By Jan Marie Werblin
Genetic research and addiction
A significant advance in understanding the role of genetics in addiction occurred in 1990 when researchers linked the D2 dopamine receptor (DRD2 gene) to severe alcoholism. Studies of the brain showed that those with the A1 variation of the DRD2 gene have significantly fewer dopamine receptors in pleasure centers of the brain. Persons who become addicted to drugs that increase dopamine levels do so to compensate for that deficiency. Subsequent studies have linked the A1 variation of the DRD2 gene to other addictions including, cocaine, amphetamine, heroin and nicotine.
These studies suggest that people with this genetic trait are much more susceptible to addiction and likely to fall into severe forms of addiction.
Ernest Noble, professor of psychiatry and biobehavioral sciences and director of the Alcohol Research Center at the University of California, Los Angeles says that while drugs such as naltrexone are being tried, with acamprosate undergoing trials in Europe but awaiting FDA approval in the United States, they are not currently dispensed based on an individual's genetic profile.
"Those drugs are given to all types of alcoholics, whether the alcoholics are the genetic type or the non-genetic type," says Noble, who is also former director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
Psychiatrist Noble and pharmacologist Kenneth Blum of the University of Texas, San Antonio, were the researchers that found a strong association between alcoholism and a variation of the DRD2 gene. The gene variation — A1 — was present in more than two-thirds of 35 deceased alcoholics, whereas it appeared only in one-fifth of 35 deceased non-alcoholics. They coined this gene the "reward" gene, which was associated with addiction. It was often erroneously reported that they had found the "alcoholism gene," implying that there is a relationship between just one gene and one specific behavior.
According to Noble, the A1 variation of the DRD2 gene, which is found in a large percentage of alcoholics, drug abusers, smokers, and other addictive, compulsive or impulsive disorders, produces fewer dopamine receptors in the brain and disallows individuals the appropriate rewards and pleasures in life.
"It is only when these individuals abuse drugs and alcohol that they feel those pleasures because the drugs stimulate dopamine production, which in turn stimulates their few dopamine receptors with the result that these individuals begin to feel good," he adds. "But there's a trap in that," says Noble, "because continued use of the drug causes you to become addicted."
Research done by a team at the National Institute on Alcohol Abuse and Alcoholism could not find the genetic differences between alcoholics and non-alcoholics, and subsequently both positive and negative study findings have ensued. However, an analysis of these combined studies (a meta analysis) revealed the DRD2 variation to be strongly associated with alcoholism, particularly its' severe type.
However, Noble and Blum joined forces with medical geneticist David E. Comings, MD, director of the Department of Medical Genetics at City of Hope Medical Center in Duarte, California, to explore the gene's ability to influence other compulsive disorders including cocaine addiction and obesity.
The dopamine D2 receptor, one of the early genes to be associated with a range of addictive behaviors, was misinterpreted by some researchers' as not playing a role in addictive conditions because of the researchers inability to understand polygenetic disorders, explains Dr. Comings. "A polygenic disorder is caused by the additive effect of many genes that are acting with the environment, and each gene has only a small effect on the total picture.
"What happened with that polymorphism is that some people found an association with different behaviors, especially alcoholism, and some people did not. Some people interpreted this as meaning that the gene plays no role in these conditions," says Comings, who is also former president of the American Society of Human Genetics and editor of the American Journal of Human Genetics.
"Different studies may find that the gene that one person found played a role, may not play a role in their group, but instead of meaning that that gene is uninvolved in anything, it just means that in some groups it is involved and in some groups, it is not. That is why we think that you need to look at the additive effect of multiple genes to get a true picture."
Comings' team of researchers has done studies examining more than 35 genes in a group of pathological gamblers. The researchers chose genes that play a role in dopamine, serotonin, norapinephrine and other types of neurotransmitters and they developed polymorphisms (a genetic variant, which is common in the population) at those genes. They looked at the role played by each gene, compared them and totaled each group.
What they found when a large number of people were examined was that many of the genes studied played a significant role. They hope to reverse the process, examine the role of different genes in a given individual, and determine whether that individual's pathological gambling is predominantly dopaminergic, serotonergic, neurotonergic or something else. Based on those findings, they believe it will be possible to determine whether the individual might require a serotonin reuptake inhibitor, or a stimulant medication, or a mood stabilizer or other medications or therapies before starting treatment.
Treatment
Treatment for pathological gambling can include psychotherapy alone or in-group or both, as well as medication, says Comings. However, he asserts that there is a tendency currently to do only group therapy for addictive behaviors and to temper or even prohibit the use of medication in helping addicted people to recover.
