Society for Neuroscience: Advances in Treating Drug Abuse
Speakers: Eric J. Nestler, MD, PhD, University of Texas Southwestern Medical Center; Zheng-Xiong Xi, MD, PhD, National Institute on Drug Abuse, Baltimore, Maryland; Abraham Zangen, PhD, Weizmann Institute for Science, Rehovot, Israel; Matt W. Feltenstein, PhD, Department of Physiology & Neurosciences, Medical University of South Carolina, Charleston; and Fanny F. Botreau, PhD, Concordia University, Montreal, Canada
Novel approaches to blocking the activity of certain neuro-transmitters might be able to help users of illegal drugs quit the habit and prevent relapses after they have stopped using drugs, scientists report. Researchers have discovered that applying electrical stimulation to the brain has helped to prevent drug addiction and relapse in animal studies.
Neurotransmitters such as dopamine, and the receptors where they create their actions, help to regulate our sensation of reward—the “high” that keeps the cycle of drug use going. Studies over the past few years suggest that such neuro-transmitters may play a role in addiction to marijuana, opiates, nicotine, and alcohol.
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Blocking the dopamine D3 receptor in animals diminishes the rewarding effects of marijuana and might be a potential therapy for marijuana abuse, report Zheng-Xiong Xi, MD, PhD, and his colleagues.
The investigators used the compound SB-277011A to block dopamine D3 receptors in rats and examined how this affected the brain areas that register reward. Then they measured dopamine levels in the brains of rats that were given marijuana alone and in rats that were first given the dopamine blocker and, next, 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 delivered a strong rewarding effect.
Rats receiving marijuana needed less electrical stimulation to sustain the feeling of reward than rats not given marijuana, because the marijuana reward and the electrical stimulation reward combined to produce the overall reward effect. When rats received the dopamine blocker, the reward effect of marijuana was significantly lowered or eliminated, so that these animals needed more electrical stimulation to create the same effect. canadian cialis online
In the second experiment, rats were injected with marijuana. Samples of neurotransmitters were collected from the nucleus accumbens, one of the brain’s major reward centers. Dopamine levels were 50% above normal in the rats given marijuana alone, but rats that were 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,” Dr. Xi says.
Dr. Xi and his co-investigators 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 neuro-transmitters (called CB1 receptors) are involved in addiction to marijuana, opiates, nicotine, and alcohol; however, their function in cocaine addiction remains unclear. They appear to be involved in relapse to cocaine use, but their role in producing the direct rewarding effects (the high) of cocaine, sought by drug addicts, has been controversial.
The first experiment was similar to the work with the dopamine D3 receptor. Rats were implanted with an electrode in the medial forebrain bundle and were allowed to self-administer rewarding electrical stimulation. Animals that received cocaine needed less electrical stimulation to sustain the brain’s reward system, because the overall reward effect was the sum of the cocaine and the electrical stimulation effects. The rewarding effect of cocaine was diminished or abolished when the rats were given AM 251, a compound that blocks the CB1 receptor.
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The investigators then studied the effects of AM 251 on the self-administration of intravenous (IV) cocaine. Each rat was surgically implanted with an IV catheter and was 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 reached a point at which they stopped their drug-taking behavior because the amount of work needed was not worth the cocaine, called the “breakpoint.” Rats pre-treated with AM 251 had a lower breakpoint, 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,” Dr. Xi explains. “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 have shown 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 associates 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. buy kamagra
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; each of these brain areas is involved in reward and addiction. The rats were then exposed to the cocaine lever again. This time cocaine was not available, but cocaine-seeking behavior could be measured by the rate at which the rats pressed the cocaine-associated lever.
Rats that received the electrical stimulation did not press the lever to receive cocaine as much as the untreated rats. In another test, these rats were willing to work less to receive a subsequent dose of cocaine.
To understand how the electrical stimulation treatment affects addictive behavior, the researchers measured receptors to glutamate in the brain areas related to drug addiction. (Glutamate is a neurotransmitter thought to enhance the environmental cues associated with cocaine.) Electrical stimulation seems to normalize the levels of some glutamate receptors in some reward-related brain regions, whereas cocaine alters 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,” Dr. 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.”
He suggests that this animal model might be applied to humans through deep transcranial magnetic stimulation, which uses alternating magnetic fields to stimulate areas of the brain noninvasively. Another option would be to surgically implant a stimulating device inside the brain, similar to deep-brain stimulation, which is used to treat Parkinson’s disease, he says. kamagra soft tablets
One of the most difficult problems for the long-term treatment of cocaine addiction is the likelihood of relapse during abstinence. Triggers for relapse might be environmental cues or small doses of the drug that bring up memories of prior drug use. In animal models of relapse, these events can also re-instate cocaine-seeking behavior. Several studies suggest that these triggers may induce relapse by increasing levels of the neurotransmitter dopamine in the brain’s reward centers.
The antipsychotic agent aripiprazole (Ability, Bristol-Myers Squibb/Otsuka) helped to lessen the drug-seeking behavior of abstinent laboratory rats when they were exposed to drug-associated cues or were given small doses of cocaine, compared with controls, in studies by Matt W. Feltenstein, PhD, and his colleagues. Aripiprazole stabilizes dopamine activity. It has a relatively low side-effect profile compared with some other drugs.
Another agent that might help prevent relapse in cocaine users is D-cycloserine, says Fanny F. Botreau, PhD. In experiments by Dr. Botreau and her team, rats were tested for the probability 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 were designed to extinguish the association between cocaine and the environment; other rats were not given the compound. Rats receiving D-cycloserine immediately after each extinction trial took significantly fewer days to stop preferring the cocaine-associated environment than did control rats.
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“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 Dr. Botreau. “These types of drugs could be used to avoid or at least reduce craving during the periods of detoxification and abstinence.”
