Wow! Scientopia has some fantastic readers! This year's drive for Donors Choose has so far collected $5734 for students! Go readers!

Several of the projects on the Neurodynamics giving page have been funded! This is really exciting to see. All those kids are going to experience SCIENCE thanks to a bunch of people who kicked in a couple dollars apiece and gathered together to make their projects happen.

We still have a couple of weeks for this year's Donors Choose drive, and Scientopia is in the #2 spot after ScienceBlogs! Another reason Scientopia readers are awesome! How many projects can we fund, how many kids can WIN by the time the challenge is said and done? Only time will tell!

Another project I like quite a bit is some grade-school microbiology. This is too cool- they want to investigate bacteria in their school, see what makes it grow, and generally get some hands-on fun with science. They need some very basic lab supplies. Agar, petri dishes, beakers, stuff that we professionals take for granted. These supplies will also benefit future classes, so your donation goes farther than just this year's students. They need $143.53 to reach their goal. This is not very much if we get together to help these kids. And anyone can help- even a $5 donation is that much closer to reaching their goal! Got a couple bucks to spare this week for some future microbiologists?

Equally as interesting as pharmacology, toxicology is a closely related field that studies deleterious effects of chemical compounds applied to the body. We hear a lot of generic use of the word "toxins" out and about in the world today, but what exactly is this supposed to mean anyway?

Toxicology of a given compound is determined by three main factors: what is the physiologic action of the compound, how potent is it, and what dose is being applied? Let's take a closer look at each of the factors and what they mean.

What's it do?

That's the first thing I think when I hear someone say something is a toxin. There is no single "toxic" reaction out there. Every toxicologically active chemical entity out there has its own mechanism, its own target. Some are more recoverable than others, some have pretty dire consequences; some we have antidotes for, some not. Some exert an effect quickly, while others can take their time. They can target any physiological system, or multiples.  Cause death, permanent injury, reversible injury, minimal harm, or anywhere in the middle. Locally, regionally, systemically. There are many, many examples of different actions that a given compound could do. The severity of the effects is important to evaluate.

How potent is it?

Potency is critical in toxicology. The more potent a compound is, the less of it is required to cause an effect. So if something is extremely potent, we're gonna be worried about it and carefully scrutinize any exposure level. On the other side of the spectrum, if it's not at all potent, the likelihood that a common encounter will result in severe effects is very low. This is a major consideration when thinking about how harmful a given exposure could be. If it takes literally bathing in something to cause any harm, well, it's less to worry about than a potent snake venom toxin where less than a milligram could knock you dead. This determines the amount of caution with which we approach a given compound.

Figure 1. Potency concept. (x axis should be more appropriately labeled drug dose.) High potency drugs cause effects at a much lower doses than low potency drugs. In the context of toxicology, this means that a low-level exposure is of much greater concern if the compound is of higher potency.

What's the dose?

This matters mainly because the potency factor matters. I list it separately because dose is a related but distinct factor, and also because putting vastly excessive amounts of many things into the body can cause physiological damage.

Like therapeutic effects, one can generally observe a dose-response effect when examining toxic effects of a given compound. Like so:

Figure 2. Increasing toxic effects observed as a factor of increasing dose.

In this imaginary case (as in most real cases) some doses are so low that there simply is not enough of the imaginary compound in the body to cause any effect at all. LOAEL is the lowest observable adverse effect level, or the lowest dose that reveals any adverse effects at all. Beyond that level, things start to get more detrimental. What dose someone actually gets exposed to is a major factor in the level of toxic effects might happen as a result.

Of course, exposing oneself to exaggeratedly too much of anything can be harmful. A popular example is water, since it seems pretty harmless. Drinking stupidly excessive amounts of water can screw up the body's salt balance, causing hyponatremia and possibly death. So it's not too far out there to say that going ridiculously way-out-there overboard with just about anything has the potential to cause harm.