"Some treatment programs say you have to be off all medications before they'll let you into the program, while in fact, if people have a genetic predisposition to a certain type of problem, medication may be critical for them to get over the addictive behavior." When Noble and colleagues at UCLA treated alcoholics with bromocriptine, a medicine that boosts the amount of dopamine available to the brain, they found that the medication quieted the craving and ultimately helped alcoholics with the DRD2 A1 variant to fight their addiction. Further studies shed light on why some were helped and others were not.
"What our studies have shown, and growing studies are showing, is that drugs that stimulate D2 dopamine receptors like bromocriptine and others are the ones that primarily help those that have the genetic form of the disease — that is, have the DRD2 A1 variant," says Noble.
The impact of treatment, based on genetic background, has also been ascertained in heroin addicts. Noble and colleagues published a study evaluating methadone treatment outcome in heroin addicts based on whether they had the DRD2 A1 variant. The results showed that those addicts who failed treatment had more than four-fold higher frequency of the DRD2 A1 variant than those who successfully completed the program. This suggests that heroin addicts who carry the DRD2 A1 variant may require a more intense pharmacological and psychosocial treatment than those patients who lack this variant.
Appropriate treatment
"But now we are finding that everybody gets the same kind of treatment, whether it's drug treatment or psychosocial treatment, and other approaches," says Noble. "Well, we can see that about half are going to do well and half are not going to do well. No distinction has been made thus far to identify those who have the genetic form and those who have the non-genetic form and give them the appropriate treatment that they require."
Research findings point out that drug abusers with a genetic propensity toward addiction typically require one of an expanding collection of innovative prescription drug therapies to conquer their addiction. Those without the gene, Noble asserts, more often respond to counseling that addresses environmental issues that promoted their drug use.
"That's why the success in the treatment arena has been not very salutary," notes Noble. "Yes, there has been some improvement, but the real underlying issue is that the treatment community has not kept up with the research community in terms of the findings that they are making."
Progress in linking genetics to appropriate medications to treat addictions has been slow for several reasons, suggests Noble.
"I think that there is a slow progression of applying findings from the bench to the bed," says Noble. "Also there are some people who just don't believe in genetics. They believe that everything is environmentally induced or caused by poor parenting, peer pressure, etc. An appreciation of the genetic aspect of addiction has not really dawned yet."
Noble's recent commentary on the genetic propensity for addiction that appeared in the Los Angeles Times, prompted many individuals to contact him seeking help for themselves or family members who were suffering from alcoholism or other addictions.
"I would like to turn this over to the treatment community," says Noble. "There are people out there who repeatedly fail, end up in jail, hurt themselves and hurt their families. This is a major problem we are dealing with — alcoholism and drug addiction — it is not a minor problem."
Bringing research to treatment
Noble feels that other studies have shed light that would advance the treatment of addictions if only those engaged in the treatment field would become familiar with and keep abreast of the findings and implement suggestions derived from those findings into treatment.
"We and others have found that the personalities of the people with the DRD2 A1 variant are different. They are great novelty seekers and risk takers. One of the great risk-taking forms of behavior is to use drugs.
"We also have brain electrophysiological findings that show that the people who have the A1 variant have a much-prolonged latency. In other words, it takes them a long time to react to the stimulus, which means that they (like people with Parkinson's Disease) have lower dopamine tone in their brain."
Noble is surprised that there is little discussion among treatment professionals of the findings of published genetic studies.
"We are going head on and getting these people so-called treatment and they then end up in jail," says Noble. "We are now in the 21st century. We should use all the best findings that we have to help them."
How current genetic studies influence addiction treatment
Researchers are looking at human development and substance abuse from a basic approach. They are seeking individuals who express a greater vulnerability to addiction.
Research has shown that children with an emerging personality disorder or a mood disorder such as anxiety disorder, post-traumatic stress disorder, bipolar disorder or a depressive disorder, have a greater susceptibility to addiction, according to Frank J. Vocci, Jr., director of the National Institute on Drug Abuse (NIDA) Division of Treatment Research and Development.
"There are also, interestingly enough, genes that are suggested to actually determine our initial response to drugs of abuse," says Dr. Vocci.
Some genes, he notes, may determine whether or not individuals like a drug, and scientists speculate that other genes determine whether or not individuals might become abusers or whether they will become addicted to a drug. These genes have not yet been found, but population studies show that not everyone who tries a drug becomes addicted. About 85-90 percent of individuals who experiment with marijuana or cocaine do not develop accelerated patterns of use and become abusers or addicted.
