Exposing the Roots of Addiction

by Kate Egan

There are many schools of thought on what drives people to drug addiction, be it biological predisposition, lack of willpower, or plain bad luck. Most scientists agree, though, that addiction is a complicated and combustible recipe, a potent mix of chemical, environmental, and social ingredients. They also agree that intense and uncontrollable cravings are what thwart most addicts' efforts to stay clean over the long haul.

Emory researchers are looking for ways to help addicts kick their habits, to get clean and stay that way. They are probing the underpinnings of addiction in different stages, across species, from various angles -- chemically, genetically, and behaviorally. Their work includes opioids and benzodiazepines, which also will shed light on addictions to alcohol and nicotine. But their most immediate goal is to create a medication to help cocaine users, for whom no treatment currently exists.

Developing a cocaine substitute

"We could use a cocaine medication to
stabilize the user and a vaccine at the
same time so that if they started using
cocaine again, it would have no effect,"
says Mike Kuhar.

A cocaine medication needs to have a gradual effect to avoid the precipitous lows that send users running back to their habit

Part of the strategy in their cocaine research is to develop a substitute drug, like methadone for heroin.

Cocaine achieves its euphoric effect by raising dopamine levels in the brain, allowing dopamine to remain outside the cell for longer than usual. With chronic cocaine use, the dopamine system becomes reset and can take months or years to normalize after drug use has stopped.

To speed up normalization of the dopamine system, Georgia Research Alliance Scholar and Yerkes scientist Mike Kuhar and his collaborators at the Research Triangle Institute (RTI) in North Carolina have developed a class of drugs called phenyltropanes. Like cocaine, they act by binding to transporters to prevent reuptake of dopamine back into the cell. But because they are more potent than cocaine and more specific for certain transporters, the hope is that they can be used in lower doses, with lower abuse liability, less toxicity, and fewer side effects.

Studies of these drugs progress from rats to monkeys and, eventually, to humans. After Kuhar tested the top phenyltropane candidates in rats, Leonard Howell, a behavioral neuroscientist in psychiatry, tested them in squirrel monkeys, which he had trained to self-administer cocaine in response to certain cues.

The monkeys provided Howell with information on potency and onset of action. A cocaine medication should have a slow onset of action, to achieve a gradual effect. "We want to help restore normal dopamine function in people who have just come off of cocaine," says Howell. "But we need to do it gradually to avoid the precipitous highs and lows you get with cocaine," he says. "The lows are what send people running back to their habit."

When pretreated with phenyltropanes and then allowed to self-administer cocaine, the animals took less cocaine. The hope is that humans will experience the same reduction in drug use.

Would cocaine addicts have to stay on the substitute drug forever, the way that heroin addicts use methadone? Hopefully not, says Kuhar, although it's still too early to tell. Phenyltropanes are designed to normalize dopamine levels gradually. Once levels are normal, the need for the drug may be eliminated.

Moreover, stimulants like cocaine work very differently from opioids like heroin and morphine, and withdrawal is less severe, so indefinite maintenance therapy may be unnecessary. Yet if continuing with the drugs is the only way to manage cravings longer term, Kuhar is unopposed to prolonged use, provided it is safe. The answer will depend on the results of trials and the drug substitute's toxicity in humans.

One exciting possibility for these drugs, says Kuhar, is to use them as part of combination therapy. He's collaborating with researchers at Columbia University who have developed a vaccine for cocaine abuse created from monoclonal antibodies, which bind to and break down cocaine. Phenyltropanes do not interfere with the antibodies in the vaccine, so the therapies could be used together. "We could give a phenyltropane as a cocaine substitute to stabilize the user and help stop the craving -- and then vaccinate them at the same time so if they started using cocaine again, it would have no effect," says Kuhar. "This approach could be useful against all drugs of abuse."

Fast-tracking to clinical trials

Last fall, Howell and the team at RTI received a $3.5 million program project grant from the National Institute on Drug Abuse (NIDA) to fast-track development of a viable cocaine medication to human clinical trials within four years.

Howell is taking the lead on the primate segment of the project, testing phenyltropane compounds on rhesus monkeys. He'll conduct functional PET brain imaging and send the cream of the crop of drug candidates into human trials.

PET imaging of awake monkeys as they work for cocaine is a feat few researchers have ever attempted. "It's extremely time-consuming to train animals for imaging, but we think it is important to get real-time images of the brain in awake animals, rather than anesthetized ones," says Howell. After pretreating them with a phenyltropane, he'll define the dose at which the animals begin to decrease their self-administration of cocaine. PET data will help determine what level of transporter occupancy is necessary to achieve that therapeutic effect. Then the same test will be done in human addicts to determine if their therapeutic threshold is similar.

"When we have a drug that we know works in monkeys, we'll then test it in humans," says Howell. "And the human information will help us refine the drugs further."

