Tuesday, February 28, 2006

Treatment for drug addiction?

Well, that's interesting:

Some habits are hard to break. Others become addictions. The latter group could be a figment of the past thanks to a new universal addiction-blocking substance developed by an international research effort led by the University of Saskatchewan.

The team created a peptide, a short chain of amino acids, from PTEN, a natural enzyme that acts on the ventral tegmental area, the reward center of the brain, where most drugs take effect. The peptide blocks the natural rewards that an addict experiences from an increase in serotonin—a neurotransmitter associated with learning, sleep and mood—when taking his or her substance of choice. The regulation of serotonin then modulates the levels of dopamine, a neurotransmitter active in the brain’s pleasure system...

...The study published in the March issue of Nature Medicine found that rats given large doses of both nicotine and THC, the active ingredient in marijuana, for eight days straight would show no signs of addiction or withdrawal when treated with the peptide after their course of the illicit substance ran out...

...The chemicals that wash over a human brain while under the influence of a drug are more complex than those that are active in a rat brain, and the peptide only blocks out serotonin receptors right now. Also, it’s more difficult to inject the peptide directly into a human brain.

(emphasis mine)

Okay, this really looks like a textbook example of popular media jumping the gun, which is something I wouldn't expect from Seed. Let's look at this:

1. A lab has demonstrated a method of pharmacologically manipulating a rat brain in a fashion that seems to block addiction (and it's not clear how at all, from this article, but I'll get into that later). This is actually pretty common in the literature. For instance: I, a lowly undergrad, am currently helping run an experiment in which we are currently using our third manipulation intended to prevent development of addiction. Now, I admit that there's a difference between prenting development, expression, and blocking addictive behaviors--but it's not clear from this which they're doing.

2. The phrasing of the article implies that the modified form of PTEN is taken at the end of a drug course week: "rats given large doses of both nicotine and THC, the active ingredient in marijuana, for eight days straight would show no signs of addiction or withdrawal when treated with the peptide after their course of the illicit substance ran out," although explaining that "the peptide blocks the natural rewards that an addict experiences from an increase in serotonin—a neurotransmitter associated with learning, sleep and mood—when taking his or her substance of choice" makes it sound like it would have to be taken concurrently with drug.

Now, obviously, taking a drug while you're taking cocaine specifically designed to prevent the cocaine from having effects has obvious drawbacks as a prevention paradigm. But it makes a bit more sense, from their explanation, to believe it may need to be administered within a day or two of the last drug use. You see, there's some evidence starting to build for a model of a two-step (at the level of simplification to absurdity) circuit for drug addiction, involving the Ventral Tegmental Area and the Nucleus Accumbens. The basic idea of this model (which is by no means noncontroversial) is that the VTA seems to undergo short-term changes in response to addictive drugs--lasting on the order of a day or two after last drug administration. These changes seem to induce long-term changes in the NAc, which seems to be a long-term site where addiction is maintained. Now, obviously, there's a whole lot more going on than this, but the gist of it is that I would strongly suspect that pharmacological interventions in the VTA needed to be performed within a matter of days after last drug use to have any meaningful impact on addiction. But I'll check out the article, and find out if I'm wrong (seriously, the standard "I'm an undergrad" caveat applies throughout here).

3. At present, the drug has to be injected directly into the brain. I really think that's all that needs to be said. But I can throw in a bit more: there are two possible reasons this may need to be done, and either or both may apply:

  • It can't cross the blood-brain barrier. There are a couple of ways this may be overcome. One is that it's often viable to come up with a less polar version of a drug with basic chemical modifications, that can still be bioactive at the brain's pH. I have no idea how easy this approach is, however, and suspect it can be a bit of a long shot. The other option is my household's favorite: it's also possible to circumvent the BBB via nasal administration. Yes, snorting medications is the way of the future. Unfortunately, I haven't heard of any medications taking this novel approach yet; this may be because it's still relatively new information, or perhaps just because of the obvious difficulties in standardizing doses plus the social stigma. Still, we have high hopes.

  • There is difficulty getting drug to the site of action in appropriate quantities. This is also a definite possibility, and one I have no idea how to approach. They're dealing with a modified enzyme here (which seems a bit odd, and I suspect the article might've gotten that wrong, since the only PTEN I'm aware of is a tumor suppressor gene), and it has to have more sites of activity than just the VTA. So it's quite possible that if you systemically administer enough of the drug to assure activity at the VTA, you could have all sorts of systems going haywire. So in this case, you'd have to administer directly to the VTA to limit the range of effect.

Now, I would like to make clear that I'm not trying to show any disrespect to the work of Dr.s Zhang and Quirion here, I'm just trying to demonstrate how easily a popular science article can take an interesting--but not world-changing--publication and hype the results far beyond what they seem to actually imply. I'll try to find time to look at the journal article later today, and let you know what I think about it itself and what I was wrong about.


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