Vocci contends that there has been no gene identified to predispose people to addiction.
"There hasn't been any gene to date," says Vocci. "There hasn't been any simple gene. The alcohol studies have come up with several potential candidates."
Vocci cites a study by Centers on Genetics of Alcoholism, comprised of two cohorts. However, candidate genes found in the first cohort have not yet been validated in the second cohort. A proposed study of 5,000-6,000 alcohol-dependent individuals to be conducted by a developing consortium in Europe will look for candidate genes for alcoholism.
"There have been from time to time reports of variants of either dopamine receptors or the dopamine transporters that may be linked to a greater susceptibility to become addicted — what some people call a reward deficit model of some sort," says Vocci. "But, unfortunately, they have not been verified by other investigators."
Controversial issues
Controversy surrounds the roles of the neurosciences and genetics in addiction, and researchers sometimes differ in their evaluations of study results. Noble asserts that at a recent conference on Reward Deficiency Syndrome: Genetic Antecedents and Clinical Pathways, George Uhl of the neuromolecular branch of NIDA's intramural research program did link the DRD2 A1 variant with drug abuse vulnerability.
Vocci explains that the effect sizes of genetic studies are likely to be small. "The effect of a gene that explains 2-3 percent of the variants is likely what you'll find with most of the drugs that will eventually be linked to various neurological, psychiatric and addictive disorders. Given that, it's not hard to see that if a study is undersized or if it is poorly controlled, that associations will likely not be found that may actually exist. This is essentially called a false negative study. Alternatively, one can poorly control a study and wind up with a false positive. What we are looking at here are very small effect sizes and I think this is probably what the D2 allele and polysubstance abuse is. It only explains probably about 3 percent of the variants. Most of the time, scientists like looking at things that explain 20-25 percent of the variants and they feel much better about something being real because it's a more robust effect and these are very small effects and I think that's where some of the issues are coming in."
Other factors are going to be equally, if not more important when the strongest association shows 3 percent of the variants, maintains Vocci.
"Genetics aren't determinative here," he says. "This isn't genetic Calvinism, so the fact that someone has a gene that is associated with something doesn't necessarily mean that they are going to express the disorder. The addictive disorders are going to be clearly polygenetic."
"We [NIDA] are being chided by some people for sounding deterministic. We are trying to avoid that," says Vocci. "We are trying to present a balanced view. The probability of becoming addicted to a drug is not unitary. Some people are clearly going to have — with their genetic, neurological and behavioral factors — a greater disposition to become addicted than others are. Given that, how do you explain that without sounding deterministic?
A dopamine B-hydroxylase variant appears to predispose people to the noxious effects of cocaine, he explains. When individuals with the variant use cocaine they become anxious, suspicious and hostile, and because of that they stop using or lower their doses. Researchers hypothesize that the drug disulfiram [Antabuse] may mimic these effects in humans.
Genetically driven pharmacological treatments
"We have taken things directly through the human genome, through molecular biology and these other techniques that we are looking at, both in human genetics and also animal genetics," says Vocci. "We are studying the molecular biology and the geneotypic and phenotypic expression of drugs and individuals as they may relate to addiction and its treatment."
"There are two or three findings in molecular biology that may be especially salient with respect to first the dopamine system and then maybe some other interesting systems," says Vocci. "One is that through molecular biology techniques we have been able to expand our knowledge of the dopamine system. Twenty years ago, it was clear through pharmacological analyses that there were essentially two types of dopamine receptors — D1 and D2.
"Through molecular biology analysis, we still believe that there are two families of dopamine receptors but there is now a D1 and D5 family and a D2, 3 and 4 family. We now have five dopamine receptors, and those other receptors D3, D4 and D5 were discovered by molecular biology cloning techniques. They have different functions than the other D1 and D2 that we had already known about, and some medicinal chemists and pharmaceutical companies have made D3 and D4 drugs."
Vocci's team is developing some of those drugs for testing in addictions. One drug, as of this writing unnamed but labeled BP897, reduces in rats the conditioned stimuli associated with cocaine administration and self-administration in monkeys, and what is called a second-order paradigm, in which a drug administration and a light or tone are paired to eventually drive behavior. Research animals press a bar for the light, knowing that when they have pressed the bar so many times and the light lights, that they will get cocaine.
The light acquires secondary characteristics or stimulus properties. To evaluate a differential effect of blocking the cue instead of blocking the drug, researchers study the first session of the day when the animal has not yet received cocaine and is working for the light. When researchers see less work emitted for the light, it suggests that the conditioned stimulus does not have the same motivational properties that it did before the administration of drugs that day.
