Alumnus XI Zhengxiong leading research in drug addiction

wusm 贴于2005/11/23 08:19 （武汉大学校友论坛）

From Society for Neuroscience
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NR-11-05 (11/15/05). For more information, please contact Sara Harris at (202) 462-6688 or sharris @ sfn . org .

NOVEL APPROACHES MAY HELP ILLEGAL DRUG USERS QUIT AND STAY CLEAN, ACCORDING TO NEW WORK

WASHINGTON, DC, November 15, 2005 — Novel approaches to blocking the activity of certain neurotransmitters—chemicals that carry signals from brain cell to brain cell—could help users of illegal drugs quit the habit and prevent relapses to drug use after they have stopped, scientists report. And in other work, researchers suggest through animal studies that applying electrical stimulation to the brain could help prevent drug addiction and relapse.

“Currently available treatments for drug addiction are ineffective for many people with addiction problems, but these studies herald several new leads for addiction treatments based on animal research,” says Eric J. Nestler, MD, PhD, of the department of psychiatry at the University of Texas Southwestern Medical Center in Dallas, Texas.

Neurotransmitters such as dopamine and the receptors where they create their actions help regulate an individual’s sensation of reward—the “high” that keeps the cycle of drug use going. Studies over the past several years suggest such neurotransmitters may play a role in addiction to marijuana, opiates, nicotine, or alcohol.

Blocking the dopamine D3 receptor in animals diminishes the rewarding effects of marijuana and may be a possible therapy for marijuana abuse, report Zheng-Xiong Xi, MD, PhD, of the National Institute on Drug Abuse in Baltimore, MD, and his colleagues.

The investigators used the compound SB-277011A to block dopamine D3 receptors in rats and looked at how this affected the brain areas that register reward. Then they measured dopamine levels in the brains of rats given marijuana alone and in rats first given the dopamine blocker and then marijuana.

In the first experiment, the investigators surgically implanted rats with an electrode in the medial forebrain bundle, a brain circuit tied to reward. The rats were allowed to administer electrical stimulation through the electrode, which delivers a strong rewarding effect.

Rats receiving marijuana needed less electrical stimulation to sustain the feeling of reward than those not on marijuana because the marijuana reward and electrical stimulation reward combined to produce the overall reward effect. When rats were given the dopamine blocker, the rewarding effect of marijuana was significantly lowered or abolished, so these animals needed more electrical stimulation to create the rewarding effect.

In the second experiment, rats were injected with marijuana and samples of neurotransmitters were collected from the nucleus accumbens, one of the brain’s major reward centers. Dopamine levels were 50 percent above normal in the rats given marijuana alone, but rats pretreated with SB-2770011A and then given marijuana had no increase in dopamine levels.

“These findings strongly suggest the dopamine D3 receptor is a potential target for therapies to fight drugs of abuse,” Xi says.

Xi’s laboratory took a similar approach to show that blocking certain cannabinoid-like receptors in the brain inhibits cocaine's rewarding effects.

Like the dopamine D3 receptors, these receptors for cannabinoid-like neurotransmitters, called CB1 receptors, are known to be involved in addiction to marijuana, opiates, nicotine, and alcohol. But their role in cocaine addiction remained unclear. Although they appear to be involved in relapse to cocaine use, their role in producing the high, or direct rewarding effects of cocaine that drug addicts seek, has been controversial.

The first experiment was similar to work with the dopamine D3 receptor. Rats were implanted with an electrode in their medial forebrain bundle and allowed to self-administer rewarding electrical stimulation. Animals on cocaine needed less electrical stimulation to sustain the brain's reward system, because the overall reward effect was the sum of the cocaine and electrical stimulation effects. The rewarding effect of cocaine was diminished or abolished when rats were given AM 251, a compound that blocks the CB1 receptor.

The investigators then studied the effects of AM 251 on rats’ self-administration of intravenous cocaine. Each rat was surgically implanted with an intravenous catheter and allowed to press a wall-mounted lever in its cage to receive cocaine. The experiment was set up so that the rats had to work harder for each subsequent cocaine infusion.

