How much was previously known about the cellular mechanisms of alcohol dependence?
In the brain there are both excitatory and inhibitory neurotransmitters. These are molecules that are released from nerve endings in the brain and in the periphery and either excite or inhibit other nerve cells, also known as neurons.
A key effect of alcohol is to increase the inhibitory tone in the brain. Over time, the brain adapts to having alcohol on board and the brain’s own natural inhibitory tone gets lower so that the brain functions relatively well in the presence of alcohol.
However, after the alcohol is gone, the neurotransmitters affected by alcohol will rebound and there will be too much excitation in their brains.
This is why after having had excessive amounts of alcohol, people are agitated and also depressed, which may lead to resumption of alcohol drinking to self-medicate as well as drinking progressively increased amounts of alcohol.
Why is gamma-aminobutyric acid (GABA) release in the central amygdala critical in the transition from recreational drinking to alcohol dependence?
One way alcohol increases the inhibitory tone in the brain is by weakening the action of the main excitatory neurotransmitter, glutamate, and strengthening the action of the main inhibitory neurotransmitter, GABA.
Through these actions, at low doses like social drinking, alcohol will reduce anxiety, while at progressively higher doses it will induce euphoria and at still higher doses will cause hypnosis, i.e., it will make people sleepy.
The amygdala is part of brain’s limbic system, an older part of the brain that is key for emotions. In particular, the amygdala is involved in fear and stress responses. Excessive activation of the amygdala and other interconnected brain regions in the limbic system are associated with anxiety and depression.
We believe that the effects of alcohol on GABA release in the central amygdala are linked to alcohol’s ability to reduce anxiety and, after the alcohol is gone, to increase anxiety and cause depression. However, we do not know exactly how that happens.
What is neurofibromatosis type 1 (Nf1) and why did you think Nf1’s regulation of GABA release might be relevant to alcohol consumption?
Nf1 is a gene that was originally found as the cause of a disease called neurofibromatosis. This a disease characterized by multiple benign tumors along nerves (called neurofibromas) as well as other manifestations.
The Nf1 gene plays a key role in regulating an intracellular signalling pathway that is involved in various cellular responses, in addition to the growth of these and other tumors.
Importantly, we found that it is important in regulating the release of the neurotransmitter GABA and its regulation by alcohol, and in the increased release associated with the development of alcohol dependence.
How did your research solve the mystery of why this specific signalling pathway is associated with alcohol dependence?
Certain strains of mice will readily learn to drink alcohol, and if they are allowed to get repeatedly drunk they will increase their drinking considerably. This is a bit like the binge pattern of drinking that is unfortunately popular with college students and that can lead to alcohol use disorders.
Well, we observed that lack of the Nf1 gene abolished the effect of alcohol to increase GABA release in the amygdala and prevented the transition to increased drinking in these mice.
Did your study show a correlation between rodent and human data?
Yes. We found that variation in this specific gene, NF1, in people is correlated with the risk of becoming dependent on alcohol.
These studies were carried out in collaboration with geneticists Drs. Henry Kranzler of the University of Pennsylvania, Richard Sherva and Lindsay Farrer of the Boston University School of Medicine, and Joel Gelernter of the Yale University School of Medicine who study the genetic basis of alcoholism.
What are the long-term clinical implications of this work?
Our research provides a clue of the signalling mechanisms that alcohol hijacks to alter GABA neurotransmission in the brain. Thus, it gives us a glimpse into the molecular machinery behind the effects of alcohol, which can help us identify novel and perhaps more effective targets for new medications to treat alcohol abuse.
Ultimately, we hope that by exploiting Nf1 and its targets we will be able to revert the effects of alcohol dependence that manifest in the negative emotional symptoms during withdrawal – such as anxiety and depression - which promote relapse and loss of control over alcohol intake.
However, alcohol use disorders are heterogeneous and behind them is the interplay of genetic and environmental factors thus, ultimately one can envision that certain therapeutic strategies will be effective in some individuals and other strategies in others.
What should future research focus on?
Nf1 reduces the activity of an intracellular signalling pathway that seems to be required for the changes in the brain that are behind the transition to excessive drinking. However, the role of Nf1 is complex, both too little and too much activity of the pathway prevents increased drinking.
We need to better understand the rest of the system in which Nf1 is active to be able to identify how to target it.
Where can readers find more information?
http://www.biologicalpsychiatryjournal.com/article/S0006-3223%2814%2900606-4/fulltext
About Dr Sanna
Pietro Paolo Sanna is an MD who specializes in pharmacology. His lab at The Scripps Research Institute studies the molecular basis of addiction.
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