What Is Sweeter than Cocaine?

It's been a while since Sci covered a good post on stimulants, and I've begun to feel the lack. I start to get the shakes, as it were.

And this post covers something particularly interesting about cocaine, something VERY interesting about refined sugars, and even more interesting, this paper looks at some of the bugs (or features!) with our current models of drug abuse in animals.

ResearchBlogging.org Lenoir, et al. "Intense sweetness surpasses cocaine reward" PLoS ONE, 2007


(You know, I wasn't going to do something this literal, but when I saw this one...well...)

When scientists are trying to study the way that addictive drugs work in the brain, and what the long term (and short term) consequences of drug use are, you basically have to find a good animal model. Humans do NOT make good drug abuse subjects, most drug abusers have been on and off of drugs for variable lengths of time, and all of them are doing far more than one drug. No one ever does JUST cocaine, so how can you know if the effects you're looking at are the result of the cocaine, the amphetamine, the alcohol, or the cigarettes? What about the marijuana. All of these drugs work in slightly different ways, and the long term consequences of each one are different, depending on length of use, how often and in what quantities people use, and so on. And of course, it's not generally a good idea to go up to a non-addicted human and say "hey, will you become a crack addict for our study?" And even if you have a non-addicted human, is what you're looking at the result of the cocaine, the alcohol they sometimes drink, the allergies meds they are on, or their ADHD medication? When it comes down to it, very few humans are really naive to drugs.

So if you want to get down to the bottom of what drugs do and how they do it, you have to look in an animal model. And this is where drug self-administration comes in.

When it comes to studies on drugs of abuse, drug self-administration is the gold standard. Basically, you give a rat a lever which grants them access to a drug (sometimes they can get the drug orally, sometimes you use a catheter which implants directly into a vein, sometimes they use a probe implanted into the brain). If a drug is rewarding or reinforcing, the rat will figure out pretty quickly that there's some goodness coming when it presses that lever. Pretty soon, if you put a rat on, say, cocaine, the rat, when it enters the room with the lever, will start banging away to get its fix.

This is a really good model for several reasons. First of all, the rat gets to give himself drug, on his own schedule, which much more closely mimics what a human would do, rather than what would happen if the scientists was giving the drug to the rat on the scientist's schedule. Secondly, the model is a good one, as if you give the rat access to an addictive drug every day, the rat will become addicted over time, showing tolerance and increased drug taking (under the right schedules). Thirdly, with a rat as a model, you can not only look at behaviors related to drug addiction (how much drug it takes over time, how hard it will work to get some drug, how it responds to similar or different drugs), you can also then look at the brain, sometimes afterward and sometimes AS the rat is working, to see what the drug you are looking at is doing to the brain over time. Obviously, it's a really great model.

And you can use a rat model of drug self-administration to look at more than just drugs. What about...sugar?

After all, sugar has a very long history with humans, and an even longer history with mammals in general. Our bodies love a good regular sugar, like a nice sweet fruit or some honey or...a Slurpee.

*slurp* (Sci loves herself a slurpee for her late night summer blogging).

In this paper, the authors didn't want to look at regular sugars in the diet, like in fruits. They wanted to look instead at refined sugars, the ones that Western humans in particular have been consuming in very large amounts. Sugars are so lovely that people (and animals) will consume them in some truly vast amounts, and can even show some signs of abusing refined sugars, though the results obviously need more work. What is definite is that there are a lot of similarities between the effects of drugs and sugar on the brain, and there are some behavioral similarities as well.

And what they wanted to look at in particular was the rewarding aspects of refined sugars. In this case, they were actually looking at saccharin, not actual sugar, because they didn't want the caloric content of sugar to weigh into the rewarding aspects of the sweetened taste. And to look at the rewarding aspects, you need to compare it to something. And for comparison, the scientists chose the gold standard of drug self-administration: cocaine.

What they did was this: take a rat. Give it a cage with two levers. Pressing one lever gets you a sip of saccharin sweetened water, while pressing the other lever gives you cocaine.


(When I first saw this movie, I really thought that the pill on the right was a liquid Advil. I still think it is, actually.)