Therapeutic index

A final note- this is a pharmacology blog, after all. Yes, there are plenty of drugs out there that have toxic effects at some dose or another. Since we typically look at/discuss therapeutic effects, it is worth mentioning that this toxicological dose-response is also considered in the process of drug development. The difference between the dose-response for therapeutic vs toxic effects is generally called the therapeutic index. Something with a very narrow space between therapeutic effect and toxic effect is said to have a very narrow therapeutic index, while something with a pretty nice distance between the two curves has a pretty favorable therapeutic index.

Figure 3: TI, or therapeutic index. The therapeutic effects (open circles) and the toxic effects (closed circles) are compared, and the difference between the curves is used to determine the therapeutic index. This imaginary example is definitely not an ideal TI, since the therapeutic and toxic effects have substantial overlap. The more space between the curves, the better.

The TI is an important consideration when looking at dosing regimens. If accidentally taking a dose twice (or slipping up on dose timing, which is something that just happens from time to time) would bump up the circulating drug levels enough to put someone on the toxic effects curve, that's something that should be avoided as much as possible by adjusting dosing regimens- or considering alternatives with more favorable TIs.

In summary

Think about this next time you run across the broad-brush phrase including how terrible "toxins" can be. What toxins is the broad-brusher referring to? What do they do? How potent are they, and how much of these toxins are we exposed to? We live in a world full of chemicals, and we're exposed to damn near everything at some level or another. Some of these do hold potential for harm. Some do, but not at levels that we're exposed to. But I suspect you'll find that asking specifics about the broad-brush "toxins" phrasing commonly used will get you some hand-waving or stunned silence. Empower yourself with understanding. Toxicology is fascinating stuff, and definitely not something to be hand-waving over.

Here's one more about the postdoc experience. A second "if only I knew" post, perhaps.

I was at the top of the grad student food chain by the time I defended my dissertation. I was a data collecting machine, I knew exactly what I was doing, and did not need to rely on anyone else to walk me through anything. (Unfortunately, this led to me making brain sections until daybreak some days.) People came to me to ask questions about techniques and equipment, and that annoyed the fuck out of me because it detracted from my insane levels of productivity. I was kicking ass, and I was not to be trifled with.

But what happens when you take that data machine and tear it from its wall plug, transport it across the country, set it down and plug it back in? Not quite so simple as returning to a data-cranking state. No, there are new connections to be made, a whole new environment to which the machine needs to habituate, probably some new techniques, some log scale administrative crap as mentioned in another recent post, and so on and so forth.

This, this is a supremely uncool transition. It's a major bump, going from the full-speed-ahead state to the re-orienting state. Expectations are entirely different. That is not to say that one should require years to get up to full speed like the first couple of years spent in grad school. No, there is pressure to get the ball rolling quickly because the duration of funding is not going to be forever. But be warned.

You are not in Kansas anymore, sweetheart. This world is not yet your oyster.

[I deny ever having said that to someone who whined too much.]

It's good practice. Nobody stays in one place forever, and if you're going to go on to do anything anywhere else, you're gonna have to learn those survival and rebuilding skills. So sack up, ramp up, and work to get that data machine status back. And learn from your mistakes, because you will make a lot of em.

up-front disclaimer: not all drugs work the same way. also, receptor adaptation does not apply uniformly, but really, what the hell DOES apply uniformly across biological systems? the brain is really, insanely complex and i can’t by any means explain all of that in a textbook, much less a blog post. i’m going to try to keep this to conceptual talk and broader principles using specific examples. now, let’s ride!

basic pharmacology

drugs work by altering the usual business of their targets. oftentimes, but definitely not always, that target is a receptor of some kind. we categorize the actions of the drug upon the receptor using the terms “agonist” and “antagonist”. an agonist increases the activity of the receptor- stimulating whatever intracellular action the receptor directs. an antagonist does the opposite- it silences the signals sent by the receptor. there are several descriptives in between- partial agonists only partially stimulate the receptor. in the case of receptors that are intrinsically active, the inverse agonist can decrease the signaling of the receptor to below the usual baseline signal.

