Monday, October 17, 2005

Science May One Day Find An Answer...

My Natal Astrological Chart

Thursday, October 13, 2005

Letting Others Find Their Own Way

California Business & Professions Code §2052.
(a) Notwithstanding Section 146, any person who practices or attempts to practice, or who advertises or holds himself or herself out as practicing, any system or mode of treating the sick or afflicted in this state, or who diagnoses, treats, operates for, or prescribes for any ailment, blemish, deformity, disease, disfigurement, disorder, injury, or other physical or mental condition of any person, without having at the time of so doing a valid, unrevoked, or unsuspended certificate as provided in this chapter or without being authorized to perform the act pursuant to a certificate obtained in accordance with some other provision of law is guilty of a public offense, punishable by a fine not exceeding ten thousand dollars ($10,000), by imprisonment in the state prison, by imprisonment in a county jail not exceeding one year, or by both the fine and either imprisonment.

(b) Any person who conspires with or aids or abets another to commit any act described in subdivision (a) is guilty of a public offense, subject to the punishment described in that subdivision.

(c) The remedy provided in this section shall not preclude any other remedy provided by law.
The practice of giving medical advice is rampant in the groups I attend. I often warn people that telling an addict what they should do to overcome addictive compulsions is against the law, punishable by jail and a heavy fine. Also, any inaccurate or unfounded direction to take such-and-such action exposes the would-be medical practitioner to civil liability for negligent misrepresentation – a lesser form of fraud & deceit. In addition, any failure to disclose risks or alternative treatments may expose the would-be practitioner to civil liability for failure to disclose.

However, mere suggestions and accurate recitals of the speaker's own diagnosis, prognosis, treatment, and outcome fall outside medical advice. This is what we mean by the term "sharing." A suggestion is not a subtle command (as I've heard "suggested"), but a suggestion merely informs the listener of an option that may have been overlooked. A recital is merely an account of this happened, then this happened – no causation or mechanism is stated, no advice given. E.g., a recital would be: "I prayed for rain, and in a few hours, it rained." An explanation would be: "I prayed for rain, which caused God to be moved by pity, which caused God to send the rain within a few hours." Advice (bad advice, I might add) would be: "If you want rain, you better pray."

Another person’s recovery is extremely personal, and we must guard against trying to stop them from finding their own way. Most of us aren't trained to think scientifically. And even if we were, most of us don't have the time or resources to keep up with the abundance of peer-reviewed material and epidemiological and double-blind statistical studies. The only notable exception to this would be a medical doctor, psychologist, counselor, or social worker who earns their living from keeping up with the literature.

The last page of AA's Living Sober has a wonderful passage that I think groups would do well to consider as a closing reading, somewhat along the lines of "A Vision For You":

Finding Your Own Way
Living Sober, pp 85-86
As you stay sober, you are sure to think of new ideas not recorded here. We hope so. We also hope that when you do come up with fresh ideas on this subject, you will pass them on. Please do share. (You'll recall that the act of sharing can itself be helpful to you.) The more experience we can all pool, the more problem drinkers can be helped.

Some of us go back to drinking a time or so before we get a real foothold on sobriety. If that happens to you, don't despair. Many of us have done this and have finally come through to successful sobriety. Try to remember that alcoholism is an extremely serious human condition, and that relapses are as possible in this ailment as in others. Recovery can still follow.

Even after setbacks, if you continue to want to get well, and remain willing to try new approaches, our experience convinces us that you have embarked with hundreds of thousands of companions on the path of happy, healthy destiny. We hope we see you among us in person.

But whatever track you travel, along with us or on your own, you go with our strongest good wishes.

Friday, October 07, 2005

No time ago

no time ago
or else a life
walking in the dark
i met christ

jesus)my heart
flopped over
and lay still
while he passed(as

close as i'm to you
yes closer
made of nothing
except loneliness

– e. e. cummings

The Gift

You tell me that silence
is nearer to peace than poems
but if for my gift
I brought you silence
(for I know silence)
you would say

"This is not silence
this is another poem"
and you would hand it back to me.

-- Leonard Cohen

I'm not sure about this. I imagine this.