The rats eventually reach a point at which they stop their drug-taking behavior because the amount of work needed is not worth the cocaine, called the “break point.” Rats pretreated with AM 251 had a lower break point, showing that the rewarding effect of cocaine was decreased in these animals.

“These findings suggest that the brain's cannabinoid-like neurotransmitters are involved in cocaine’s rewarding effects,” Xi says. “Future studies will look at whether AM 251 inhibits the rewarding effects of other addictive drugs, and could lead to effective anti-addiction treatments for use in humans.”

In other work, scientists show that applying electrical stimulation to rats’ brains alone—without blocking receptors in the brain’s reward system—was enough to reduce the animals’ drug seeking behavior.

Dino Levy, Abraham Zangen, PhD, and their colleagues at the Weizmann Institute for Science in Rehovot, Israel, trained rats to press a lever to self-administer cocaine via a catheter in their jugular vein. After 10 days of training, the rats self-administered a large amount of cocaine.

For the next 10 days, some of the rats received electrical stimulation for 30 minutes through miniature metal electrodes implanted in the prefrontal cortex or lateral hypothalamus, brain areas involved in reward and addiction. The rats were then exposed to the cocaine lever again. This time cocaine was not available; however the animals’ cocaine-seeking behavior could be measured by the rate at which they pressed the cocaine-related lever.

Rats that received the electrical stimulation did not press the lever to receive cocaine as much as the nontreated rats. In another test, these rats were willing to work less to receive a subsequent dose of cocaine.

To help understand how the electrical stimulation treatment affects addictive behavior, Levy, Zangen, and their colleagues measured receptors to glutamate—a neurotransmitter thought to enhance the environmental cues associated with cocaine—in brain areas related to drug addiction. The electrical stimulation seemed to normalize the levels of some glutamate receptors in some reward-related brain regions, whereas cocaine is known to alter their levels.

“We show that by applying electrical stimulation to specific brain regions it is possible to break, rearrange, or even reverse alterations caused by repeated drug use,” Zangen says. “These findings pave a way for a novel treatment strategy for reducing craving for drugs of abuse, and could help drug addicts quit the habit or prevent relapse.”

This animal model could be applied to humans through deep transcranial magnetic stimulation, which uses alternating magnetic fields to stimulate areas of the brain noninvasively, Zangen says. Another option would be to surgically implant a stimulating device inside the brain, similar to the deep brain stimulation treatment for Parkinson's patients, he says.

One of the most difficult problems for the long-term treatment of cocaine addiction is the high likelihood of relapse to drug seeking and taking in abstinent users. Triggers for relapse include environmental cues or small doses of the drug that bring up memories of prior drug use. These events can also reinstate cocaine-seeking behavior in animal models of relapse. Several studies suggest that these triggers may induce relapse by increasing levels of the neurotransmitter dopamine in brain reward centers.

The drug aripiprazole (Abilify) helped lessen abstinent laboratory rats’ drug-seeking behavior when exposed to drug-associated cues or given small doses of cocaine, compared to controls, according to studies by Matt W. Feltenstein, PhD, and colleagues at the Medical University of South Carolina department of neurosciences. Aripiprazole is an antipsychotic drug that stabilizes dopamine activity.

Another agent that could help prevent drug addicts from relapsing to cocaine use is D-cycloserine, say Fanny F. Botreau, PhD, and her colleagues at Concordia University in Montreal, Canada.

In Botreau's experiments, rats were tested for their likelihood of returning to an environment where they had previously received cocaine. Some rats were given D-cycloserine after each of several so-called “extinction trials,” which are designed to extinguish the association between cocaine and the environment; others were not given the compound. Rats treated with D-cycloserine immediately after each extinction trial took significantly fewer days to stop preferring the cocaine-associated environment than did control rats.

“Our findings suggest that D-cycloserine or similar agents could be used to help human drug addicts extinguish the emotional responses and thoughts induced by environments and cues previously associated with drug use,” says Botreau. “These types of drugs could be used to avoid or at least reduce craving during the periods of detoxification and abstinence.”

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