun" approach to brain function by throwing a bunch of chemicals at pretty much every brain region and hoping they'll produce a strong therapeutic effect by hitting the desired targets. In the meantime, there's often a lot of collateral damage in the form of side effects... and these vary across the population taking the drug in question. It's still a very messy approach.
What's in the future?:
---More selective chemicals that will target subpopulations of receptors. (e.g., SSRIs keep more serotonin active in the system, but what if only one subtype is the problem? There are more than a dozen known types of serotonin receptors. SSRIs are indiscriminant among these.)
---Better delivery methods. (e.g., Many mood disorders originate in the prefrontal cortex and/or limbic system, yet the drugs applied affect common receptors found throughout the brain, not just in the errant brain regions.)
---Genetic manipulation. (e.g., The sky's the limit here, guys.)
Anyone looking to be a millionaire should look into solving any and all of these problems.

Neuroscience for Dummies
[Posted to the neuroscience group on MySpace.com]
>is there anything special in the head that sends crap to our bodies to enable us to move and think?
I'm not sure if this is a serious post or not, but I guess I'll address it either way.
On a gross level, certain neurotransmitters are usually associated with specific functions. For example, the one typically associated with movement (thanks to its role in Parkinson's disease) is dopamine (commonly abbreviated DA), although acetyl choline (aka ACh) acts at the neuromuscular junction so that neurons can basically tell specific muscles to "jump" at a given moment.
As for thinking, well, that's a bit more difficult to address concisely. By that, I mean that "thinking" has a lot to do with the architecture of the brain as much as the neurotransmitters, but most of that has never been worked out. That being said, the main NT usually associated with the brain is glutamate (yes, the basic amino acid), although GABA is also very important (you would have nothing but a continuous seizure without it), as well as countless neuromodulators and several other neurotransmitters like NO and serotonin (5-HT).
Note that most of these transmitters play multiple roles (e.g., DA in pleasure-seekig behavior and addiction), so the story is much more complicated that the above might lead you to believe. Regardless, that's a start.
Search for "neuroscience" and some of the above terms and you will likely find some good primers on the web. I also posted some links on here earlier to good resources including my own links page (shameless plug).

Balance
Most psychologists would argue that people try to achieve balance. They look for excitement when things are dull and try to find calm when things are too intense. In a sense, you're self-medicating with something other than external chemicals.

Wiring
Ultimately, in treating mental disorders, I'm sure the attention will be directed toward the wiring, not just the currents (i.e, "chemicals") running through them. That's where the real problem lies. The hope is that the wiring will slowly alter itself into a healthy configuration while the patient uses the drugs as a crutch. Unfortunately, they typically need this crutch all their lives.
One approach toward altering aberrant connections is to combine behaviorism with pharmacotherapy such that, at least in this example, disorders such as post-traumatic stress disorder may be "cured" (or at least attenuated sufficiently that it no longer impairs function). The paradigm is to treat the patient with canabanoids (read: marijuana and/or its derivatives) while exposing the patient to the normally caustic stimuli (e.g., gunshots, police sirens, or whatever else normally triggers a panic attack). Since he is relaxed by the drugs under the controlled conditions, the exposure fails to trigger as dramatic a response. This is essentially an exercise in extinction by behaviorist methodology, just "suped up" (or down, as the case may be) by the presence of the drug(s).
Pot also has the much-studied effect of "unwiring" emotional memories in the amygdala, which is exactly where these PTD memories most persistently reside (they also trigger cortical episode memories of the events surrounding the initial stressor, such as being in the battlefield, but the emotional component is in the amygdala). The future of addiction therapy lies down a similar path. And, I note the irony of giving drugs to addicts, but a number of therapies (methadone being the standout) have been accepted.

Tom Cruise
Tom Cruise quoted in the Boston Herald: "When you talk about postpartum, you can take people today, women, and what you do is you use vitamins. There is a hormonal thing that is going on, scientifically, you can prove that. But when you talk about emotional, chemical imbalances in people, there is no science behind that.'' (from http://thetrack.bostonherald.com/moreTrack/view.bg?articleid=88217) Yep, he's an authority. Apparently, hormones are made from vitamins. Everything you learned in biochemistry is wrong. Well, according to Jerry Maguire.

Numbers
As always, things are rarely so black and white that they can be prescribed without a lengthy list of possible side effects. But there's a huge gulf between possible and probable. Which one do you plan your day around?

Drugs
>Did you do acid during your Pink Floyd days?
No, but that was something I really wanted to try. However, I was always afraid to do it for a couple reasons. A lot of my friends were doing it at the time (late '80s, early '90s), so I heard the good and the bad. I saw some of them become burnouts from it. You know the type that has a 5 second delay between when you ask them a question and when you can get an answer out of them? Also, some of them were doing it often enough to experience flashbacks, and that was something I really didn't want to deal with. It's one thing to set aside an afternoon to trip, but I didn't like the fact that there was no control when it came to the flashbacks.

