By David N. Leff

Science Editor

Q: How many psychiatrists does it take to change a light bulb?

A: Only one. But the bulb must want to be changed.

This golden oldie has a certain resonance vis-à-vis addiction to drugs of abuse.

"The irony of that 'Just-say-no-to-drugs' slogan," observed neuroscientist Eric Nestler, at Yale University, "is that despite everything that's been said about 'say no,' a cocaine addict really has to want to get better.

"For me," Nestler told BioWorld Today, "the transition from initial drug abuse to addiction comes when a person can't say no any more. When despite horrendous feedbacks that would dissuade normal people from using the drug — such as losing a job or a relationship, getting physically sick, whatever — when a user loses that self-control, the addiction takes over.

"A lot of things have been talked about over the years," Nestler pointed out, "but to this day there is no well-established, clearly effective treatment for cocaine addiction."

In the widespread research movement to find pharmacological fixes for cocaine addiction, Nestler, who directs the laboratory of molecular psychiatry at Yale, is presently focused on an elusive gene called Fos and its mysterious delta-FosB proteins.

"Cellular Fos," he recalled, "was first found as a gene responsible for osteosarcoma, an often-fatal bone cancer. Then," he continued, "it was cloned and found that, in addition to being an oncogene, it occurred in normal cells. In the late 1980s," Nestler went on, "researchers at the Roche Institute, in Nutley, N.J., discovered that Fos is induced dramatically in brain, in response to all sorts of perturbations. Almost anything that would insult the brain selectively activates Fos in those assaulted neurons.

"We've known for a long time," he pointed out, "that those delta-FosB proteins are induced in brain by drugs of abuse. These proteins are transcription factors," he explained, "which bind to DNA and regulate the expression of other genes. So they are thought to play a critical role in controlling the function of cells, including neurons."

But the identity and functions of these proteins remained on the most-wanted list.

To track them down, Nestler and his colleagues constructed knockout mice that lacked the Fos gene. "And it turned out," he recounted, "that these knockout mice are hypersensitive to cocaine and its effects. That led us to hypothesize that the cocaine-induction proteins that happen in a normal animal represent its neuron's attempts to counter cocaine action."

Hyper Mice Act Out Cocaine's Behavior

Today's Proceedings of the National Academy of Sciences (PNAS), dated Sept. 16, 1997, carries an article, of which Nestler is senior author, titled: "FosB mutant mice: Loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine's psychomotor and rewarding effects."

Their experiments compared two kinds of behavior by delta-FosB-minus rodents and wild-type animals, both fed addictive doses of cocaine. One test measured their restless movements in a cage. "Cocaine makes mice move," Nestler observed, "and the more of it we gave them every day, the more and more their locomotor activity increased. That's drug sensitization.

"Interestingly," he added, "the knockout mice, on placebo, looked as if they were already presensitized. Their stepped-up locomotor activity made it look as if they had already been exposed to cocaine."

The second behavioral experiment mimicked the well-known human phenomenon that even fully reformed addicts feel their old craving kick back in when they see, hear or visit old haunts where they used to get high.

"Our place-preference assay," Nestler recounted, "put a mouse in a color-coded cage with two halves, one striped, the other solid-color. Mice can tell the difference, but normally they don't care; they'll hang out equally in both.

"We'd treat a mouse with cocaine," he recounted, "and put it on the striped side, then give it a placebo and place it on the solid side. Days or weeks later, when we gave the now-drug-free animal a choice, it would hang out on the side where it used to get the cocaine. And the knockout mice were much more susceptible to developing this behavior than their normal wild-type counterparts."

Findings Bring Anti-Addiction Fix Closer

When the Yale team analyzed the brains of cocaine-treated knockouts, they found that "the delta-FosB proteins were totally absent from the specific brain regions that normally react to such drugs.

"If delta-FosB is indeed providing this feedback-protective role to the brain," Nestler went on, "we propose that it could potentially be exploited for pharmaceutical development. There are biotech firms devoted to that purpose," he added, "Probably the best known is Tularik Inc., in South San Francisco. Their goal is to target transcription factors for drug development, although in the context of cancer. Targeting the brain is a bit more challenging, but certainly worth investigation."

Meanwhile, Nestler's group has constructed transgenic mice wherein they can induce delta-FosB selectively in various key regions of the brain's striatum. "We would predict," the Yale molecular psychiatrist said, "that by so doing we'd make them more resistant to cocaine; they'd have the opposite effect to our knockouts."

His next step is to cross-breed both experimental rodents "and induce a correction of the deficit seen in the knockout. That's where we're heading now."

Nestler concluded: "I think that pharmacological therapy for cocaine has been a very challenging area for the pharmaceutical industry. And it's one that a lot of companies have not devoted a lot of attention to. But it's something that is clearly needed in society. And I think that neurobiologically, it's really a question that can be addressed now in a rational way." *