Genetic fingerprinting of addiction

Scott Hemby studies gene "chips" to see
how genetic functions change in addiction
and how these alterations may become
permanent with long-term drug use.

Learning which genes are functionally relevant in cocaine abuse can help in understanding other disorders such as schizophrenia and depression

Pharmacologist Scott Hemby is amplifying the work of researchers like Kuhar and Howell by using DNA microarray technology, which allows him to scrutinize as many as 20,000 genes simultaneously. He is looking to see which ones may be up- or down-regulated in the brain as a response to addiction, what functional effect these changes may have, and how and when they may become permanent in response to long-term drug use.

"The brain is amazingly plastic," says Hemby. "When cocaine and other drugs disturb its chemical balance, cells in different brain regions adjust to a new level of homeostasis. We want to explore genetically how the brain adapts to this insult and why certain regions respond more than others." The brain regions most directly involved in cocaine response are those in the "reward" pathway -- the ventral tegmental area (VTA) and the nucleus accumbens, which also become activated during sex and eating.

He's starting by looking at gene expression in cocaine-addicted rats, particularly those genes related to dopamine synthesis and intracellular signaling, to determine if these functions change as a result of drug use.

In addition to allowing a view of many genes all at once, microarray analysis allows him to see genetic changes that take place within a single neuron. For instance, Hemby can target a discrete population of cells, such as the dopamine neurons within the VTA, and define their genetic alterations after cocaine use to see how they contribute to long-term neuroadaptive changes and how these alterations may vary from one individual to another. Using postmortem brain tissue from human cocaine addicts, Hemby recently identified 400 genes that are "disregulated" in cocaine addicts. Of those, he will focus on the ones related to dopamine in the VTA.

"When we get a handle on gene expression pattern in these human subjects, we'll take the information back to our animal model and see which altered genes deserve the most attention, which ones are functionally relevant," he says.

Once the pertinent genetic information has been obtained, Hemby hopes to tailor treatments to fit each addict's individual brain chemistry profile. One person may experience an up-regulation in one gene and down-regulation in another, while in a second the opposite may occur. Getting a fingerprint of each person's homeostatic levels would make medication more specific and therefore more effective.

Individualization of treatment will help address the complex and messy issue of drug addiction in humans. Not only do individuals start with widely varying brain chemistry, they've also been exposed to different experiences and environments and may be hooked on more than one drug. One using cocaine, nicotine, and alcohol will have a different brain chemistry profile from one with a single-drug addiction.

The interaction of all the relevant genes will tell us how to treat patients for cocaine and other addictions, maintains Hemby. "If we stick to genes that are functionally relevant, for example, dopamine-related genes in cocaine abuse, we can use the information later as well for understanding other psychiatric diseases, like schizophrenia and depression, both of which derive in part to altered dopamine function."

Hemby also plans to set up a brain database that will catalog what the "normal" brain looks like in terms of gene expression. After all, says Hemby, you can't fix an impaired brain until you know what a normal one is supposed to look like.

Understanding susceptibility

Working with animal models, Clinton Kilts
helps obtain PET images, which vary mar-
kedly when cocaine is self-administered
as opposed to being administered by

In addition to genetic studies like Hemby's, Emory researchers are investigating the effect of stressful environmental factors during early development on one's susceptibility to addiction. Why is one person able to use drugs socially a few times and then quit, while someone else becomes hooked? Pharmacology researcher Steve Holtzman has confirmed previous reports that rat pups separated from their mothers for just three hours a day in the first two weeks of life are more prone to permanent changes in the endocrine stress response. He found these animals were less sensitive than controls to morphine's analgesic effects and had more intense withdrawal symptoms.

"The animals that experienced maternal separation had a higher physical dependency on opioids as adults," says Holtzman. "Are these changes orchestrated by the body's endogenous opioid genes or by some other system?"

Holtzman also has found that dependence on morphine or other opioids can begin as early as the first administration of the drug, whereas previously it was believed dependence took weeks. His behavioral research team is attempting to characterize what happens in acute dependence, determine what treatments might block it, and define how it is related to chronic dependence, all of which hinge on determining underlying neurochemical substrates.

Hemby plans to augment Holtzman's opioid studies to uncover the genetic mechanisms at work in acute and chronic dependence.

Although ultimate success may be some time off, these Emory scientists are making real progress toward identifying the long-term effects of drug abuse. The group is in the process of applying for an interdisciplinary NIH center grant, and the brainstorming appears to be paying dividends. As the behavioral team learns from the gene team and vice versa, they are discovering new ways to optimize their efforts, sowing the seeds of a collaborative culture they hope will expose the roots of addiction. And in their craving for answers, they may glimpse some profound revelations about other intractable psychopathologies as well.

Kate Egan is managing editor of ACS News Today, at the American Cancer Society.


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