results of initial use

these modifications of receptor activity can be used to correct errant pathways. say you have regular heartburn, and have decided to take an over-the-counter drug to remedy it. you might be taking something like Zantac, a histamine H2 receptor antagonist. this drug works by blocking the effects of histamine on certain cells in your stomach, and the endpoint is a reduction in acid production by the cells in question while the receptors are blocked. now you feel great! no more burning pain, you can go about your day.

one class of drug that you can get addicted to, but can get serious withdrawal from without being addicted, is the opioid drugs. oh man, do these have a reputation! think of percocet, vicodin, morphine, etc and usually images of addiction pop into people’s minds. however, these are legitimate clinical drugs with legitimate clinical uses, and with careful monitoring can be safely used. but let’s talk about the initial effects of the opioid drugs before we get too far into the next point i want to make. in general narcotics provide analgesia by agonist properties at the opioid receptors. usually, narcotic drugs are paired with a different type of pain reliever (such as ibuprofen or acetaminophen) for several reasons. primarily, these adjuvant pain relievers can act synergistically to provide increased relief. also, they are a deterrent for people looking to take a very high dose of the drug (but it still happens, sadly.)

one more example, this time another agonist. the underlying cause of Parkinson’s disease is the loss of dopamine-secreting cells in a very specific part of your brain called the substantia nigra. these cells are responsible for control of movement, and as they reach critical losses, motor control dissipates and leads to the symptoms of PD including tremors, rigidity, and dyskinesias. the first line remedy is to supply the brain with the dopamine it’s missing, in the form of L-DOPA. this is a pretty cool drug, so i’m gonna talk about it a little bit. L-DOPA is what’s known as a pro-drug, which means it becomes active only after it is metabolized. (also, it will not cross the blood-brain barrier in its metabolized form.) since we want the drug to work in the brain, L-DOPA is usually taken along with carbidopa, an inhibitor of the peripheral L-DOPA metabolizing enzyme. this ensures the drug makes it into the brain where we want it, before it gets metabolized away.

but over the long term… homeostasis!

it’s awesome that we have so many drugs at hand to alter the body’s function, isn’t it? the downside to all this is that the body is amazingly adaptable. you alter a system, the body alters it back! eventually, tolerance develops and you need more and more drug to maintain that same initial effect. but the big question i’m writing about is… WHY?

the answer is… homeostasis! let’s define. homeostasis is the tendency for the body to work toward an system-wide equilibrium, to work to maintain a stable state. that means the body will try to adapt to whatever drug you put into it to return to the state you are trying to correct.

tolerance of the receptor signaling system you’d like to manipulate can come from several different points in said system. cells are great at adapting to signal, and can alter receptors or any downstream components after the receptor.

receptor downregulation and uncoupling

one very common mechanism involved in tolerance to an agonist is the downregulation of the receptor. this can be via internalization/recycling, degradation, or alteration of production of new receptors. overall, the effect is that there are fewer receptors on the cell surface to receive and transmit the signal from the outside to the inside. the same amount of drug gradually has less effect! the cell has adapted to the increased amount of signal (aka drug) on the outside, and has adapted the processes on the inside to maintain its normal function despite the concentrations of drug out there. the reverse is true for antagonists. if the cell is not getting signaling from the receptors in question, it can increase receptors on the surface to scavenge as much signal as possible. now you need more drug to block the bigger number of receptors.

receptors can also uncouple from their signaling partners inside the cell, while remaining on the cell surface. i am most familiar with g-protein coupled receptors, so i will put them up as an example. g protein coupled receptors (which is a giant pain to type, so from here on out they are GPCRs) send their signal along to g proteins. these g proteins then stimulate (or attenuate) all kinds of other processes inside the cell. but some of the downstream steps of g proteins can temporarily alter the structure of the receptor itself (via phosphorylation and then recruitment of the arrestin protein, for example) to stop the receptor from transmitting signal to the g proteins. in this way, the receptor itself is “turned off” by the cell.