I don't know it for certain,
but I imagine that a man
and a woman fall in love one day,
little by little they come to be alone,
something in each heart tells them that they are alone,
alone on the earth they enter each other,
they go on killing each other.
It all happens in silence.
The way light happens in the eye.
Love unites bodies.
They go on filling each other with silence.
One day they wake up, over their arms.
Then they think they know the whole thing.
They see themselves naked and they know
the whole thing.
(I'm not sure about this. I imagine it).

Jaime Sabines

Thursday, October 06, 2005

The Genetic Basis of Addiction

by Eric J. Nestler, M.D., Ph.D.
Psychiatric Times * February 2002 * Vol. XIX * Issue 2

Genetic factors play a significant role in addiction. Epidemiological studies have long established that alcoholism, for example, is familial, with estimates that 40% to 60% of the risk for this disorder is genetic (Kendler et al., 2000; Reich et al., 1998; Tsuang et al., 1998). Other studies have suggested similar rates of heritability for other drug addictions, such as to opiates and cocaine (Kendler et al., 2000; Kendler and Prescott, 1998; Tsuang et al., 2001). Numerous genetic linkage and association studies are now underway to identify the specific genes that comprise this risk. While investigators have identified several relatively large chromosomal regions as being possibly involved, no specific genetic polymorphism has yet been tied to addiction vulnerability with certainty. The one exception is the genetic defects found in certain East Asian populations in enzymes (e.g., alcohol and aldehyde dehydrogenases) that metabolize alcohol (Chen et al., 1999). These defects dramatically increase side effects of acute alcohol intake, thereby reducing the individual's vulnerability to alcoholism.

It is well-established that inbred strains of mice and rats show robust differences in behavioral and biochemical responses to drugs of abuse (Berrettini et al., 1994; Brodkin et al., 1998; Crabbe et al., 1999; McBride and Li, 1998). In addition, lines of rodents have been selectively bred for alcohol (or other drug) responsiveness. While the genetic variations that occur in animal models may be different from those in humans, identification of genes will provide insight into mechanisms underlying the addiction process. No specific genetic polymorphism has yet been identified in these animal models.

The difficulty in finding genes that contribute to risk for addiction parallels the difficulty in finding genes for other psychiatric disorders and, in fact, for most common diseases. Among the many reasons for this difficulty is the fact that addiction is a complex trait with many genes possibly involved. Thus, any single gene might produce a relatively small effect and would, therefore, be difficult to detect experimentally. It is also possible that variants in different genes may contribute to addiction in each family or rodent model.

Of course, vulnerability to addiction is only partly genetic; nongenetic factors -- which may include stochastic or random events during development or a host of environmental factors throughout life – are also important (Jacob et al., 2001). Such environmental factors remain only vaguely defined (e.g., poverty, crime, delinquency). In animals, environmental factors such as stress can interact with an animal's genotype to determine its ultimate responses to a drug of abuse. As a result, delineating the mechanisms by which specific genetic variations and specific environmental factors interact is an important focus of investigation.

A gene could contribute to addiction vulnerability in several ways. A mutant protein (or altered levels of a normal protein) could change the structure or functioning of specific brain circuits either during development or in adulthood. These altered brain circuits could change the responsiveness of the individual to initial drug exposure or the adaptations that occur in the brain after repeated drug exposure. Likewise, environmental stimuli could affect addiction vulnerability by influencing these same neural circuits. Perhaps combining genetic approaches with more narrowly defined phenotypes would facilitate the identification of addiction vulnerability genes.

Genetic Dissection of Behavior

In contrast to the difficulty in finding genetic factors that control individual risk for addiction, great strides have been made in demonstrating the role of specific gene products in the complex behavior of addiction as assessed in animal models. The general strategy is to modify the amount of a particular gene product, or in some cases to modify the product itself, and to characterize the consequences of such modifications in behavioral tests. The genetic approaches used most often are constitutive mutations in mice (knockouts and overexpressors); such mice continue to provide important insight into drug mechanisms. In more recent years, mice with inducible and tissue-specific mutations have been used increasingly to overcome some of the limitations of the first-generation mutants. Other genetic approaches include viral-mediated gene transfer, intracerebral infusions of antisense oligonucleotides and mutations in nonmammalian model organisms.