The rats were given time before each session to test out the levers. Then, they would get one of three conditions:

1) Nothing but cocaine choice (the saccharin lever was was there, but it didn't do anything, they called this S-/C+)
2) Nothing but saccharin choice (the cocaine lever was there, but it didn't do anything, they called this S+/C-)
3) Both (S+/C+)

And here's what they got:

The white circles are when the rats had only cocaine access. You can see that they chose cocaine pretty much exclusively and at high levels (the march of circles going down shows how often they chose cocaine, which is the bottom half of the graph). The black triangles marching up are when they only had saccharin available, and obviously they picked that most of the time (the top have of the graph is saccharin).

But look at those black circles! Those are the circles where they had BOTH saccharin and cocaine available, and...they picked saccharin. THE WHOLE TIME.

The scientists went over a bunch more experiments in this vein, including changing the dose of cocaine (raising it so high as to almost cause convulsions). Never failed, the animals banged on the saccharin lever every time.

They even got rats who had previously been just administering cocaine (the S-/C+ condition) to SWITCH to saccharin when saccharin was also on offer.

And it turned out it wasn't just saccharin, they could ALSO get the same effects with a high dose of good old sugar.

So what's going on here? The scientists concluded that sugar could be considered, by the criteria in their experiment, the most addictive drug of all. I am...not sure I agree.

I do think that sugar is highly rewarding, and it SHOULD be. But there's no denying that when you're dealing with a cocaine addict, giving them a Slurpee is not going to make them ignore that line over on the mirror. The authors talk a little bit about dopamine levels in the striatum, and that sugar may produce a larger increase in dopamine signaling than cocaine (though not as large of an increase in extracellular levels). If that sounds complicated, it kind of is. You can see some of my posts on cocaine and dopamine.

But Sci is still not entirely sure about this. There are a couple of things in this paper...

First off, they did send the cocaine dose UP from a middle dose, but they didn't bring it DOWN. It's pretty well known that higher doses of cocaine have higher levels of side effects. Not only that, some behavioral economics studies have shown that lower doses of cocaine can produce similar, or even higher rates of responding. I wonder what would have happened if they had used some lower doses than their base dose of 0.25 mg/kg.

Secondly, they didn't run a progressive ratio. This is a measure of how hard an animal will work for a drug or other tasty thing, like sugar. You have the rat press once, gets some. The next time though, it has to press twice to get some. Then four times. Then eight, then 16, then...you get the idea. At some point the rat will decide that it's just not worth it and quit. So while this study DOES show that rats prefer saccharin to cocaine under these conditions, we don't know whether they will work more or less for the saccharin.

And finally...well, this could be a bug, or a feature, of self-administration in rodents. If it DOES turn out that saccharin is more rewarding than cocaine in rats, and this is not the case in humans (you could probably test parts of thing in some humans, which would be interesting), well, this could be a difference between humans and rats. It could ALSO be an issue with the self-administration model itself. Some people have criticized drug self-administration in rats, because it doesn't lead to the rat banging on the lever constantly in desperation or other things we would assume are associated with addiction. This could be just that rats aren't in for that sort of thing. It could ALSO be that there are problems with the doses we give the rats, the schedules they can administer drug under, or even the environments the drug is administered in.

All of this means that maybe self-administration isn't the best possible model. But it can be changed, and it's certainly the best model we HAVE by a long shot.

In the meantime, until we get self-administration down, there are other experiments we can do to probe just WHAT saccharin means to the brain, and how that compares to drugs of abuse, and this may be able to tell us a lot about our natural reward systems, and what drugs do to them that more natural rewards like sugar do not.

One thing is certain. Sci may not know much about coke, but her Slurpee, and her science blog, are highly rewarding indeed.

*slurp*


(Behold the power of saccharin!)

Lenoir, M., Serre, F., Cantin, L., & Ahmed, S. (2007). Intense Sweetness Surpasses Cocaine Reward PLoS ONE, 2 (8) DOI: 10.1371/journal.pone.0000698

EDIT: After some consultation with the authors, the methods for the study (the C/S conditions) were edited for clarity.

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