to make things even more complex (damn i love receptors), different internalization and recycling patterns of receptors emerge with different strengths of agonist! this is particularly true for my favorite receptor. when treated with a full agonist, receptors are recycled and sent right back to the membrane. partial agonist sends them to be degraded. my receptor downregulates MORE in response to a PARTIAL agonist! (this is perfectly logical when you see the science behind it, actually, and if anyone wants a deeper explanation i can provide it.)

adaptations after the receptor

cells are tricky in that they can alter production of just about any protein. so say you have a drug that triggers a decrease in adenylyl cyclase activity. (AC produces the second messenger cAMP, which gets itself into MANY signaling pathways.) the cell can just make more AC, homeostasis here we come. you see the cell means business in this whole homeostasis game. the house will not be beaten, so to speak.

the end result?

so what happens? the same amount of drug becomes less effective. that zantac might still leave you with a little bit of heartburn. the opioids don’t relieve the pain like they used to, and in desperation a patient takes a little more, a little more. (as i mentioned before, clinical use of narcotics includes close monitoring and drug holidays to give the system a chance to re-sensitize to the narcotics. meanwhile, patients are given a non-narcotic pain reliever and some anti-withdrawal drugs just in case.) the parkinson’s and L-DOPA case, well, that’s far more complex than a simple drug-receptor interaction. presence of dopamine leads to negative feedback- cells that are still alive and releasing dopamine start to release less of it. this, as you can imagine, only exacerbates the problem in the long run.

and getting back to withdrawal…

so now we’ve covered a LOT of ground. this is a far longer post than i expected to write! and let’s circle back to the original question: why do we have withdrawal symptoms, and why are they not a sign that you are addicted to the drug you just stopped taking?

after your cells have had some time to adapt to the presence of that certain concentration of drug you’ve been taking, they are basically optimally positioned for existence in that particular chemical environment. but you decide to stop taking the drug and remove the chemical, and pow! the cells have to re-adapt again. cells don’t usually accomplish this in an immediate manner. it takes time for the changes in signaling to instigate change in the cell’s protein composition (and therefore, function!) remember, these receptors all have their very own normal jobs to do, and what we’re doing is basically interfering with that to produce our desired effect.

sometimes this amounts to some very strong effects. when a longish-term vicodin user stops taking vicodin, for example, the opioid receptors have desensitized and downregulated so that it takes a presence of a certain amount of drug to perform the normal opioid receptor functions. suddenly, that drug is gone! receptors are not very sensitive anymore, and the amount of endogenous opioids (that is, endorphins) is not nearly high enough to maintain that new “normal” level of function! now you get the withdrawal effects as the opioid system can’t maintain its usual level of function- which includes regulation of digestion and breathing, among MANY other things. narcotic withdrawal is pretty extreme, and withdrawal from other drugs won’t necessarily be as horrible. (caffiene withdrawal, for one, is associated with nasty headaches, but i’ll take that over narcotic withdrawal.)

so withdrawal is a consequence of tolerance, and tolerance is a consequence long-term presence of a drug in your body and your cellular adaptations to it. these are all perfectly usual responses to the fact that you’re altering your body’s normal chemistry to cause a desired effect, and do not necessitate that you have developed the disorder of behavior known as addiction.

unfortunately, i have missed a lot (there is much to discuss!) but this is a very long post already, and i hope it is informative in its own right.

So you've done it! You've finished your PhD, and you've wandered your way into the right training environment. The kind where you feel challenged and like you're learning new and useful things on a day to day basis. Congratulations, now here are the keys to the quiet room where you go to bash your head against the wall repeatedly. Trust me, you will need these keys, because the amount of administrative crap that you have to deal with is on its way to a log-scale increase.