Behavioral Tests for Addiction

Animals with altered levels of a particular gene product in the brain are then subjected to a variety of behavioral tests to assess their responses to drugs of abuse (Nestler, 2000). The most widely used tests are measures of locomotor activity (most drugs of abuse increase activity in rodents when given acutely) and the progressive increase in locomotor activity (locomotor sensitization) that occurs with repeated drug exposure. While the relationship between locomotor responses and drug reward and addiction remains a matter of some debate, locomotor responses are mediated by the mesolimbic dopamine system, which is also implicated in reward and addiction.

A more direct measure of drug reward is conditioned place preference, where an animal learns to prefer an environment that was paired with drug exposure. Conditioned place preference is also mediated partly by the mesolimbic dopamine system and is thought to model some of the powerful conditioning effects of drugs that are seen in humans. Place-conditioning assays, like measures of locomotor activity, are amenable to relatively high throughput, which explains their wide use. However, neither test directly measures the behavioral abnormalities (i.e., compulsive drug-seeking and drug-taking) that are the core features of human addiction.

To get closer to such abnormalities, operant tests must be used. In self-administration tests, animals work (press a lever) to give themselves an intravenous or oral dose of a drug of abuse. The paradigm can also be used to study incentive motivation for drug and relapse after a period of abstinence. In intracranial self-stimulation, animals work to electrically stimulate a particular brain area (e.g., mesolimbic dopamine system). This test is thought to measure the affective state of an animal and the sensitivity of brain reward pathways to drugs of abuse. In conditioned reinforcement, animals work to obtain a previously neutral conditioned stimulus (e.g., light) that has been paired with a natural reinforcer (e.g., water). Drugs of abuse potently stimulate incentive motivation for the conditioned reinforcer. However, these tests generally are far more complicated to perform, particularly in mice. Thus, to date, the tests have been applied to only a small number of genetically altered animals. A major challenge for the field is to devise schemes that make application of these behavioral tests more widely available.

Confirming Initial Drug Targets

One of the most straightforward ways that genetic tools have been used in the addiction field is to confirm the initial protein target for a drug of abuse. While classic pharmacological approaches have revealed many initial drug targets, they often have failed, for example, to identify which of several receptor subtypes is most important. In this way, tests of knockout mice lacking the μ-opioid receptor, dopamine transporter, CB1 cannabinoid receptor or ß2 nicotinic acetylcholine receptor have confirmed that these are the initial targets that mediate the acute rewarding and other effects of opiates, stimulants, cannabinoids or nicotine, respectively.

Implicating Other Neurotransmitter Systems

Genetic tools are also providing evidence for the numerous neurotransmitters and receptors (and postreceptor signaling pathways) beyond the initial drug target that can modify responses to acute and chronic drug exposure. In some cases, the information obtained has confirmed earlier evidence from pharmacological approaches with receptor agonists and antagonists. In other cases, genetic studies have yielded fundamentally new insight into mechanisms of drug action.

As just one example, mice lacking the serotonin 5-HT1B receptor show enhanced responsiveness to cocaine and alcohol in several behavioral paradigms. Most importantly, the mice self-administer the drugs at higher levels, compared to wildtype controls (Crabbe et al., 1996; Rocha et al., 1998). The mice also show higher levels of ΔFosB, a Fos-like transcription factor implicated in addiction (see below), under basal conditions. These data suggest particular mechanisms through which serotonergic systems may be involved in addiction.

Nonmammalian model organisms are also proving useful in identifying novel biochemical pathways related to the actions of drugs of abuse. In one recent study, Drosophila melanogaster lacking the clock gene (the master regulator of circadian rhythms) showed reduced locomotor sensitization to cocaine (Andretic et al., 1999). This evidence raises the possibility that circadian genes in mammals may contribute to the mechanisms by which the brain responds to cocaine exposure.

At first it may seem implausible that something as complex as addiction can be modeled in flies; however, it is important to clarify two points. First, the locomotor responses of flies to cocaine (acting via dopamine pathways) are remarkably similar to that seen in mammals, which means that the use of dopaminergic neurons in motor circuits was obligated over 1 billion years ago in evolution. Second, even if flies may not develop the more complex (e.g., cognitive, emotional) aspects of addiction seen in mammals, they certainly can be used to identify the types of genetic and biochemical pathways that are perturbed as nerve cells adapt to a drug of abuse over long periods of time.

Identifying Transcriptional Mechanisms

The stability of the behavioral abnormalities that characterize addiction suggests that drug-induced changes in gene expression may be one important mechanism involved. Since classic pharmacological agonists and antagonists are not yet available for most proteins involved in gene regulation, genetic tools have provided the best approach to explore such processes in addiction.

