Academic journal article Alcohol Research

Alcohol Dependence and Genes Encoding [Alpha]2 and [Gamma]1 GABA^sub A^ Receptor Subunits: Insights from Humans and Mice

Academic journal article Alcohol Research

Alcohol Dependence and Genes Encoding [Alpha]2 and [Gamma]1 GABA^sub A^ Receptor Subunits: Insights from Humans and Mice

Article excerpt

One approach to identifying the causes of alcoholism, particularly without crossing ethical boundaries in human subjects, is to look at the person's genome (and particularly at the variations that naturally arise in the DNA) to identify those variations that seem to be found more commonly in people with the disease. Some of these analyses have focused on the genes that encode subunits of the receptor for the brain chemical (i.e., neurotransmitter) γ-aminobutyric acid (GABA). Different epidemiological genetic studies have provided evidence that variations in certain GABA^sub A^ receptor (GABA^sub A^-R) subunits, particularly subunits α2 and γ..., are correlated with alcohol dependence. Manipulations of these genes and their expression in mice and rats also are offering clues as to the role of specific GABA^sub A^-Rs in the molecular mechanisms underlying alcoholism and suggest possibilities for new therapeutic approaches. Key words: Alcohol dependence; alcoholism; genetic factors; DNA; genetic theory of alcohol and other drug use (AODU); genetic vulnerability to AODU; genetic variants; γ-aminobutyric acid (GABA); GABA^sub A^ receptor (GABA^sub A^-R) subunits; GABRA2; GABRG1; single nucleotide polymorphisms (SNPs); ion channels; neurotransmitters; gene association studies; human studies; animal studies; mice; rats

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Even though the consequences of alcohol dependence (AD) clearly are devastating and obvious to observers, the molecular mechanisms involved in the development of the disease are far from clear and understood. The search for these mechanisms is made even more difficult by the vast number of genes, proteins, and pathways in the human body that potentially could be involved, and by the obvious limi- tations of conducting research with human subjects without crossing ethical boundaries. Yet despite these complexities, various approaches already have allowed researchers to gather much knowledge in recent years, and the essential players in alcohols mechanisms of action and in the development of AD already may have been identified. Thus, research has found that the primary targets of alcohol seem to be proteins prominently involved in neuronal communication, including:

* Ion channels in the neuronal membrane that are activated by signaling molecules (i.e., neurotransmitters) such as ?-aminobutyric acid (GABA) (i.e., GABAa receptors), glycine (i.e., glycine receptors), glutamate (i.e., A^-methyl- D-aspartate receptors [NMDA-Rs]), acetylcholine (i.e., nicotinic receptors), and serotonin (i.e., 5-HT3 receptors);

* Ion channels regulated by changes in the electric potential across the neuronal membrane (i.e., voltage-gated channels), such as voltage-gated calcium channels; and

* Ion channels regulated by a type of regulatory molecules called G-proteins, such as G-protein-coupled inwardly rectifying potassium channels (GIRKs).

Alcohols actions on these primary targets trigger the involvement of other systems that ultimately culminate in the development of dependence (Vengeliene et al. 2008).

Many techniques have yielded insight into alcohols effects on the organism, but perhaps the most challenging field, given the logical ethical constrains, is the study of the neuronal structures and mechanisms that are affected by alcohol and/or which play a role in the development of AD in living humans. One way of circumventing these limitations is by studying how the natural variations (i.e., polymorphisms) between individuals in the genomic DNÄ relate to AD- that is, whether any specific variants are found more or less commonly than would be expected by chance in people with the disorder. This analysis can provide a glimpse of which genes or gene variants contribute to and shape the develop- ment of the disorder.

These natural differences in the genomic DNA between individuals arise from spontaneous mutations of single DNA building blocks (i.e., nucleotides) and are called single nucleotide polymorphisms (SNPs). …

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