Of all the medical problems that burden society, few are more destructive than addictive disorders. In the United States, the National Institute on Drug Abuse estimates that the economic costs alone are $161 billion annually. New research presented at the 2002 meeting of the Society for Neuroscience in Orlando may help neurologists understand which areas of the brain are affected in addiction, how neuronal rewards systems are involved, and how therapeutic agents may be developed to bypass the affected pathways.
“The current excitement in studies of reward pathways and addiction in the brain is fueled by the convergence of excellent animal models and the latest in molecular technologies,” said Craig M. Powell, MD, PhD, Assistant Professor of Psychiatry and Neurology at the University of Texas Southwestern Medical Center in Dallas. “Drug addiction likely involves long-lasting plasticity in the reward pathways of the brain. The field is now focusing on the molecular changes responsible for this plasticity.”
Dr. Powell has coauthored several addiction studies using animal models with his colleague Eric Nestler, MD, PhD. Dr. Powell noted that Dr. Nestler is exploring long-lasting changes in gene expression associated with chronic cocaine administration using gene chip technology. “Rather than simply looking at a host of genes regulated by cocaine administration, the group is exploring the regulation of gene expression by transcription factors known to be active and critical for drug reward in the nucleus accumbens,” Dr. Powell said. He added that Dr. Nestler and colleagues have developed transgenic mice in which these transcription factors can be activated in brain reward areas.
“Addiction is powerful because abused substances take over and amplify the brain's natural reward systems that drive us to stay alive,” Dr. Powell said. “Advances in the understanding of our most basic survival drives, such as feeding and sexual behavior, are going to converge naturally with the drug addiction field.
“These advances are renewing interest in the involvement of areas of the brain that are critically involved in feeding behavior, and the potential interaction between molecular pathways involved in feeding behavior and the drug reward system,” he added.
Research by Barry J. Everitt, PhD, Professor of Behavioral Neuroscience at the University of Cambridge, and colleagues shows how environmental stimuli that an addicted animal associates with the addictive substance can trigger drug-seeking behavior. For example, addicted animals that always receive the addictive substance in a box or by pressing a lever will associate that box or lever with the substance.
Dr. Everitt pointed out that environmental stimuli affect animals in ways similar to addicted humans; they take drugs compulsively even though they no longer get the buzz. “As neurobiologists, we want to know what part of the brain is involved and whether the action part is different from the rewards system,” he said, adding that the portions of the brain involved in habitual behavior in animals are the nucleus accumbens and the caudate putamen.
He and colleagues measured the dopamine levels of rats when they were working to get drugs by pressing levers that had previously released the substances to which the animals had become addicted. “We found that the nucleus accumbens is quiet but the caudate putamen is very active during drug-seeking behavior,” he said.
When people take drugs, they acquire habits by having those actions represented in the dorsal part of the striatum, Dr. Everitt said. He noted that previous research has shown that this portion of the striatum, in both animals and humans, is typically not involved in learning because it is not involved in the rewards mechanism, but that it is involved in the acting out of habitual behavior.
He noted that the prefrontal cortex is under-active in human cocaine addicts who have abstained from cocaine for three months, a phenomenon that may impair executive function and cause loss of cognitive control over habitual behavior. This impairment of executive function may explain the return of habitual drug-seeking behavior in an individual who is trying abstain from drugs, he said.
“When we treat addicts, we need to know if they are taking drugs to get the effects, which is typical of early addiction, or out of habit, an aspect of later addiction,” he said. For example, established addicts who are trying to abstain from drugs may initiate drug-seeking behavior if they are in a neighborhood associated with the drug; a smoker trying to quit may light up when seeing another person smoking a cigarette, despite the commitment to smoking cessation. According to Dr. Everitt, these behaviors represent the effect of habit.
Animal research with pharmacological therapies shows that some agents may help interfere with craving and drug-seeking behavior, Dr. Everitt said. He noted that treatment with either a dopamine-3 (D3) receptor antagonist or a gamma-aminobutyric acid-B (GABA-B) receptor agonist inactivates the dopamine system, and therefore interferes with drug cues activating that system. “Cocaine addicts don't crave if they're treated with a GABA-B agonist,” he said. GABA-B agonists are typically used as anticonvulsants and include baclofen and gabapentin.
“The D3 receptor antagonist is just going into trial.” Animal studies of several D3 receptor antagonists have been promising and have included agents such as raclopride and nafadotride.
Dr. Everitt noted that D3 receptor antagonists not produce the tardive dyskinesia associated with the D1 and D2 receptor antagonists that are used to treat psychotic disorders.
