Actions of Alcohol in Brain: Genetics, Metabolomics, GABA Receptors, Proteomics and Glutamate Transporter GLAST/EAAT1
Authors: Kashem Mohammed Abul , Šerý Omar , Pow David V. , Rowlands Benjamin D. , Rae Caroline D. , Balcar Vladimir J. 
Published: April 2020

We present an overview of genetic, metabolomic, proteomic and neurochemical studies
done mainly in our laboratories that could improve prediction, mechanistic understanding and possibly
extend to diagnostics and treatment of alcoholism and alcohol addiction. Specific polymorphisms
in genes encoding for interleukins 2 and 6, catechol-O-methyl transferase (COMT), monaminooxidase
B (MAO B) and several other enzymes were identified as associated with altered
risks of alcoholism in humans. A polymorphism in the gene for BDNF has been linked to the risk
of developing deficiences in colour vision sometimes observed in alcoholics. Metabolomic studies
of acute ethanol effects on guinea pig brain cortex in vitro, lead to the identification of specific subtypes
of GABA(A) receptors involved in the actions of alcohol at various doses. Acute alcohol affected
energy metabolism, oxidation and the production of actaldehyde and acetate; this could have
specific consequences not only for the brain energy production/utilization but could influence the
cytotoxicity of alcohol and impact the epigenetics (histone acetylation). It is unlikely that brain
metabolism of ethanol occurs to any significant degree; the reduction in glucose metabolism following
alcohol consumption is due to ethanol effects on receptors, such as α4β3δ GABA(A) receptors.
Metabolomics using post-mortem human brain indicated that the catecholaminergic signalling may
be preferentially affected by chronic excessive drinking. Changes in the levels of glutathione were
consistent with the presence of severe oxidative stress. Proteomics of the post-mortem alcoholic
brains identified a large number of proteins, the expression of which was altered by chronic alcohol,
with those associated with brain energy metabolism among the most numerous. Neurochemical
studies found the increased expression of glutamate transporter GLAST/EAAT1 in brain as one
of the largest changes caused by alcoholism. Given that GLAST/EAAT1 is one of the most abundant
proteins in the nervous tissue and is intimately associated with the function of the excitatory
(glutamatergic) synapses, this may be among the most important effects of chronic alcohol on
brain function. It has so far been observed mainly in the prefrontal cortex. We show several experiments
suggesting that acute alcohol can translocate GLAST/EAAT1 in astrocytes towards the plasma
membrane (and this effect is inhibited by the GABA(B) agonist baclofen) but neither the mechanism
nor the specificity (to alcohol) of this phenomenon have been established. Furthermore, as
GLAST/EAAT1 is also expressed in testes and sperm (and could also be affected there by chronic
alcohol), the levels of GLAST/EAAT1 in sperm could be used as a diagnostic tool in testing the
severity of alcoholism in human males. We conclude that the reviewed studies present a unique set
of data which could help to predict the risk of developing alcohol dependence (genetics), to improve
the understanding of the intoxicating actions of alcohol (metabolomics), to aid in assessing
the extent of damage to brain cells caused by chronic excessive drinking (metabolomics and proteomics)
and to point to molecular targets that could be used in the treatment and diagnosis of alcoholism
and alcohol addiction.