GABA and Glutamate Impact of Genetic Vulnerability to Alcoholism

Graeme F. Mason, Ph.D.

Yale University

Funded in June, 2005: $100000 for 5 years
LAY SUMMARY . ABSTRACT . HYPOTHESIS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Using Imaging to Explore Genetic Predisposition to Alcohol Addiction

Investigators will use MRI imaging to determine if there is a direct link between a variant in a specific gene that may produce an increased susceptibility to alcohol dependence and two neurotransmitters that may be involved in addiction.

Research has found that alcohol dependence is associated with a variant of a gene that directs the development of receptors on certain brain cells that take up the neurotransmitter GABA to communicate with one another.  When cells receive GABA, they are receiving a message to inhibit their actions.  These receptors also bind to an excitatory neurotransmitter, called glutamate, which balances GABA’s message to slow down.  Importantly, these same cell receptors also bind to alcohol.  The investigators hypothesize that drinking alcohol reduces the levels of both of these neurotransmitters, but that the levels are reduced less in people who have the genetic variant compared to those who do not.  A finding that the adults with the alcohol genetic variant have only slightly reduced levels of the two neurotransmitters would help to explain why they are less sensitive to alcohol’s effects, feel less impaired by alcohol, and are more likely to drink more, and more often.  To test this hypothesis, the Yale researchers will identify adults with the genetic variant and those who do not have it, and will use MRI in both groups to measure levels of GABA and glutamate, while participants drink alcohol.

Significance:  This study could provide direct evidence linking a genetic predisposition to alcohol dependence to its effects on two neurotransmitters.  This evidence would advance our understanding of the interrelated chemical and genetic bases of alcohol dependence and may lead to new therapeutic approaches to preventing or treating alcohol addiction.

ABSTRACT

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GABA and Glutamate Impact of Genetic Vulnerability to Alcoholism

Strong and growing evidence supports the theory that vulnerability to ethanol dependence can be inherited, and recent work has revealed specific genetic risk factors. These factors include variants of genes coding elements of the g-aminobutyric acid (GABA) neurotransmitter system genes. GABA is the main mammalian inhibitory neurotransmitter, and ethanol bound to the GABAA2 receptor potentiates GABA's inhibitory effects. In a large population, a strong association of single nucleotide polymorphisms at the GABRA2 locus (the gene encoding the GABAA2 receptor subunit) and alcohol dependence was found, and we have replicated that finding in two additional groups. The receptor subunit is a primary binding location for ethanol, which potentiates the action of GABA at the receptor, so it is conceivable that differences in the form of this subunit could affect some aspects of alcohol intoxication. In our first sample, one marker (rs279858) was more strongly associated with trait (p = 0.002) than the others. Those with the rs279858 marker were less affected by alcoholic drinks than those without it. This observation is consistent with the idea that people who are less impaired by alcohol may actually be at greater risk of dependence, because they may perceive less need to stop or avoid drinking.

In the proposed study, we will expand on the genetic correlation between the GABA receptor and alcohol dependence by evaluating alcohol-induced changes in neurotransmitter concentration and turnover as a function of genetic vulnerability. We plan to use 1H and 13C MRS to measure the concentration of brain GABA and the rates of glutamate-glutamine neurotransmitter cycling and GABA synthesis in healthy subjects who are homozygous either for the risk allele or the alternate allele of the GABRA2 receptor marker. These measures provide a direct assay of brain excitatory activity (glutamate/glutamine cycle) and GABAergic cell function. The MRS measurements will be repeated, once with and once without intravenous administration of ethanol clamping the blood alcohol level at 0.06%.

We hypothesize that these three metabolic parameters will be more affected in the less vulnerable people than in the more vulnerable people. We also plan to reverse the standard approach of genetic testing of subjects who undergo MRS. Until now, the format for preliminary translational research has been to obtain DNA samples on subjects who participate in MRS studies of alcoholism. However, screening in search of genetic effects generally requires more subjects than can be studied with the fairly complex MRS measurements. We propose here to use an alternative approach in which candidate genes are preselected and prescreened, and a group of subjects is selected for MRS studies based on their being homozygous for the risk allele or homozygous for the alternative allele. We hope to identify evidence supporting a specific functional GABAergic gene effect that will allow us to understand why genetic variation in GABRA2 affects risk for alcohol dependence.

HYPOTHESIS

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Hypothesis:
A widespread, previously observed genetic vulnerability to alcoholism is associated with blunted responses of the GABAergic system to ethanol.

Goals:
1. Evaluate the effects of the genetically varied GABA receptor on brain GABA levels and glutamate-glutamine neurotransmitter cycling.
2. Evaluate the impact of the genetic variation of the GABA receptor on the response of brain GABA and glutamate-glutamine neurotransmitter cycling to an acute dose of ethanol.

Methods:
Two healthy groups of subjects without alcohol dependence will be studied, half with the risk-associated form and half without. Brain GABA levels will be measured with 1H magnetic resonance spectroscopy (MRS), and glutamate-glutamine neurotransmitter cycling will be measured with 13C MRS. The measurements will be done with and without administering alcohol.

SELECTED PUBLICATIONS

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Pierucci-Lagha A., Covault J., Feinn R., Nellissery M., Hernandez-Avila C., Oncken C., Morrow A.L., and Kranzler H.R. GABRA2 alleles moderate the subjective effects of alcohol, which are attenuated by finasteride.  Neuropsychopharmacology. 2005 Jun;30(6):1193-203.

Mason G.F., Gruetter R., Rothman D.L., Behar K.L., Shulman R.G., and Novotny E.J. Simultaneous determination of the rates of the TCA cycle, glucose utilization, a-ketoglutarate/ glutamate exchange, and glutamine synthesis in human brain by NMR. J Cereb Blood Flow Metab. 1995 Jan;15(1):12-25.

Rothman D.L., Petroff O.A., Behar K.L., and Mattson R.H. Localized 1H NMR measurements of gamma-aminobutyric acid in human brain in vivoProc Natl Acad Sci USA 1993 Jun 15; 90(12): 5662-5666.