“So far, the only treatments available are substitutes such as methadone and nicotine patches,” Dr. Everitt said. “But there are drugs that are generally behaviorally inert that can stop the neural mechanisms associated with addiction from being engaged.” The D3 receptor antagonist and GABA-B agonists are drug classes that may have such properties.
ROLE OF M5 IN ADDICTION
Anthony Basile, PhD, Director of Biological Research at Alkermes, Inc., a pharmaceutical company based in Cambridge, MA, found that one pathway may be involved in several substances of abuse. Dr. Basile conducted his research when he was a senior investigator at the National Institutes of Health (NIH), with his colleague there, Jurgen Wess, PhD, the NIH Section Chief for Molecular Signaling.
“We used a transgenic mouse,” he said. “In the experimental animal, Dr. Wess had deleted the M5 muscarinic cholinergic receptor, previously identified as critical to receiving pleasure from the addictive substance. The deletion of this receptor,” he said, “makes animals less receptive to becoming addicted.”
Dr. Basile's work focused on place conditioning. When addiction had been induced in genetically normal mice, the animals would stay in the box where they received morphine for several hours, he said, even if no morphine was given. The animals had become addicted through the use of self-administered morphine, which the investigators had made available. “However, mice lacking the M5 receptor did not stay in the box.”
He and his co-investigators inferred from the animals' lack of drug-seeking behavior that obtaining morphine was unimportant to them. However, the knock-out mice retained the analgesic effects of morphine, as shown by delays in the time it took these mice to recognize noxious stimuli, such as a hot plate under the paw or an annoying substance on their tails.
“We repeated the same experiment with cocaine and added a self-administration test,” Dr. Basile said. “Knockout mice showed a big reduction in the use of cocaine, and it took a much higher dose to involve the reward mechanism.”
These findings indicate that the M5 receptor is involved in a variety of addictive substances, he said. “If so, this pathway could also be involved in other reward systems, such as overeating, sexual risk-taking, gambling, and dangerous behaviors. We think this pathway is involved with reinforcement from many different sources.”
UNIVERSAL ADDICTION TREATMENT DRUG?
In other research published in February, Stanford University investigators identified neuronal changes induced by drugs of abuse that have different molecular mechanisms (Neuron 2003;37(4):577–582). The affected cells are in the ventral tegmental area, according to principal investigator Robert C. Malenka, MD, PhD, Professor of Psychiatry and Behavioral Sciences at Stanford University Medical Center.
He and his team gave several addictive chemicals to mice and found that glutamate stimulated neurons in the ventral tegmental area to release dopamine, and that these cells were sensitized to glutamate for up to a week. The chemicals included cocaine, morphine, amphetamines, nicotine, and alcohol.
Stress had a similar effect on the brain, although non-addictive drugs that act on the brain did not. In order to induce stress in the mice, the investigators subjected them to the Porsolt Forced Swim test, in which the animal is placed in cold water for a few minutes. Dr. Malenka and his colleagues concluded that these findings could yield insights regarding the association between stress and relapses in people with addictions who have been abstinent. They found that the glucocorticoid receptor antagonist RU 486 blocked the effects of stress, but not cocaine, on the affected brain cells.
HOPE FOR FUTURE
All of the experts who were interviewed expressed hope that their findings would lead both to a better understanding of the neuronal pathways involved in the addictive process and to effective interventions. “These findings challenge the older attitude that people only become addicts because they're weak-willed,” said Dr. Everitt. “The stigma is now reduced a bit. Medications that we are investigating in this area may eventually be found to be effective against dependence on legal drugs, such as alcohol and nicotine, as well as illicit drugs.”
ARTICLE IN BRIEF:
- ✓ New research may help neurologists understand which areas of the brain are affected in addiction, how neuronal rewards systems are involved, and how therapeutic agents may be developed to bypass the affected pathways.
- ✓ Using transgenic mice, Dr. Barry J. Everitt and colleagues at the University of Cambridge showed how environmental stimuli that an addicted animal associates with the addictive substance can trigger drug-seeking behavior.
- ✓ Animal research shows that agents such as dopamine-3 receptor antagonists or gamma-aminobutyric acid-B inactivate craving and drug-seeking behaviors.
- ✓ Dr. Anthony Basile, of Alkermes, Inc., found that one pathway – the M5 muscarinic cholinergic receptor – may be involved in several substances of abuse. In animal studies, he and colleagues found that when the receptor was deleted, animals were less receptive to becoming addicted.
- ✓ Stanford University investigators identified neuronal changes induced by drugs of abuse that have different molecular mechanisms. The affected cells are in the ventral tegmental area.