Alcoholic hallucinosis refers to a condition in which a chronic heavy user of ethanol displays persistent auditory hallucinations and related delusional beliefs but remains oriented, with intact memory, and does not manifest other psychotic behaviors. This is a relatively rare complication of chronic alcohol use, and the underlying mechanisms are poorly understood. However, it is not unlikely that the NMDA antagonist properties of ethanol play a role because drugs that block NMDA receptors are notorious for inducing psychotomimetic symptoms. As discussed later, drugs that have NMDA antagonist properties have the potential to cause psychotic symptoms, including auditory hallucinations and delusions, and also have the potential to cause physical injury and even death of cerebrocortical neurons. Phencyclidine (PCP; angel dust) is a well-known example of a drug that has powerful psychotomimetic actions that are solely attributable to its blocking action at a recognition site within the NMDA receptor ion channel. Another well-known NMDA antagonist that has psychotomimetic activity is ketamine, a drug that is used in human medicine as a general anesthetic. Because of its psychotomimetic properties, ketamine has recently become a popular drug of abuse (street name, special K). The psychotic reactions associated with ketamine anesthesia have been referred to as "emergence" reactions and it was learned many years ago that these reactions could be substantially ameliorated by treatment with drugs that activate GABAa receptors, sometimes called GABAmimetic agents. