Actions of Alcohol in Brain: Genetics, Metabolomics, GABA Receptors, Proteomics and Glutamate Transporter GLAST/EAAT1

Abstract

: 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 consist ent 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.

Illustration of a Novel Gut-Brain Axis of Alcohol Withdrawal, Withdrawal-Associated Depression, Craving and Alcohol-Severity Index in Alcohol Use Disorder Patients

“…We also showed these effects on serotonin pathways previously 73,74 . Others have examined GABA 75,76 , dopamine synthesis 14 and the release of short chain fatty acids [77][78][79][80] (derived from the gut microbiome). All these end products have potential neuroactive properties 55 .…”

Voluntary alcohol consumption disrupts coupling of prefrontal cortical activity to arousal

“…Although considerable mechanistic research has been done on the acute cellular effects of ethanol, including effects on the fast time scales of ion channel activity and synaptic transmission [102][103][104][105][106][107] , as well as the chronic long-term circuit neuroadaptations 36,[108][109][110] Significance testing with one-way Kruskal-Wallis test.…”

Principles of dose-setting in toxicology studies: the importance of kinetics for ensuring human safety

“…The CNS-depressant effects of ethanol are also high-dose effects that occur secondary to saturation of metabolic capacity and the resultant change from first-order to zero-order kinetics (Høiseth et al 2016 ; Jones 2010 ; Norberg et al 2003 ). The CNS toxicity of ethanol, for which it is intentionally consumed as a social inebriant, depends upon sufficient concentrations in brain to perturb nerve cell membrane viscosity, slow neurotransmission, and inhibit the activity of GABAergic neurons and other receptor signaling pathways in the CNS (Kashem et al 2021 ). At low consumption rates, ethanol does not reach CNS-depressant levels in brain due to first pass liver metabolism, which prevents its concentrations from accumulating in blood.…”