April 22, 2012 | 2
I spent the first day of Experimental Biology 2012 at the Behavioral Pharmacology Meeting, where people who focus on drugs and behavior came to share the latest and greatest findings. Most of the studies were on drugs on abuse, and this study in particular caught my eye.
Drug addiction is a vicious cycle, but the original high is not the problem. What is the problem are the changes in our brains and behavior that drive us to seek the next high, and the next. The relationship between drug-taking and the resulting high is what behavioral pharmacologists refer to as “reinforcement”. And if we are able to alter the reinforcing value of a drug, how much we desire to get that next hit, we might be able to help addicts overcome their addictions.
There are various methods that pharmacologists have tried over the years to decrease the reinforcing value of drugs in experimental situations. You can accompany a drug with an antagonist that blocks the drug effects, like combining heroin with naltrexone so that an addict attempting to take the drug cannot get high. This blocks the high, but people can always try to take more drug to overcome the antagonist effects. Another method is using long-acting, low dose drugs as replacements, such as methadone, to block the withdrawal of from drugs such as heroin or morphine. But again, people can always take more drug on top of it. Finally, there is the idea of using drug punishment. In this paradigm, you use a drug that induces nasty effects, like nausea or pain, in conjunction with the abused drug, to make people stop taking the drug. We call this paradigm a “drug punisher”.
This is the idea that Kevin Freeman, Brian McMaster, and William Woolverton of the University of Mississippi Medical Center, in their presentation at the Experimental Biology 2012 Behavioral Pharmacology meeting, have decided to work with in cocaine using rhesus monkeys. They trained the monkeys to self-administer cocaine by pressing a lever, which delivered a shot of cocaine into the monkey’s veins. This method, known as drug self-administration, can be used to study the maximum rewarding value that animals place on a drug, and how other drugs or environmental changes might be used to stop the animal from taking the drug. In this case, the authors wanted to study in particular the reinforcing value of cocaine, and how a drug punisher might change it. They put the monkeys on a special schedule of drug self-administration called a progressive ratio (PR). The monkey begins slowly, say having to press the lever only 5 times before it receives some cocaine. But after a short time of this, the requirements increase. Now the animal has to press 10 times. Then 50, then 100. At some point, it’s just too much work, and the monkey will give up, and stop pressing. Freeman et al. used this paradigm to determine how much ‘value’ an animal placed on the cocaine injection. They then set about trying to decrease that value using histamine.
Why histamine? You might be familiar with histamine as something involved in allergic responses, but it also is a punisher. It suppresses a lot of behaviors, including food self-administration. And in this case, adding histamine to cocaine self-administration made the monkeys ‘value’ the drug less. It also decreased the potency of cocaine as a reinforcer, the monkey ‘valued’ the drug less at low doses and lever-pressed for it less, showing that histamine as a drug punisher could decreasing the reinforcing value of the cocaine. And the effects of histamine on cocaine self-administration were dose-dependent, with low doses of the drug producing very little effect on how hard the monkeys worked for cocaine, while higher doses decreased cocaine’s reinforcing effects.
What can we do with this knowledge? After all, some punishment drugs have been tried before. Disulfuram, otherwise known as antabuse, is a punisher that creates severe nausea when even a small amount of alcohol is consumed. Unfortunately, it doesn’t work particularly well in alcoholics, who simply avoid taking the drug. But this is not what Freeman wants to do with the results of this research. Instead, he envisions eventually using drug punishers in combination with drugs before they are abused. If you combine an opioid painkiller with a low dose of drug punisher, for example, you could have the painkilling effects of the drug with no effects of punishment. But if you go on to try and get high off the drug by taking a lot of it, the dose of the punisher could become high enough to make you regret your choice. This may be able to stop recreational use of prescription drugs, and the accompanying reinforcement, before the habit develops.