Mechanistic Considerations A Mechanisms Operative in the Adult Brain

It is generally agreed that chronic heavy use of ethanol by human adults results in a substantially higher incidence of neurodegenerative disorders than is encountered in a comparable population of individuals who are not chronic heavy users of ethanol. However, in a high percentage of cases, nutritional deficiency, uncontrolled seizure activity, head trauma, or factors other than direct impingement of ethanol on CNS neurons can account for the damage to the brain. The question that remains unanswered is whether ethanol, by a more direct toxic action on neurons, can trigger neurodegeneration in the adult brain. To address this question it may be useful to examine the known mechanisms by which ethanol interacts with neurons and consider whether ethanol, acting through any of these mechanisms, might have an injurious effect on neurons.

Of the known mechanism by which ethanol interacts with CNS neurons, there is only one mechanism that is known to have neurotoxic potential—the NMDA receptor blocking action of ethanol. In several studies, ethanol has been shown to have NMDA antagonist properties when applied to neurons in concentrations comparable to those attained in the ethanol-intoxi-cated human brain. It is well established that systemic administration of drugs that block NMDA glutamate receptors causes acute pathomorphological changes in cerebrocortical neurons of the adult rat brain. Low doses of NMDA antagonist drugs produce reversible pathomorphological changes in restricted cerebrocor-tical brain regions, whereas higher doses induce irreversible neuronal degeneration, not only in these restricted regions but also in many other corticolimbic brain regions and in the cerebellum. Most experiments demonstrating the neurotoxic properties of NMDA antagonist drugs have involved acute administration. However, it has also been shown that continuous infusion of low to moderate doses of an NMDA antagonist drug to adult rats over a 4-day period results in widespread irreversible degeneration of corticolimbic neurons. Therefore, because of its NMDA antagonist properties, ethanol would be expected, following either acute high-dose intake or chronic lower-dose intake, to be damaging to the brain, and the logical question to be addressed is how adult humans have been able to use ethanol in high doses either acutely or chronically without routinely incurring damage to the brain.

It might be argued that the neurotoxic action of NMDA antagonist drugs is a species-specific effect to which rats are vulnerable but humans are not. However, it is well-known that human adults are vulnerable to another type of toxic effect caused by NMDA antagonist drugs, namely, a psychotoxic effect. Phencyclidine is an NMDA antagonist that was introduced into human medicine as a general anesthetic in the 1950s and was soon withdrawn because of the severe psychotic reactions it produced. Subsequently, it has become notorious as a psychoto-mimetic drug of abuse. Ketamine, an NMDA antagonist that is less potent than PCP, has been used in human medicine as an anesthetic for several decades and is well-known to produce psychotomimetic reactions that are termed emergence reactions. In recent years, many newly developed NMDA antagonist drugs have undergone clinical trials for certain neu-rotherapeutic indications, and all such trials have been prematurely stopped because of the psychotomimetic side effects of these drugs. Given this clear-cut evidence that NMDA antagonist drugs cause psychotic reactions in adult humans, how is it possible for adult humans to use ethanol in high doses either acutely or chronically without its NMDA antagonist action triggering psychotic symptoms?

The most likely answer is that ethanol has a built-in mechanism that serves as an antidote to counteract and cancel out the neurotoxic and psychotoxic effects that would otherwise occur due to its NMDA antagonist properties. In support of this interpretation, ethanol has been shown to have GABAmimetic activity and it is well established that GABAmimetic drugs prevent either the neurotoxic action of NMDA antagonist drugs in adult rats or the psychotomimetic actions of these drugs in adult humans. Therefore, a logical explanation for the observation that in human experience ethanol triggers neither acute psychotoxic nor neurotoxic reactions is that in the same circuits through which the NMDA antagonist action of ethanol would be expected to trigger psychoneurotoxic effects it exerts an action at GABAA receptors that nullifies these effects. In other circuits, ethanol may exert both NMDA antagonist and GABAmimetic actions, which combine in an additive manner to produce relaxation and a sense of euphoria. This would explain why ethanol has been perceived by human adults for many centuries as a user-friendly and relatively innocuous nectar from the gods.

From this information, an interesting question arises: Is the postulated GABA protective mechanism a totally fail-safe mechanism? A working hypothesis currently being entertained is that the GABAmimetic action of ethanol may effectively counterbalance and nullify its toxic potential in acute situations and in the context of intermittent or long-term moderate use, but under conditions of heavy chronic intake the GABA protective mechanism may gradually weaken (e.g., through receptor downregulation) and lose its ability to prevent the NMDA antagonist psychotomimetic or neurotoxic actions from being expressed. This might explain why alcoholic hallucinosis occurs in some chronic alcoholics and why a pattern of corticolimbic and cerebellar neurodegeneration occurs in others. It is noteworthy that the Wernicke pattern of neurodegeneration that can be attributed to thiamine deficiency is a pattern involving the thalamus, hypothalamus, midbrain, and brain stem, whereas another pattern of damage frequently seen in alcoholics which is not explained by thiamine deficiency involves corticolim-bic and cerebellar neurons. Consistent with this hypothesis are recent reports that a single high dose of ethanol does not induce brain damage, but a steady infusion of ethanol at a dose that maintains a state of constant inebriation for 4 days results in degeneration of corticolimbic neurons in certain regions of the adult rat brain in which the NMDA antagonist mechanism would be expected to be operative.

Although this proposal is speculative, it is built on a foundation of evidence pertaining to the known properties of ethanol and is the most promising hypothesis that has been generated to date to explain how ethanol can appear to be relatively harmless for human adults but be associated with deterioration of neurological or cognitive function in more cases than can be easily explained by obvious mechanisms such as nutritional deficiency, head trauma, or uncontrolled seizure activity.

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