While the dangers of mind-altering drugs come from their health consequences, the most striking aspect of drug abuse is its ability to control behavior: The drug acts on motivational brain mechanisms, i.e., those circuits that make people want things.

That is what makes addicts, from cigarette smokers to cocaine users, unable to stop even in the face of extreme aversive health and social consequences.

It's also thought to be one reason that addiction is so difficult to treat - altering the response to reward has consequences not just for individuals' drug addiction, but also on their response to other rewarding stimuli such as food, which brings its own set of problems. Previous studies have shown that different neurons can be sensitive to different types of reward, but no one had yet investigated whether that could have specific behavioral consequences.

Research in the April 2005 issue of Nature Neuroscience suggested that in attempting to shake addiction's grip on motivation, it might be possible to separate the baby from the bathwater. In a paper titled "The Subthalamic Nucleus Exerts Opposite Control on Cocaine and Natural' Rewards," researchers from the French Centre National de la Recherche Scientifique (CNRS) in Marseille and Bordeaux chip away at the concept of a single motivational circuit.

The authors studied the subthalamic nucleus, a midbrain structure more familiar to neurologists in the context of motion than motivation; in fact, "the subthalamic nucleus is now well targeted by neurosurgeons for the treatment of Parkinson's disease" by either deep-brain stimulation or outright lesioning, said Christelle Baunez, chargé de recherche (the equivalent of an assistant professor) at the CNRS campus in Marseille and lead author of the Nature Neuroscience study.

In a series of experiments, the scientists lesioned the subthalamic nucleus of rats and tested how the lesions affected the animals' response to rewards. The fix: sucrose pellets (also known as table sugar) or cocaine.

The researchers started by investigating the effects of subthalamic nucleus lesions when either sugar or cocaine was easy to get. That experiment was more about learning that a reward can be had by pressing a lever, and the ability to perform the necessary movement than about motivation per se.

Whether they were working for sugar or cocaine, lesioned rats showed the same level of intake as controls, suggesting that a given reward is just as motivating to a lesioned animal as a normal one. It also suggested that the lesions did not affect the rats' ability to perform the task - a significant concern given that the subthalamic nucleus is known to be involved in controlling movement.

However, the picture changed when the researchers made the rewards progressively harder to get. Such experiments allow scientists to assess motivation by finding the "breaking point" for a given reward - that is, the point at which an animal will stop working for the reward because it is not worth the effort.

When the ever-receding reward was cocaine, lesioned animals stopped working sooner that controls; apparently, the cocaine was less rewarding to them. The opposite effect was seen with sucrose pellets. There, the lesioned animals kept pressing the lever, on the average, a good deal after controls had decided that a lump of sugar was not worth all the work.

"If we consider what we teach to students regarding the motivational circuit,' it is very surprising," Baunez told BioWorld Today.

In a final set of experiments, the scientist investigated whether the animals, when given a choice, would prefer to spend time in the environment in which they had previously received sugar or cocaine, and how strong such a preference would be. At the time of the experiment, no rewards were given, and so the rats' preference was indicative of the positive associations they had due to previous rewards. The results of that experiment also supported the notion that subthalamic nucleus lesions have opposite effects on food and drug rewards, meaning that while all groups of rats, regardless of either lesion status or reward, showed a preference for being in the place where they had once received rewards, that preference was stronger for lesioned animals in the cocaine group, while it was stronger for unlesioned animals in the sugar group.

It is hard to say how the new findings ultimately might be applied to clinical practice. Baunez pointed out that high-frequency stimulation and lesions of the subthalamic nucleus have both been used with success in Parkinson's patients, but Parkinson's is a progressive neurodegenerative disorder. Given that addiction is not universally fatal, and that behavioral therapies are available, patients and doctors might be much less willing to use extremely invasive methods to treat addiction.

Also, subthalamic nucleus lesions do clearly affect the response to natural, as well as drug, rewards - the lesioned rats worked harder for sugar pellets than their control brethren, and had a stronger positive association with the environment in which they received their sugar fix.

Nevertheless, the research suggests that, at least in principle, it is possible to independently affect the desire for drugs and other, healthier types of rewards. Baunez said, "I hope that my results will highlight this dissociation so that people start to focus more on the possibility for various motivational circuits."