An example approach
[Posted to the experimental psych group on MySpace.com]
Before I address the specifics of the possibility of a NMDA/psilocybin connection, let me look at some general issues:
Receptors aren't everything.
If you're looking for pharmacological effects at the level of feelings and/or behavior, receptors are only one link in a very lengthy chain, and there are a lot of caveats along the way.
Depending on how particular you want to be about this analogy, receptors act as "switches" or "knobs" that trigger and/or modulate firing of neurons. And if you're talking about a particular compound acting as a neurotransmitter, you also have to realize that the same NT may act on multiple receptor subtypes (e.g., the, what, 20+ types of serotonin receptors! I haven't checked for the latest count), each of which may act in an excitatory or inhibitory (or even modulatory?) fashion.
At the cellular level, which neurons are affected is important because, just at the most basic level, you may be stimulating (or not) an excitatory neuron or an inhibitory one. As a result, somewhere downstream you may have the completely opposite effect of activating or depressing something via the same upstream signal.
And then at the level of brain regions, you may be dealing with a network (or collection of networks) that contribute a positive or negative effect to a process (e.g., the prefrontal cortex inhibits impulsive behavior initiated/mediated by more primitive brain regions while the cortex continues to process and determine the best course of action in the face of a set of stimuli).
It's a complex story, and you'll notice that the greatest certainty anyone can offer is at either extreme. We can speak authoritatively at the level of pharmacology of what binds to what, and we can speak about behavior and subjective effects on perception, etc., but everything in between is only incompletely understood... but it *is* at least incompletely understood.
So... psilocybin?
I have never run across anything that indicated that psilocybin binds directly to NMDA receptors. But it's a big world with research constantly going on, so I could be wrong, but I didn't turn up anything in the literature with a few casual attempts. As you mentioned earlier, there are simple enough (well, relatively) ways of testing to see if a given compound as any affinity for given receptor. Further, if such an affinity was found, follow-ups could be performed in expression systems (e.g., Xenopus oocytes, etc.) and patch clamped to determine if there was any biological effect (i.e., acts as agonist? antagonist? modulator?).
All that being said, I wouldn't have expected psilocybin to have an effect directly on the NMDA receptors simply because it is already mimicking a common NT: serotonin. Of course, once again, it wouldn't be unprecedented for an NT from one family to make an appearance in another receptor. For example, glycine (an NT in its own right) is required in not one but two binding sites in the NMDA receptor in order for it to function.
A little more about the NMDA receptor
This receptor is widely-regarded as central in learning and memory (mainly because of empirical evidence to that effect and partly) because it has a complex mechanism of gating that facilitates the Hebbian model of "fire together, wire together." Like other receptors (e.g., GABAa), the NMDA receptor has multiple binding sites for both endogenous compounds (and ions!) as well as quite a variety of drugs.
It is also one of the most plentiful receptors in the cortex (I've heard it said that the cortex is more that 90% glutamatergic neurons), so even small effects on this system could conceivably cause large effects collectively. And these need not be direct effects on the receptors themselves. For example, in Aghajanian & Marek (1999, cited/linked above), it was pointed out that there was an increase in glutamatergic release, so this was an upstream mechanism. Depending on the architecture of the system, this might even mean that the effects at the serotinergic level were amplified.
All this probably goes the opiate (aka, more commonly, "opioid") receptors as well, but I know less about them, so I'm keeping quiet where they're concerned.
So... you were saying?
Regardless, I'm still not getting to the basis of the euphoric effect you're looking for. This isn't something I keep up with as much as I'd like to, so rather than drawing from my own limited knowledge at this point, I'm just going to give you a possible approach.
Personally, I would search for what is known about which brain region(s) is(are) involved in euphoric states. For example, something like this study: "Cortical gray matter volumes are associated with subjective responses to cocaine infusion" or "" Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria will tell you what is thought to be typically activated/depressed in order to achieve euphoria. These might also tell you whether your hypothetical "cascade" of multiple brain regions is on the right track (though I'm guessing not; as you describe it, such an even is more akin to epilepsy than an emotional state).
From findings like those, you might examine the literature for studies of receptor densities for pharmacological effects of interest. On a related note, you might pursue the anatomical literature for tract tracing studies to determine which areas project to/from the region(s) in question. It all depends on what you're trying to ask (and it may be more than you ever thought was implicit in the original question).
Ultimately, like everything else in neuroscience, you may find that you haven't really found answers so much as really, really refined questions.
I'll be curious to see what you come up with, so keep us posted.




Copyright Alexplorer.

Back to the index