One such mechanism is related to the Fos-like transcription factor ΔFosB (Nestler et al., 2001). It accumulates in the nucleus accumbens (a target of the mesolimbic dopamine system) after chronic, but not acute, exposure to any of several drugs of abuse, including opiates, cocaine, amphetamine, alcohol, nicotine and phencyclidine (PCP). This is in contrast to all other Fos-like proteins, which are induced only transiently after acute drug administration. The ΔFosB protein accumulates because it is highly stable, unlike other Fos-like proteins. Consequently, ΔFosB persists in the nucleus accumbens long after drug-taking ceases and thereby provides one mechanism by which changes in gene expression (and resulting changes in neural function and behavior) can be relatively stable.

Such a role for ΔFosB has been confirmed recently in transgenic mice, in which ΔFosB can be induced selectively within the same subset of nucleus accumbens neuron where it is normally induced by drug administration. Such mice show enhanced responsiveness to cocaine in several animal models, including locomotor activity, place conditioning, self-administration and relapse assays, which suggests that ΔFosB may function as a relatively sustained molecular switch that contributes to a state of addiction.

One challenge of current research is to identify target genes through which ΔFosB, as well as other transcription factors, produce their behavioral effects. Two general approaches have been used. One approach considers particular candidate genes that contain putative response elements for the transcription factor in question or whose products are implicated in drug mechanisms within the brain region of interest. The other approach is more open-ended and involves analysis of differential gene expression in certain brain regions (e.g., nucleus accumbens) under control and drug-treated conditions. For example, there is currently a great deal of excitement in the use of DNA array technology to identify genes involved in addiction. In encouraging news, the use of various arrays (filter-, glass- and chip-based) in preliminary studies has led to the identification of thousands of potential drug-regulated genes. The daunting news is that the field needs to learn how to better evaluate this vast amount of new information (beyond evaluating single genes with traditional approaches) to identify which genes truly are drug-regulated and contribute to addiction.


In contrast to the difficulty in identifying genes that underlie individual differences in vulnerability to addiction, genetic tools have been invaluable in increasing our understanding of neurobiological mechanisms involved in the addiction process.

One weakness of the field is that, in some cases, a genetic mutation is shown to result in altered behavioral responses to a drug of abuse, but there is no plausible scheme explaining how the mutation actually causes the abnormal behavior. However, the increasing sophistication of genetic tools and the increasing predictive value of animal models of addiction make it increasingly feasible to fill in the missing pieces and to understand the cellular mechanisms and neural circuitry that ultimately connect molecular events with complex behavior.

Study Examines Role of Cannabinoid Receptors in Alcohol Abuse

Another brain receptor confirmed to affect alcohol intake; may serve as treatment target

September 7, 2005

UPTON, NY - A new set of experiments in mice confirms that a brain receptor associated with the reinforcing effects of marijuana also helps to stimulate the rewarding and pleasurable effects of alcohol. The research, which was conducted at the U.S. Department of Energy’s Brookhaven National Laboratory and was published online September 2, 2005 by the journal Behavioural Brain Research, confirms a genetic basis for susceptibility to alcohol abuse and also suggests that drugs designed to block these receptors could be useful in treatment.

“These findings build on our understanding of how various receptors in the brain’s reward circuits contribute to alcohol abuse, help us understand the role of genetic susceptibility, and move us farther along the path toward successful treatments,” said Brookhaven’s Panayotis (Peter) Thanos, lead author of this study and many others on “reward” receptors and drinking (see: this release and ,

Earlier studies in animals and humans have suggested that so-called cannabinoid receptors known as CB1 — which are directly involved in triggering the reinforcing properties of marijuana — might also stimulate reward pathways in response to drinking alcohol. Thanos’ group investigated this association in two experiments.

In the first experiment, they measured alcohol preference and intake in mice with different levels of CB1 receptors: wild type mice with normal levels of CB1; heterozygous mice with approximately 50 percent levels; and so-called knockout (KO) mice that lack the gene for CB1 and therefore have no CB1 receptors. All mice were given a choice of two drinking bottles, one with pure water and one with a 10 percent alcohol solution — approximately equivalent to the alcohol content of wine. Mice with the normal levels of CB1 receptors had a stronger preference for alcohol and drank more than the other two groups, with the CB1-deficient mice showing the lowest alcohol consumption.