As a senior graduate student you were likely at least vaguely aware of the existence of some of this stuff. But you had no. fucking. clue. as to how much of your PI's time this stuff took up. And if you did, you might have been just a little more thankful for the whole bit where you had someone to facilitate the environment for your doing of the science.

Hindsight... 20/20.

From here on up, New Postdoc, you should know there will forever be far too much administrative crap all up in your science. What, nobody really warned you about this, you say? That's nothing new. Just hold your breath and dive on in.

Pot, aka marijuana, comes from the dried flowers of the Cannabis sativa plant. Cannabis has got that familiar leaf shape we've likely all seen before... except that this part of the plant doesn't contain a whole lot of psychotropic compound. The part that does contain the psychoactive stuff is the flower bud in female plants. So this is the part that is burned and inhaled, and gives you a "high."

Figure 1. Marijuana. (from the DEA, via about.com)

What you're effectively doing when you smoke this stuff is inhaling a vapor of all the chemicals contained in the plant. Cannabis, as you might imagine, produces a lot of molecules that have been named cannabinoids. Not all of the cannabinoids are particularly psychoactive. But among those cannabinoids is the psychoactive molecule delta-9 tetrahydrocannabinol, or THC.

Figure 2. Molecular structure of THC. (via wikimedia)

THC is a very, VERY lipid-soluble compound, which means it slips right through the membranes in your lungs after you inhale it and takes the bloodstream highway up to your blood-brain barrier. From there it easily crosses the highly lipophilic blood-brain barrier and starts acting on the brain.

It really takes very little time for the drug effects to kick in when you smoke marijuana. Eating it is another story. If you'd like to catch up on your pharmacokinetics to understand why this is, check out an older post.

But now that we've covered some of the basic background stuff, what specifically is going on here?

THC targets two major receptors that we currently know of, and as you might guess, they are called cannabinoid receptors. They are G protein coupled receptors quite creatively named CB1 and CB2, and they have quite different functions. I'm going to go backward and just briefly mention CB2, because we will be spending most of the discussion on CB1. CB2 is primarily involved in immune regulation- activation of this receptor results in suppression of immune system events like immune cell activation and proliferation, as well as production of some inflammatory mediators. It is not responsible for the psychoactive effects of THC.

CB1 is the receptor target of THC that does cause psychotropic effects.

CB1 receptors are expressed very widely in the brain. The actions of these receptors, in the various parts of the brain where they are expressed, are responsible for the many and varied effects of THC upon central nervous system function. Before I can tell you why these effects are what they are, we need to discuss how the cannabinoid signaling mechanism normally works. Let's zoom way in from the level of "brain" to the synapse, where two neurons interact.

Figure 3. The model inhibitory synapse.

Here we have an inhibitory synapse. In this case, the presynaptic neuron provides an inhibitory input, decreasing the likelihood that the postynaptic neuron will fire. I have marked the presynaptic and postsynaptic neurons, and the direction of neuronal firing. The neurotransmitter dots in the presynaptic vesicles and in the synapse are marked red because they are inhibitory. The postsynaptic receptors are red because they are receptors for this inhibitory neurotransmitter.

Now like in all synapses, information flows from the presynaptic neuron to the postsynaptic neuron via release of neurotransmitter and activation of postsynaptic receptors. This leads to changes in the activity of the postsynaptic neuron. But the cannabinoid signaling mechanisms cause a pretty uncommon event in the world of neuronal information transmission: they allow the postsynaptic neuron to modify the activity of the presynaptic neuron. Now we have two-way communication across the synapse, rather than the presynaptic neuron being the one-way communicator.

Take a look at the green part of the figure. This is the "backward" or retrograde communication that goes on from postsynaptic cell to presynaptic cell. The green dots represent the endogenous ligands of the CB1 receptor, the endocannabinoids. These are produced by the postsynaptic cell and are able to activate CB1 receptors located on presynaptic terminals. They are produced and released on demand, not stored in vesicles like many other neurotransmitters, so there are very specific triggers for endocannabinoid production.

