Sci deeply considered titling this post “Becoming Lindsay Lohan: Cocaine Escalation in Rats”. But then I thought…nah…too much. 🙂
Anyway, a post over at Drugmonkey yesterday got Sci to thinking about drug self-administration in rats, and more particularly, HOW we use it to model cocaine addiction in humans. Because, like other models, drug self-administration in rats has evolved over time, and will probably evolve a lot more as we come up with better ways to model how humans proceed from drug taking that is once in a while and normal, to the kind of drug taking that takes over a life. We call this escalation, and many scientists believe that there is something very important in the switch between the recreational drug taking, and that escalation toward uncontrolled drug taking that is a hallmark of drug addiction.
And what better way to talk about this, than to go to the paper that, in many ways, changed the drug self-administration world?
Ahmed and Koob. “Transition from Moderate to Excessive Drug Intake: Change in Hedonic Set Point”. Science, 1998.
But first, let’s have a little overview on drug self-administration in rats (or mice, or monkeys, you get the idea).
Drug self-administration, usually in rats, is considered the gold standard in drug addiction research. It’s the only model where the animal gets to control their own drug intake in a way that is similar to humans. Basically, you give a rat a catheter in it’s back that allows access to a vein. The catheter connects to a syringe filled with drug (often cocaine, so we’ll use that) which is attached to a pump. You then give the rat a lever. When the rat presses the lever, the pump turns on, and the rats get a shot of cocaine right in the jugular. Within certain parameters, the rat can press as much or as little as it likes, providing a picture of what animals (and thus what possibly humans) will do when given access to cocaine.
When this model was developed, the scientists working on it often gave the rats a certain amount of time per day where they were exposed to the lever, and thus to the drug. The scientists found that when you did that, the rats would perform a nice, stable amount of lever-responding for cocaine. Like this:
You can see there that rats given a short access (one hour per day) to cocaine developed a stable number of responses per hour which never really moved, no matter how long you trained them on the protocol. They would administer roughly the same dose of cocaine for days, weeks, even months.
This is really useful for people trying to study how steady rates of cocaine affect the body and the brain, of course…but is it ADDICTION? Is it out of control drug taking? Scientists didn’t think so. The drug taking never escalated, and the rats quickly became tolerant to the stimulant effects.
So for this paper, the scientists compared the effects of rats given short term access to cocaine (I’m calling these short term rats, 1 hour per day) to rats given a longer term access to cocaine (6 hours per day, I’ll be calling these long term rats). While the 1 hour per day guys showed stable drug intake as normal, the long term access guys…well…
You can see that the short term access rats are in the black circles, and the long term rats are in the white circles. While the short term rats stay flat, the long term rats…escalate. Not only that, in the panel on the right, you can see that the long term rats take more cocaine even in just the first HOUR when compared to the short term rats. The long term rats took more cocaine over all, and they also escalated their cocaine intake over time, and continued to do so for over 22 sessions. It looked like the long term rats had a more uncontrolled rate of drug taking, more similar to what you would see in a human addict.
Of course, the next question was, what could this mean. It could mean that the rats were having an actual escalation of drug intake, but it could ALSO mean that the long term rats were just more tolerant to the effects of cocaine. The authors tested this by giving the short term and long term rats different doses of cocaine. They hypothesized that if the long term rats were tolerant, and thus less sensitive to the effects of cocaine, they would take more cocaine at higher doses and less cocaine at lower doses, shifting a graph of doses to the right.
But what they got was this:
You can see that the long term rats (still the white circles) were obviously taking more cocaine (which is what you’d expect from all the coke they had been taking), but the curve wasn’t SHIFTED at all. They took more cocaine at low doses AND more cocaine at higher doses, meaning they really were just taking more cocaine, they weren’t just more tolerant to the effects.
The authors hypothesized that what they were seeing here was a change in “hedonic set point”. While the short term rats needed only a certain lower level of drug, the long term rats, even though they were just as SENSITIVE to the effects of cocaine as the short term rats, needed larger amounts of drug to be satisfied. But the final question for this paper was: not how much did they need it, but how much would they MISS it.
One of the characteristics of drug addiction is relapse, the inability to quit for good, and the tendency to go back to not just taking drug, but to taking even more of it than before. To test this in the rats, they simply made them quit by taking away the lever for about a month.
When the short term rats got the lever back, they just resumed cocaine taking as before, at the same constant level. But the long term rats went to town, and escalated their drug intake even more than before, showing a strong relapse.
So what does it all mean? It meant (this was back in 1998, after all), that the way people had been doing cocaine administration in rats, with constant, low administration, wasn’t going to cut it. Those rats were doing coke at the party, but they weren’t addicts. The long term access rats, however, came a bit closer, showing an out of control drug-taking behavior that resulted in much higher levels of drug intake. That out of control escalation looks a lot more like someone becoming a drug addict.
The tolerance question is an important one here. While the graph above with the different doses seems to show that the long term rats are not more tolerant to cocaine than short term rats, there still may be differences in tolerance. But even with the tolerance, what you get out of the escalated drug intake is the idea of a higher “hedonic set point”, that rats with long term access to cocaine are trying to reach higher levels of…high, than short term access rats.
This paper ALSO shows, as the escalation of drug intake is gradual in these rats, that there isn’t a simple “switch” where one day you’re doing coke at clubs for fun and the next day you’re an addict. Instead, it appears to be a gradual increase in drug taking, and a gradual decrease in control. And it gives us all something different to look at in drug addiction. Instead of looking at the stable drug taking over time, look at the escalation, the gradual increases and the gradual loss of control over drug-taking in humans. And with that information available to us in rats, it gives us another way to look for ways to stop that escalation, and stop the descent to addiction.
Ahmed SH, & Koob GF (1998). Transition from moderate to excessive drug intake: change in hedonic set point. Science (New York, N.Y.), 282 (5387), 298-300 PMID: 9765157
