Science Editor

Three recent papers reported a set of new findings that bookend addiction. One reported on traits that contribute to its beginnings, while two others - one clinical research, one animal study - reported on compounds that appear to be able to reduce both regular and relapse-like drinking.

The first paper, published by researchers from Cambridge University in the June 6, 2008, issue of Science teases out the contributions of novelty-seeking and impulsive behavior in the likelihood that rats will start to self-administer cocaine, and that they will continue to do so in the face of negative consequences.

"This persistence of behavior in the face of adverse or aversive outcomes," senior author Barry Everitt explained in a Science podcast, "really captures the notion of compulsive drug-taking."

In their research, Everitt and his team compared groups of animals that were naturally impulsive or tended to seek out novelty to those that were not. They found that rats prone to seeking novelty were more likely to start to self-administer cocaine than control animals. Impulsive animals, on the other hand, were no more likely to start using cocaine - but once they had started, they were less likely to stop once the cocaine was sometimes followed by an electric shock.

Drug addicts as a group show both novelty seeking and impulsive behavior, Everitt said in the podcast. However, "it's never been clear until this study whether that impulsivity and that sensation-seeking is a cause or a consequence of their chronic drug-taking. The big issue with clinical studies of addiction is that your starting point is, by and large, individuals who are addicted."

His team's studies, he said, suggested that impulsivity is a cause, rather than a consequence, of drug addiction.

The second paper, published in the June 10, 2008 issue of the Proceedings of the National Academy of Sciences, showed that the neural growth factor GDNF can reduce alcohol consumption in rats under several different circumstances.

When the authors infused GDNF into a part of the brain known as the ventral tegmental area, the animals did not press the lever as much as animals injected with a control substance, and thus decreased their alcohol consumption. The authors also tested the so-called reacquisition of a previously learned response - a form of learning that has similarities to relapse in drug addicts.

The effect was extremely rapid, with GDNF blocking both regular and relapse-like drinking within 10 minutes of its administration.

GDNF also affects the response to cocaine, but in the PNAS paper, it had no effect when sugar replaced alcohol as the reward, suggesting that it specifically affects the brain's response to addictive drugs rather than natural rewards.

Molecularly, the GDNF appears to act by blocking activation of the Mapk/Erk kinase pathway, but has no effect on PI3 kinase.

The authors concluded that their findings "put forward the potential use of targets within the GDNF pathway for the development of treatment against alcohol abuse and, most importantly, relapse."

Promising as the results are, previous attempts to use GDNF to treat Parkinson's disease have not been successful - not to mention that it has been necessary to directly infuse the drug into the brain in those studies, which might be a harder sell for alcoholism than for Parkinson's disease.

But a third paper - this one a clinical study in the June 9, 2008, issue of the Archives of Internal Medicine - showed that Ortho-McNeil Neurologics' drug Topamax (topiramate), which currently is approved for seizures and migraine headaches, also may have a future in treating alcoholism.

In a 14-week study of roughly 370 diagnosed alcoholics, the authors found that treatment with topiramate led to improvements in both the physical and psychosocial consequences of drinking, confirming and extending findings first published in 2004.

The authors found that 14 weeks of treatment with topiramate lowered blood pressure, cholesterol levels, body mass index and liver enzyme levels, including enzymes that are used as markers for alcohol consumption, which suggested that patients receiving topiramate drank less than placebo-treated controls.

The researchers also found that topiramate treatment improved patients' psychosocial outcomes, a critical issue in treating alcoholism.

Among other results, the researchers showed that patients receiving topiramate slept better and had fewer obsessional thoughts about drinking than controls.

As the authors pointed out in their paper, "its extensive secondary physical and psychosocial consequences are what make the burden of the disease so devastating."