Science Editor

WASHINGTON - In science, and in medicine, relationships that don't exist can be just as interesting as those that do.

Data presented at the Society for Neuroscience's annual meeting here in the Sunday symposium "Neuroplasticity Induced by Abused Drugs: Is It Relevant to Addiction?" was a case in point. At the symposium - co-chaired by Yavin Shaham, researcher at the National Institute on Drug Abuse, and William Carlezon, assistant professor of psychiatry at Harvard University - several speakers presented data on brain changes that occur with drug use, but specifically do not encode addiction in the brain.

"The general thinking used to be that changes in neuroadaptation must explain the increase in drug taking," Carlezon told BioWorld Today after the symposium. But with such changes observed in molecules ranging from AMPA receptor subunits to zinc finger binding proteins, clearly not all of these correlations can be causes of addiction.

To determine the behavioral relevance of various molecules that change after drug consumption, Carlezon and his colleagues use a combination of viral-mediated gene transfer to either overexpress or block certain molecules in the brain, and behavioral experiments to determine how such changes affected the response to drugs.

As part of his talk, Carlezon presented data on the transcription factor CREB and its relationship to addiction. Carlezon and his group originally were interested in CREB because they thought it might be a molecule that, when increased, can be a molecular cause of addiction. But instead, CREB appears to have quite a counterintuitive effect: It is up-regulated in response to cocaine consumption, but instead of increasing the rewarding effects of cocaine, as might be expected from a molecule that is responsible for addiction, in animal studies overexpression of CREB lead to both decreased sensitivity to the drug and to depression-like symptoms instead.

Carlezon, who in the true scientific spirit told his audience that "it's always more exciting when you find things that you didn't expect," cautioned that there are a number of ways the behavioral results can be interpreted. But one possible explanation is that CREB up-regulation after drug consumption causes aversion to the drug.

Such aversion is apparently a standard feature of cocaine addiction.

"Especially cocaine addicts will tell you that by the end, they don't even like the drug anymore," Carlezon said. However, like it or not, they do remain addicted. In practice, that means that addicts will move to polydrug use: cocaine for the addiction and another drug, often heroin, to counter the aversive effects. As if one addiction isn't bad enough.

Dorit Ron, associate professor of neurology at the University of California at San Francisco, was another speaker who showed plasticity - in this case, in response to alcohol consumption - that is not part of an addiction pathway. Instead, the pathway could be interpreted as preventing addiction. It appears to be a regulator that limits alcohol intake - in other words, something that prevents a social drinker, who drinks one or two glasses of wine at dinner, from becoming an alcoholic who guzzles six or seven.

Ron told the audience at the conference that alcoholism research has special challenges because "alcohol does not have a well-defined pharmacological site of action, unlike other drugs of abuse." Her talk focused on brain-derived neurotrophic factor (BDNF) and its regulation by the scaffolding protein RACK1.

Using a mix of molecular and behavioral experiments, Ron and her colleagues found that low levels of alcohol - "the equivalent of someone who goes to a bar and has a drink or two" - increase BDNF levels in rats via the activation of RACK1. Increased BDNF levels, in turn, will decrease alcohol consumption. Taken together, Ron interpreted those results to mean that BDNF negatively regulates alcohol consumption. Social drinking puts the brakes on further alcohol consumption, preventing it from becoming a binge.

Other speakers at the symposium included Yavin Shaham; Regina Carelli, associate professor of psychology at the University of North Carolina at Chapel Hill; Paul Vezina, associate professor of psychiatry at the University of Chicago; and Michela Marinelli, assistant professor of cellular and molecular pharmacology at the Chicago Medical School. The conference runs through Wednesday.