New research on alcohol use disorder finds gene networks – not just one, but as many as 89 up to networks of 900 genes interacting – are being looked at as ways of predicting a person’s likelihood of developing alcohol addiction. Also a person’s level of response to alcohol, their initial tolerance, i.e., needing more to feel the effects, contributes as well. Also discussed, the amino acid glutamate and neurotransmitter GABA and their relationships to craving and relapse. The muscle relaxant chlorzoxazone (Parafon Forte) can decrease craving by effecting the nucleus accumbens, the brains reward/reinforcement/ pleasure center. Dr Inaba explains.
Transcript (edited):
CNS: There are a couple of articles in Science Daily talking about genes and gene networks, how a persons level of response to alcohol influences them in terms of becoming alcohol dependent, suggesting perhaps that a person needing more alcohol than most people to become intoxicated has a greater risk of addiction. There is also a story about alcohol, craving and the possibility of relapse. How does this all interact?
DARRYL: I think there are a couple things that touch on. The one article addresses a persons vulnerability to developing an alcohol use disorder – which is the current term for alcoholism. This is something weve always suspected. In 1990, Dr. Kenny Blum and Ernest Noble announced they had found a gene a single gene that seemed to predict somebodys vulnerability to develop alcoholism. The DRD2A1 allele gene or dopamine receptor, dopamine 2 receptor. A1LL makes you more vulnerable to alcoholism than the A2 allele. Blum and Noble were immediately condemned by a lot of scientists, saying it was wrong to make such an announcement because it cant be just one gene. I tend to agree with the rest of the scientific world and now this this story that you point out in Science Daily is looking at the fact that since Kenny Blums announcement and Ernest Nobles announcement, a 2009 study released by the National Institute of Drug Abuse came out listing something like 89 genes that were related to alcoholism and other drug dependencies and an additional 900 suspected genes. So were looking not at a single gene that will indicate vulnerability, but a network of genes. Its several genes working together, interacting to bring about a level of response that is different in those people who are prone to alcoholism and those who arent. There were patho medic symptoms – definitely symptoms long before we recognized genes that seemed to be associated with a predisposition to alcoholism. One of them is as you point out an initial tolerance. It seems that people who can drink a lot more when they first begin drinking alcohol, without getting drunk, were much more prone to be an alcoholic later in life. People who had dramatic personality changes when they got drunk and/or experienced blackout or amnesia or brownout, (partial amnesia symptoms) due to drinking, were presenting symptoms that indicated that the person carried a genetic or predisposition to alcoholism. This recent study looks at how people respond to alcohol and also at glutamate; one of the neurotransmitters that have receptor sites both in the lateral hypothalamus and in the in nucleus accumbens. GABA and glutamate are counterparts. GABA is in the inhibitory neurotransmitter, the one that shuts down the synapse and glutamate activates or excites the synaptic process. But those 2 neurotransmitters are sort of assistants. They increase or decrease salience or increase the prominence of how dopamine is going to work in the nucleus accumbens or decrease the prominence of how dopamine is going to work. And now they seem to be the target of a lot of work and a lot of treatment interventions things like acamprosate looks at that system We had the Prometa looking at that system and even receptor sites involved with that is how it connected to a persons predisposition to alcohol and also has to deal with their craving. The other Science Daily news story I think you mentioned was the one that had to do with..
CNS: Craving and relapse.
DARRYL: Yes, and there was indeed something new. This seems to be a change in what Ive believed to this point about how a person in recovery for alcohol is triggered. When an alcoholic receives a sensory input like a sight, a smell, neighborhoods, walking past a familiar bar or something else that reminds them of their drinking they immediately go into an environmental queue or environmental triggered response where they crave alcohol. I thought for a long time that it was mediated. Memories we call them spikes, are emotionally fixed to the amygdale, which seeks out memories of use situations and ultimately trigger a release of dopamine from the ventral tegmental area. I believed that as the dopamine moves forward, it activated the shell of the nucleus accumbens, which created this craving response, and that actually using drugs activated the core in the nucleus accumbens. Where this new research seems to say the opposite. It seems to say that what activates first through the triggers, without using any drugs at all, is the core of the nucleus accumbens through specific calcium channels in which glutamate activate or enhance the activity of dopamine. This creates a craving response where a person wants to go out and get some alcohol or drink again even though they have been years and years in recovery. But the interesting thing is that theyve found that a muscle relaxant, Chlorzoxazone, a medication we actually used symptomatically to treat opiate addiction and alcoholism way back in the 1960s when we opened the (Haight Ashbury) clinic and developed symptomatic treatment, specifically effects those pores, those calcium pores in the nucleus accumbens core and relieves or decreases that craving response So maybe we were ahead of our times, but I just found that to be interesting that theyre pulling all of this together and again it is validating that people who relapse are not weak-willed but have the will power to deal with it.
CNS: The environmental factors.
DARRYL: Yes, and now were realizing again it is a biological situation.
CNS: This is sounding like its reaching into a deeper molecular level of understanding? Is that true?
DARRYL: Well .
CNS: Neurotransmitters are complex molecules as opposed to calcium.
DARRYL: Well, its a matter of how deep we want to go. Because what neurotransmitters do, and weve always known this, but to bring it all out at one time just could be confusing for most people who didnt even accept the fact that there were neurotransmitters in the brain, communicates through chemicals. But the way the neurotransmitters work, is they work they work on channels. They open channels for ion sodium ion calcium ion potassium ion and it is a flux of those ions that go in and out of nerve cells that create electrical potential, activating what they call, G proteins, adenylate cyclase, to bring about what we know as a synapse. Every level we reach we encounter another level of complexity and more things that can go this way and that way, so even for myself, Ive got to take it slowly, otherwise Id get overwhelmed by this flood of information.
CNS: The more closely we look at anything, the more richly complex it becomes. Something else that you may want to respond to in terms of genetic networks is the influence of family family histories. We know that alcoholic tendencies definitely have a certain proclivity towards running in families as well as in cultures. Does any of this validate that?
DARRYL: I think overall they all overlap as weve been discovering in our understanding of the addictive process that environment does play a huge role. I remember hearing a Latino speaker at a national conference saying yes, maybe theres a genetic thing, but he also sees generations of depravity, generations of oppression, generations of sexual abuse and domestic violence and so on. And where it is coming closest together for me is in that process called epigenetics. That is a new science proposing that people carry a multitude of gene liabilities, but only certain ones express themselves through the process and through stress and environmental situations, not within offspring, the next generation but solely within that individual. You can express a different expression on that gene to manifest different behaviors, and certainly if oppression and depravity are in your life, and there are many life crisiss affecting you, I think it does affect how your brain operates and how your neurotransmitters operate and how you function. All of those things add to another level of complexity that makes a person more vulnerable to addiction. Again, it is heredity, its your environment, but we also have toxicity because drugs themselves affect the chemistry of the brain and also gene expressions. So when those 3 work together, it creates a very complex series of interactions that makes one more or less vulnerable to these conditions.
CNS: And then the changes that are brought about over the time and over usage.
DARRYL: Absolutely.
CNS: Well, the work of science brings something new and interesting to the table and to our understanding of these complex parts of our brain and our functioning as human beings in cultures.