Alright, so what do CB1 receptors do when they are activated?

Figure 4.  Presynaptic CB1 receptor effects.

CB1 receptors affect the function of the presynaptic terminal. When CB1 receptors are activated, they signal through G proteins to close calcium channels, preventing entry of calcium into the terminal. Calcium is needed for vesicles to fuse with the membrane and release inhibitory neurotransmitters into the synapse. So CB1 signaling stops inhibitory neurotransmitters from being released to the postsynaptic neuron. CB1 receptor activation also results in opening of potassium channels. In a resting neuron, these channels are closed. Outflow of positively charged potassium ions leads to increases in the net negative charge across the membrane. This is called hyperpolarization, the opposite of depolarization. As you might imagine, since depolarization causes neurons to fire, hyperpolarization keeps a neuron from firing. This further decreases the chances that neurotransmitter will be released from the presynaptic terminal. There are some other effects too, which I won't detail here.

The net result is that the postsynaptic neuron signals back to stop neurotransmitter release from the presynaptic neuron. This kind of two-way communication is not a common thing in neurons, and the presence of this system indicates a need for very fine regulation of neuronal firing in response to a variety of inputs.

Are we all on board with the zoomed-in details? Let's zoom back out to the level of a simplified circuit, now that we know how regulation of synaptic communication can be disrupted.

Figure 5. A simple representation of the hunger circuit in the hypothalamus. Excitatory drive leads to hunger, but neurons that inhibit the main excitatory pathways stop that hunger trigger.

Recall I showed you how endocannabinoid stimulation of CB1 receptors on presynaptic neurons can suppress neurotransmitter release from those neurons. So if we suppress inhibitory transmission from this circuit, we have more excitation and therefore more hunger. Throwing THC into this circuit, as someone might do when they've smoked pot, can lead to the same effect even if endocannabinoids aren't being released by the presynaptic neuron. This is, in the most simple way I can explain it, why pot smokers get the munchies. They are losing suppression of hunger pathways.

Now think of all the other circuits in your brain. Reward, memory, and motivation, for example. These are all circuits where CB1 receptors can be found, that can be affected by THC and lead to alterations in behavior. THC messes up the regulation of neuronal firing timing in the hippocampus, and you suddenly aren't so great at encoding memory. It relieves suppression upon dopaminergic neurons, leading to dopamine release that is involved in reward mechanisms. There are many places that CB1 receptor modulation by THC can result in neuronal signaling changes.

Curiosity is a natural trait of kindergarteners. The whole world is still new to them, and they want to explore and understand. This is what science is all about! And yet, science support is a little short in Chicago.

The classroom teacher, Ms. C, writes:

I received basic supplies, but I do not have any science supplies or hands-on materials. Kindergartners need hands-on materials.

While we're glad that basic supplies are provided for Ms. C and her class, this lack of hands-on science for hands-on kids just won't do.

Having hands-on equipment that can feel, smell, touch, and hear helps to open up their minds. Being actively involved is very important in learning. My students do not get the opportunity to go and discover insects or even spend a lot of time outside to see nature.

What kind of hands-on science do these kids need to discover their world? Crystal growing kits, greenhouses, caterpillars and a butterfly nursery, magnifying glasses and identification materials- among many other basic topics that are great for kindergarteners.

Let's help these kids find the joy of discovery. It's never too early to become a scientist!

The word is out! The Scientopia bloggers, along with several other science blogging collectives and independent science blogs, are racing to support science students through Donors Choose! This is my first year participating in a challenge like this, and I'm very excited to be a part of the action!

If you're not familiar with Donors Choose, they give an overview of how their donation program works here, and I encourage you to check them out. You can choose the project to which you want to contribute. You choose how much you want to give. HP doubles your donation (up to $50,000 total! w00t!). When a project is funded, students WIN! And, you'll get a thank-you letter from the class that you supported.