After establishing each group’s level of drinking, the scientists treated animals with a drug known to block CB1 receptors (SR141716A) and tested them again. (These animals were also compared with animals injected with plain saline to control for the effect of the injection.) In response to the CB1 receptor-blocking drug, mice with normal and intermediate levels of receptors drank significantly less alcohol compared to their pre-treatment levels, while KO mice showed no change in drinking in response to the treatment.

In the second experiment, the scientists compared the tendency of wild type and KO mice to seek out an environment in which they had previously been given alcohol. Known as “conditioned place preference,” this is an established technique for determining an animal’s preference for a drug.

Animals were first conditioned to “expect” alcohol in a given portion of a three-chambered cage while being given an injection of saline in the opposite end, and then monitored for how much time they spent in the alcohol chamber “seeking” the drug. Wild type animals, with normal levels of CB1, spent more time in the alcohol-associated chamber than the saline chamber, showing a decided preference, while KO mice (with no CB1 receptors) showed no significant preference for one chamber over the other.

“These results support our belief that the cannabinoid system and CB1 receptors play a critical role in mediating the rewarding and pleasurable properties of alcohol, contributing to alcohol dependency and abuse,” Thanos said.

In addition, the fact that the mice with intermediate levels of CB1 exhibited alcohol preference and intake midway between those with high levels of receptors and those with none suggests that the genetic difference between strains quantitatively influences the preference for and the amount of alcohol consumed. “These results provide further evidence for a genetic component to alcohol abuse that includes the CB1 gene — the same gene that is important for the behavioral effects of marijuana,” Thanos said.

While it remains unclear exactly how CB1 triggers the rewarding effects of alcohol, one possibility is that activation of the CB1 receptor somehow blocks the brain’s normal “stop” signals for the production of dopamine, another brain chemical known to play a role in addiction. Without the stop signal, more dopamine is released to produce a pleasure/reward response.

Since blockade of the CB1 receptor with SR141716A appears to effectively reduce alcohol intake and preference, this study also suggests that such CB1 receptor-blocking drugs might play an important role in the future treatment of alcohol abuse.

This study was funded by the Office of Biological and Environmental Research within the U.S. Department of Energy’s (DOE) Office of Science; by the National Institute on Drug Abuse and the Intramural Research Program of the NIH, [National Institute on Alcohol Abuse and Alcoholism]. The DOE has a long-standing interest in research on addiction that builds, as this study does, on the knowledge of brain receptors gained through brain-imaging studies. Brain-imaging techniques such as MRI and PET are a direct outgrowth of DOE’s support of basic physics research.

Tuesday, October 04, 2005

Gene Therapy Reduces Drinking in Rats with Genetic Predisposition to “Alcoholism”

Finding confirms earlier result using better model for human alcohol abuse

May 5, 2004

UPTON, NY — As a follow up to
previous work showing that gene therapy can reduce drinking in rats trained to prefer alcohol, scientists at the U.S. Department of Energy’s Brookhaven National Laboratory have used the same technique to cut drinking in rats with a genetic predisposition for heavy alcohol consumption. The findings, along with additional results on the effects of long-term ethanol consumption on certain aspects of brain chemistry, are published in the May 2004 issue of Alcoholism Clinical and Experimental Research.

“Though we are still early in the process, these results improve our understanding of the mechanism or mechanisms of alcohol addiction and strengthen our hope that this treatment approach might one day help people addicted to alcohol,” said Panayotis (Peter) Thanos, who lead the study in Brookhaven Lab’s medical department.

Genetically predisposed alcohol-preferring rats are a much better model for human alcoholism than the rats used previously, which the scientists had to train to prefer alcohol. Without any training, the genetic alcohol-preferring rats drink, on average, more than five grams of ethanol per kilogram of body weight per day when given a free choice between alcohol and plain water. Genetically non-preferring rats, in contrast, typically consume less than one gram of ethanol per kilogram of body weight per day.