The blockade of conditioned cueing in the rat and self-administration in the monkey suggests that the D3 receptor partial agonist has interesting properties and is blocking one of the mechanisms thought by the researchers to influence people to take drugs. People who take drugs, they believe, become cued to stimuli that include persons, places and things in their environment. These stimuli can increase craving. When people become cognitively aware of the stimuli, there can also be a cognizant component to the craving.
"We don't know quite how to block the cognitive mechanism yet, but we think that we know enough of the biology of the classical conditioning mechanism, enough of the pharmacology, to start trying to evaluate drugs that might block that conditioned cue," says Vocci. "That's one way where molecular biology through cloning techniques has led us to the discovery of receptors for which ligands have been developed. These ligands, have been demonstrated in behavioral paradigms in animals to reduce a very important component of what we call craving."
"There is evidence now from three studies that disulfiram reduces cocaine use in individuals. Interestingly, individuals in clinical pharmacology studies got the anxious, disphoric effects of cocaine, although none of the individuals in the outpatient trials reported any kind of negative affect," says Vocci.
"It may be that in some individuals we get a pharmacological mimic of what might be a genetic variant."
Priming and the stress response
The priming response used by AA and smoking cessation groups discourages alcoholics and smokers from taking the first drink or smoking the first cigarette. In a formerly dependent individual the intake of a drug on which they were dependent produces a greater response in that individual than it would in a person who is not an abuser. The priming response is something that starts up certain systems that then lead people to crave more drugs or to seek drugs.
One drug, that is currently used to reduce the amount of alcohol people consume is Revia [naltrexone]. Vocci says that those who take it might sample alcohol and even have a few drinks, but they might not engage in a heavy drinking episode.
Because addicts have deregulated their systems, they perceive mild stressors as severe stressors and know that taking drugs is going to relieve that stress. NIDA researchers are studying a Corticotropin Releasing Factor (CRF) antagonist, which binds to CRF receptors in the brain to reduce stress, to block the craving response in addicted individuals by normalizing their deregulated systems.
Addicts with a genetic vulnerability to post-traumatic stress disorder who are in an environment where there is a genetic-environment interaction and that vulnerability is expressed, might have a greater susceptibility to abuse drugs. This model, though complex, is how researchers are looking at the models of genetics, environment, behavior and pathology, notes Vocci.
"And there may be multiple genes involved," says Vocci, "and what makes it even more complicated is that we think that these disorders are heterogeneous. Anxiety might not be due to just one set of genes, it might be multiple sets. Same thing with depression — same thing with vulnerability to substance abuse. You may have something that looks like the same disorder clinically, but people may get there through a variety of different pathways."
Population studies identify vulnerable populations, family studies and twin studies.
"The classical human genetic experiments that are going on will now be augmented by looking at an individual's genome and searching for candidate genes so we can identify a particular phenotype," says Vocci. "This is where the crucial part comes in. By identifying a phenotype [the physical manifestation of a gene function] you might be able to identify the genes that are responsible for that phenotype.
"If somebody's a heroin addict I might want to look at their brothers and sisters to see if they have an alteration in their CRF gene, so you study families looking for candidate genes."
Another genetic approach that Vocci believes will be fruitful, but is just beginning now, is the study of how drugs as an experience modify the brain.
"Drugs modify the brain in very profound ways and we know that they do," says Vocci. "At the genetic level, what are they turning on? What are they turning off? And how are these genes interacting with each other to change the brain?"
The effect of a treatment is evaluated by using microarray technology, in which 1,000 to 10,000 genes are displayed on a microarray plate. Scientists hope that by that technology, important genes will be identified, which in turn opens the door for pharmacological treatment of addictions.
"If a gene switches on," explains Vocci, "eventually it translates to an increase in messenger RNA. And, if you take the messenger RNA from the brain of a rat and lay it on this microarray and evaluate the genes it is switching on and what genes are being switched off, you are evaluating the effects of drugs of abuse on these kinds of genes.
"I suspect that what will happen from [microarray technology] is that there will be genes that will be switched on that we would have never, never thought of in our wildest dreams. We will gain insight into drug actions on the brain that we would never have thought otherwise," says Vocci.
Scientists are optimistic that the future of genetic research holds many promises for advances in the treatment of addiction.
"We think that genetic profiling down the line will be able to determine the best treatment for a given individual. That's where we think the field is going to be heading," says Comings.
Jan Marie Werblin is associate editor of Counselor, The Magazine for Addiction Professionals.
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