Alcohol, Excitotoxicity and Adult Brain Damage: An Experimentally Unproven Chain-of-Events

It has been claimed over the years—most recently in this journal and several others—that neuronal degeneration in adult brain arising during chronic alcohol exposure is, or is likely to be, via " excitotoxicity " A purpose of this opinion piece is to reinforce a view, noted earlier (Collins and Neafsey, 2012), that an excitotoxic mechanism underlying alcoholic neurodamage in the mature brain has never been experimentally proven in vivo. Indeed, pharmacological results in neuronal degeneration studies with repetitively intoxicated (binged) adult rats indicate that the excitotoxic route is insignificant— more about this later. Discovered over 4½ decades ago (Olney, 1969), excitotoxicity relates principally to a deleterious property of the brain's major excitatory neurotransmitter, L-glutamate. When hyper-elevated extracellularly for a variety of reasons, glutamate can overstimulate neuronal N-methyl-D-aspartate (NMDA) receptors, causing cellular degeneration; sometimes increased receptor content could also be a factor. Specifically, excessively stimulated NMDA receptors—being calcium channels— facilitate the cytosolic accumulation of calcium ions, and elevated intraneuronal calcium triggers neuropathological events or associated accomplices that include, among others, increased protease, nuclease and phospholipase activities, oxygen-and nitrogen-free radicals (oxidative/nitrosative stress), membrane lipid peroxidation, and perhaps reductions in antioxidant defenses (Pina-Crespo et al., 2014). The ensuing neuronal degeneration can be apoptotic, necrotic, or a continuum of both. Excitotoxicity is considered a chief mechanism for brain damage in acquired insults/models such as stroke, trauma, status epilepticus, hypoglycemia, and hyperglycemia. It also may have a role in the chronic neurotoxicity of toxicants such as methyl mercury and trimethyltin, and of severe vitamin deficiencies (notably, thiamine). In any event, the sine qua non proof of excitotoxicity-mediated neuronal degeneration in these and other experimental conditions is pharmacological—blockade of glutamatergic (especially NMDA) receptors and calcium elevations by effective antagonists should significantly suppress or abrogate neuronal demise. The original proposals that excitotoxicity causes chronic alcohol-dependent brain damage were based on evidence entirely from brain/neuronal cultures or cell lines, and not in in vivo adult models (Lovinger, 1993; Tsai et al., 1995). Numerous culture-based reports have appeared since those first experiments (e.g., Hendricson et al., 2007)—most recently, studies with neonatal or early adolescent-age hippocampal slice cultures treated with high alcohol for a week or more, followed by withdrawal, in which NMDA receptor antagonism reduces neurodegeneration (Stepanyan et al., 2008; Reynolds et al., 2015). However, these and other brain cultures, being perinatal and/or developmental and (in the case of dispersed cultures or cell lines) often lacking glial and cerebrovascular …