Sugar and Cocaine, Episode TWO

Sci had a chance to blog an interesting paper on the value of cocaine in rats (as compared to nice stuff like sugar), and someone pointed out to her that the authors had done a follow up! I think what they found in this followup is really rather exciting and has some very interesting implications for the field of cocaine abuse (at least, I think so).

So here we go. Cocaine vs Saccharin: WWE edition.

Cantin et al. "Cocaine Is Low on the Value Ladder of Rats: Possible Evidence for Resilience to Addiction" PLoS ONE, 2010.

To most scientists who study addiction, cocaine is one of the most addictive substances known. It's one of the gold standards for looking at addiction in rodent models like rats. If I got a nickel for all the times I have heard (and said) "well, did you look with cocaine?", I would be making one heck of a salary. Cocaine is a great drug to test in rodents. It always works, and you can see it working, and most of the time, you can get a rat to bang on a lever for it without very much trouble.

Many drug studies looking at the addictive value of a study use a model called drug self-administration. I explained it in my previous post (with pictures!), but basically, you give a rat a catheter in its back. You then put it in a cage with a lever. When the rat bumps into the lever for the first time, he gets a dose of cocaine through the catheter. The rat pretty quickly puts two and two together and starts banging on the lever for its hits.

This is a good model for several reasons. First, the rat controls its own drug taking, much like a human drug addict might. You can also get rats that are pretty well addicted to cocaine, presumably in the same way a human is, and you can then look in the brain (or in other tissues, I guess, but why on earth study anything but the brain! Brain = best organ 4ever!) and see what's going on.

But a rat is not a human, can rats get addicted to cocaine in the same way humans can? To investigate this, the scientists in this study looked at the rat's preference for saccharin (a sweetener with no food value) vs cocaine. And they found something interesting. They found that rats will choose saccharin over cocaine almost all the time.

So what does this say about saccharin? What does this say about cocaine? What does this say about rats and self-administration of drugs? This paper decided to go one better, and conducted a detailed study seeing just HOW MUCH the rats really liked this cocaine.

To do this, they had to use a schedule called progressive ratio. Give a rat two levers, one with saccharin, one with cocaine. The rat knows which is which. Then let him press. For each lever, the first press will give a shot. But the next shot takes two presses. Then four. Then 7 (for a linear increase). Then 10...and so on. The point at which the rat gives up and poops out is called the breakpoint, and scientists think that it represents the motivation a rat has to take cocaine, or how hard they will work.

What you can see here are the breakpoints and total responses rats gave for cocaine vs saccharin. It looks like the rats worked harder for the cocaine. However, this is what happened when you let them try ONLY cocaine or ONLY saccharin. If you gave them the choice of BOTH, the rats consistently ignored the coke lever. They appear to work harder for cocaine, but prefer saccharin by choice. The high PRs for cocaine here could reflect, rather than a preference for cocaine, the fact that the rats are really hopped up and just pressing like heck.

In every test they looked at, the results came up the same. When asked to respond for cocaine, the rats responded really well. But when given a choice of levers to press, most of the rats picked the saccharin lever. Only about 15% of the rats ALWAYS picked cocaine, no matter what. The scientists took this further with changing the "price" of the saccharin (with lower concentrations and the same number of presses required, the saccharin becomes more "expensive") and found that cocaine only competed with saccharin when the saccharin concentrations were so low that the water was barely sweet at all.

The authors concluded that, when no other thing was on offer, most rats will take cocaine. But when something else is there, the rats will take that instead. EXCEPT for a small group of rats, less than 15%. That small group of rats took cocaine over saccharin, they took cocaine over sugar, they took cocaine through hunger and thirst and everything else. The authors described them as having a greater "avidity" for cocaine, while other rats who always preferred sugar may have resistance to cocaine addiction

So what does all this mean? You might think this means that rats aren't addicted to cocaine and are therefore a terrible model, but I disagree. In fact, I think this is incredibly interesting and rather awesome.

Here's the deal. The vast majority of scientists have taken reports from humans saying that cocaine feels better than any other thing (food, sex, love) on earth. But the thing is, we're getting those reports from CRACK ADDICTS. This is not to say that the crack addicts are wrong. In fact, they are probably right. But they are right only in so far as the way they, personally, feel about cocaine. And the thing is, most people who try cocaine or other drugs will not become addicted to them. But enough people WILL become addicted to drugs that drugs still constitute a major social and economic problem.

And isn't that interesting. Most people who try cocaine will not become addicted to it, only between 12-16% of people who try cocaine will go on to become addicted. Most rats that try cocaine will prefer saccharin, and possibly, most humans who try cocaine will think that was a sweet ride, but not really worth it. But there's a subset of people, and a subset of RATS (interestingly around 15% in both species, though that could be coincidence with this group of rats and shouldn't be taken as an indicator), who will hit that cocaine lever and be unable to stop, and for whom cocaine has a value beyond anything they have ever tried.

This could mean two very important things for the drug abuse field. First, it means that we may need to change our definition of what we call an "addicted" rat. Until now, we've been giving rats cocaine, and using in experiments any of those that bang on the lever (what's REALLY interesting is that there are always some rats who WON'T bang on the lever. They aren't used in experiments for cocaine abuse because obviously they don't abuse cocaine. But DANG I want to look at those rats). While those rats that just bang on the lever may be fine for looking at cocaine abuse in some ways....they may not really give us the picture we want to see. Because most of those rats may never really value cocaine the way a human addict does, and when given another option, will stop. These aren't the rats we're looking for.

But what about those 15 % of rats that DO prefer cocaine to sugar?! I think it would be incredibly interesting to compare them to human addicts, and to compare them to other rats. How are they different? How are their responses different? How is their behavior different? How are their brains different? Perhaps we should be selecting (maybe breeding, or maybe using those naturally occurring in the population) rats that DO prefer cocaine to all else, focusing on the vulnerable individuals who are most like human cocaine addicts.

Are those the addicts we are looking for?

Cantin L, Lenoir M, Augier E, Vanhille N, Dubreucq S, Serre F, Vouillac C, & Ahmed SH (2010). Cocaine is low on the value ladder of rats: possible evidence for resilience to addiction. PloS one, 5 (7) PMID: 20676364

EDIT: Upon consultation with the authors, the progressive ratio methods were edited for clarity, and my spelling got a good bit better.