The great thing about Donors Choose is that every contribution adds up, and you don't have to donate a lot to make a difference! You can donate as little as five bucks, and every donation goes to help kids in a direct kind of way. That's something even the broke grad students and we almost-as-broke postdocs can feel good about without breaking the budget.

I've chosen a wide variety of projects to support through my giving page. Having grown up in a place that didn't have enough to provide the best science education to youngsters, and looking back to that from my current position, I am very enthusiastic about supporting underprivileged students in science.

Check back for updates as I feature a couple of projects I particularly like and we get some smack talk going. What, I didn't mention this is a competition? Oh, you will see.

I've briefly mentioned the BBB and other extra barriers to drug permeability in a post about pharmacokinetics. But this topic deserves a closer look.

A major challenge facing neuropharmacology is to find compounds that do what we want them to do, that are safe, and that actually get into the brain through the bloodstream.

You might think the first two are hard enough, but that third one is really the kicker. Without blood-brain barrier permeability, there's no point in giving someone a CNS-active drug. It has to be considered when considering candidate compounds for anything you want to do its job in the brain. So what is the blood-brain barrier, why is it there, and how do we have drugs that work in the brain with such a barrier in place?

The barrier, and why it's there

The BBB is a physically limiting barrier first- it's a great gatekeeper. It lets in things that need to go into the cerebrospinal fluid, or CSF (oxygen, for example, is a pretty important one) and keeps out things that have no business mucking about in the brain. As a secondary defense, it also contains pump proteins (p-glycoprotein, or PGP) that will kick out some things that manage to make it across the BBB.

Figure 1. Will It Blend Cross the BBB?

But a simple figure like this only gets the general idea across. Obviously, there is far more than a neat little black line dividing the bloodstream from the CSF. The barrier itself is made first in the blood vessels. Normally, a relatively large amount of space is present between the cells lining the blood vessels. This is to allow all kinds of things the ability to pass between the bloodstream and surrounding tissues. Anywhere else, this is a good thing and assists in immune reactions and other necessary processes. The brain, however, is not as welcoming. The spaces between the cells lining blood vessels in the brain are very narrow- they are referred to as tight junctions for good reason. To top it off, blood vessels in the brain have additional coating around the outsides in the form of astrocytes. Astrocytes are a type of glia, or non-neuronal support cell. These little guys are critical for the integrity of the blood-brain barrier, adding an extra layer of toughness and protection. The result of all this layering is something like this:

Figure 2. Astrocyte processes + tight junctions at the blood vessel wall make a very selective barrier. Look at all the cell membranes a permeable molecule has to traverse!

With a barrier like that, how do we have any drugs that get into the brain?

Some very resourceful people have taken aim at this problem over the years, and the result is that we know what properties a drug must have in order to increase its likelihood of making it across the BBB. These properties include being a relatively small molecule, being very hydrophobic (fat-soluble) to mix well with the fatty acid membrane layers, and being un-charged at blood pH (since charged molecules tend to want to hang out with water). With this information, CNS drug development has focused around these key properties. It's not always possible, though, to come up with The Ideal Solution(TM) that does what we want it to, where we want it to, safely. Probably the most compelling (and therefore overused, but i'm going with it) example is L-Dopa. In Parkinson's disease, dopamine-releasing neurons die off and cause progressively severe trouble with movement. Dopamine doesn't cross the blood-brain barrier, so it wasn't possible to just replace the dopamine that way. Someone much more clever than me came up with the idea of delivering dopamine's precursor, L-Dopa, as a pro-drug (1). L-Dopa crosses the BBB just fine, and once inside the brain gets metabolized into dopamine. Problem solved! Pro-drugs are a useful workaround for the BBB permeability issue when the option is available. Unfortunately, there is not such an elegant workaround for all cases. This is yet another reason we need more minds, more ideas in neuropharmacology- another problem that remains to be solved!