By David N. Leff

Virtue is its own reward, said the philosopher. And cocaine's reward, said the neuroscientist, is cocaine.

"Cocaine is thought to be one of the most intensely rewarding substances known," observed neuroscientist Eric Nestler, director of molecular psychiatry at Yale University, in New Haven, Conn. "This means that cocaine is rewarding because when people take it they like to take it again — and again. That psychological reinforcement keys in to the principal quality of cocaine, which leads to its compulsive use. Cocaine does produce euphoria, of course, but it's not clear whether the euphoria and the reinforcement are the same thing.

"One of the things that make us think they might be distinct," Nestler told BioWorld Today, "is the fact that people describe a phenomenon where the cocaine becomes less and less euphoriant; users get less and less of a high, yet the compulsive drive keeps accelerating."

To get a handle on this addicting behavior, and how it works in the brain, Nestler turns to laboratory rats. He reports his latest experiment on turning rodents into cocaine junkies in the current issue of Science, dated Dec. 18, 1998. Its title is "Regulation of cocaine reward by CREB." (See BioWorld Today, Sept. 16, 1997, p. 1.)

The CREB protein, he explained, stands for "cyclic adenosine 3',5'-monophosphate [cAMP] response element binding" protein. "As a transcription factor," Nestler pointed out, "CREB can turn other genes on and off. And there's evidence that CREB itself is regulated by cocaine in a brain region — the nucleus accumbens — known to be important for drug addiction."

Nestler and his co-authors transferred the gene that expresses CREB via a herpesvirus vector into the two-millimeter-wide nucleus accumbens of rats, and then tested their interest in cocaine.

That reward-assaying experiment placed these brainwashed animals in a chamber with two contrasting color-coded walls for example, one striped, the other polka-dotted. Normally, a rat couldn't care less for one or another side.

"However," Nestler recounted, "first, we took an animal and gave it cocaine, then put it in one patterned side, then placed another treated rat on the other side. When we did that a couple of times, we could go back the next day or the next week, even the next month, and see that giving the animal a choice, it will hang out on the side where it got cocaine. This placement preference test is thought to be a particularly good animal model of cue-conditioning effects of drugs of abuse that are very powerful in people also."

But cocaine was only a come-on. Then the team treated their rodent clients to CREB.

"And we found," Nestler said, "that when we mimicked cocaine action by increasing CREB function, we actually decreased the animal's interest in cocaine, whereas decreasing CREB function had the opposite effect.

CREB Pinch-Hits For Coke

"CREB being a transcription factor, we were interested in finding other genes that it would regulate," Nestler went on. "We came upon one of the body's endogenous opioid peptides, called dynorphin. It's a close chemical cousin of endorphin and enkephalin. There was evidence that dynorphin was regulated by CREB, and opposed cocaine reward. So, it seemed like a plausible target. What we did first was show that, indeed, increasing CREB function increased dynorphin expression in this brain area. And we were able to block that effect of increasing CREB function and decreasing cocaine reward by giving our rats a dynorphin antagonist.

"That kind of closed the loop on this story," he observed, "going from a change in gene expression to a change in behavior."

To confirm the effectiveness of their viral-mediated gene transfer, the co-authors scrutinized the neurons of the rats' nucleus accumbens and neighboring brain regions.

"We verified, first," Nestler said, "that the virus hadn't produced any damage to the brain area. Secondly, we wanted to find out over how large a region of brain the virus was producing its effects. As we had hoped, these effects were very well circumscribed, maybe to one or two millimeters in diameter. Thirdly, as a control, we injected the virus into a neighboring region and did not see the same behavioral effects.

"In humans, in real life," he said, "the nucleus accumbens seems to regulate people's natural rewards — deciding when to eat, when to sleep, when to drink, when to have sex, when to fight. By extrapolation it's thought to mediate the rewarding properties of even things like gambling, chocolate, shopping — obviously harder to study in a rodent.

"It's believed," he added, "that drugs of abuse are addicting because they commandeer this natural reward pathway. That they activate the pathway with such power and persistence that the pathway itself becomes less sensitive, less responsive to the cocaine. In fact, we think that one mechanism for that loss of sensitivity is the increase in CREB and dynorphin. Which means that when addicted people come off the drug, they don't feel right. And that the easiest way to feel right again is to take the drug, thus leading to a vicious cycle.

Psychiatric Mechanism Points To Medication

"If we could take advantage of this information," Nestler suggested, "we might identify compounds that dampen cocaine reward. Drugs, for example, that activate agonists to dynorphin receptors. These — or perhaps other agents that somehow activate the cAMP pathway, and thus CREB — could conceivably be used to treat cocaine addiction.

Viagra, the impotence drug, inhibits the enzyme phosphodiesterase, which breaks down cAMP. Viagra is actually a drug that increases cAMP function. It does so on a type of the enzyme that's present in smooth muscle, not in the brain. So, a number of pharmaceutical companies are trying to develop a Viagra-like substance that's specific for the brain. It wouldn't have any effect on erectile function, but would conceivably affect these reward systems."

Meanwhile, Nestler and his group at Yale "are identifying other target genes for CREB. Dynorphin is probably one of maybe 100 genes that CREB regulates. Each of those genes," Nestler concluded, "will challenge us to find out what role it plays in regulating addicting behavior, and thus represents a putative target for medication development." *