In this study, both groups were treated with gene transfer to increase the level of a brain receptor for dopamine, a chemical important for transmitting feelings of pleasure and reward and known to play a role in addiction. After the gene treatment, the alcohol-preferring rats exhibited a 37 percent reduction in their preference for alcohol and cut their total alcohol consumption in half — from 2.7 grams per kilogram of body weight before treatment to 1.3g/kg after. Non-preferring rats also reduced their drinking preference and intake after gene treatment, but not in nearly as dramatic a fashion. The greatest reductions in alcohol preference and consumption were observed within the first few days after gene treatment, and both preference and consumption returned to pre-treatment levels by day 20.

Brain scans showing fewer dopamine receptors (less red) in the nucleus acumbens, or "pleasure center," of alcohol-preferring (P) rats compared to nonpreferring (NP) rats.

The gene administered was for the dopamine D2 receptor, a protein shown in various studies to be relevant to alcohol and drug abuse. For example, low levels of dopamine D2 receptors in the brain have been postulated to lead to a reward deficiency syndrome that predisposes certain people to addictive behaviors, including drug and alcohol abuse. The alcohol-preferring rats used in this study have about 20-25 percent lower levels of dopamine D2 receptors when compared to the non-preferring rats, which may, in part, explain their tendency toward heavy drinking.

The scientists delivered the gene by first inserting it into a virus that had been rendered harmless. They then injected the virus directly into the rats’ nucleus accumbens, the brain’s pleasure center. The idea behind this type of gene therapy is to use the virus as a vector to carry the gene to the brain cells, which can then use the genetic instructions to make the D2 receptor protein themselves.

As an additional measure in this study, the scientists used micro-positron emission tomography (microPET) imaging to non-invasively assess the effects of chronic alcohol consumption on D2 receptor levels in alcohol-preferring and non-preferring rats. They measured D2 levels seven weeks after the gene therapy treatment (well after the effects of gene therapy had worn off). D2 receptor levels in alcohol-preferring rats were significantly lower (about 16 percent) compared to that in non-preferring rats. These levels were similar to previous data in naïve preferring and non-preferring rats.

In future studies, the D2 connection to alcoholism will be examined in transgenic mice that are totally depleted of D2. In addition, the scientists plan to develop a second generation D2 vector approach that will provide a longer period of treatment.

“These findings further support our hypothesis that high levels of D2 are causally associated with a reduction in alcohol drinking and may serve as a protective factor against alcoholism,” Thanos said.

This study was funded by the Office of Biological and Environmental Research within the Department of Energy’s Office of Science and by the National Institute of Alcohol Abuse and Alcoholism within the National Institutes of Health.

Monday, October 03, 2005

US & Russian Alcoholics Share Similar Gene

from ACER News Release

GABRA2 Influences Risk in Both Populations

Gamma-amino butyric acid (GABA) is the most abundant inhibitory neurotransmitter in the brain. Last year, two large genetic studies in the U.S. identified an association between genetic variations in the GABA a2 receptor subtype (GABRA2) and risk for alcohol dependence. Now, a study in the April issue of Alcoholism: Clinical & Experimental Research has extended those findings to a Russian population.

"There are braking neurotransmitters and accelerating neurotransmitters," said Jaakko Lappalainen, assistant professor of psychiatry at Yale and first author of the study. "GABA is one of the braking neurotransmitters, it brakes the neurons so that they don't get out of control."

Activating or enhancing the function of GABA receptors usually decreases activity in brain neurons and can decrease activity of the entire brain and body, as occurs in general anesthesia.

Some of alcohol's effects appear to be mediated through GABRA2, however, this only explains part of the development of alcohol dependence.

"Alcoholism is a complex disease, and an individual's vulnerability is affected both by the set of genes they inherit, and the environments they are exposed to, including their behaviors," said Howard J. Edenberg, Chancellor's Professor and professor of biochemistry and molecular biology, and of medical and molecular genetics, at the Indiana University School of Medicine. "No one gene 'makes' one an alcoholic. But it is important to discover the variations in individual genes that affect one's risk for the disease. This will improve our ability to prevent and treat the disease."

For this study, researchers recruited 113 Russian alcohol-dependent men from a St. Petersburg treatment center, as well as 100 local military personnel as controls. Blood samples were drawn from all participants and genotyped for seven GABRA2 single nucleotide polymorphisms (SNPs).

Significant Association

"SNPs are variations in the genetic code," said Lappalainen. "A person's DNA is made of base pairs; about every 100 base pairs, there is a variant that is different between individuals. We believe that a lot of the variation in the way we look, behave and respond to medications is encoded in variant sites in genes."

Lappalainen and his colleagues found significant associations between two SNPs and alcohol dependence. Furthermore, comparison of these findings to those of the U.S. population suggests that the structure and frequencies of GABRA2 haplotypes (a group of variations that are inherited together) are very similar in U.S. and Russian populations.

Previous Studies Confirmed

"These findings help demonstrate," said Lappalainen, "that regardless what different environmental factors in Russia may be in play, compared to the U.S., GABRA2 still seems to be influencing risk in that population."

Edenberg concurs. "This paper lends further support to the finding, initially reported by the Collaborative Study on the Genetics of Alcoholism (COGA), that variations in the GABRA2 gene affect risk for alcoholism," he said. "The COGA finding was also supported by a case-control study. Although the data from the current study are not as strong as the earlier reports, the consistency of support for the finding is important. It is notable that the three studies," he added, "with different study designs, all point to the same region of the same gene, making the accumulated evidence even stronger. It is exciting that this finding has been replicated and extended to a different population."

Gene Is Only One Factor

Nonetheless, both Lappalainen and Edenberg pointed out that possessing the GABRA2 gene, which is very common, does not mean an individual will become an alcoholic.

"It is important to emphasize that this is not 'the gene for alcoholism'" said Edenberg. "There is no such thing. It is one of several in which variations contribute to the risk. COGA has already identified additional genes, including GABRG3 and CHRM2, and has evidence for additional genes. It is also critical to make clear that having any one gene variant, or even a collection of genes that increase risk, does not condemn someone to being an alcoholic; the genes affect the risk, but so do the choices made by the individual. This is similar to diabetes, in which genes affect risk but so does behavior such as eating and exercise."

Researchers Identify Alcoholism Gene

Alcohol Addiction, High Anxiety Linked to Same Gene
By Jeanie Lerche Davis
WebMD Medical News
Reviewed by Brunilda Nazario, MD
on Wednesday, May 26, 2004

May 26, 2004 – A new study links a gene to alcohol addiction – backing up a long-recognized pattern showing that alcoholism runs in families.

The finding also provides evidence that an inborn high level of anxiety is part of this picture. The study appears in this week's issue of the Journal of Neuroscience.

Research has shown that alcohol addiction is a complex disease, with both genetics and a tendency toward anxiety playing "crucial roles," writes researcher Subhash C. Pandey, PhD, a psychiatrist with the University of Illinois at Chicago.

"Some 30% to 70% of alcoholics are reported to suffer from anxiety and depression," Pandey says in a news release. "Drinking is a way for these individuals to self-medicate."

Pandey's research focuses on the CREB gene, so-named because it produces a protein called CREB – cyclic AMP responsive element binding protein. The CREB gene regulates brain function during development and learning. The gene is also involved in the process of alcohol tolerance, dependence, and withdrawal symptoms, writes Pandey.

A section of the brain – called the central amygdala – is another piece of this puzzle. Both the CREB gene and the central amygdala have been linked with withdrawal and anxiety. When there is less CREB in the central amygdala, rats show increased anxiety-like behaviors and preference for alcohol.

Pandey's newest study puts it all together: It is "the first direct evidence that a deficiency in the CREB gene is associated with anxiety and alcohol-drinking behavior," Pandey writes.

Mice Bred for Alcohol Addiction

In this study, Pandey and colleagues worked with rats specially bred to be deficient in the CREB "alcoholism" gene. In a series of experiments, he found that:

  • Rats deficient in the CREB protein drank about 50% more alcohol than normal rats. They also showed more anxiety-like behavior in a maze test.

  • These rats also showed a higher preference for alcohol over water compared with normal rats; yet they had similar preferences for sugar water – indicating that the alcohol consumption was not related to taste preferences.

  • These rats also displayed more anxiety than normal mice, which decreased when drinking alcohol. The anxiety-reducing effect of alcohol was not as great in the normal rats.

  • Alcoholic rats had higher levels of the CREB protein in the central amygdala.
These results indicate that the CREB or alcoholism gene is "crucial" to the anxiety relief that triggers alcohol addiction, Pandey writes.

SOURCES: Pandey, S.Journal of Neuroscience, May 26, 2004. News release, University of Illinois at Chicago.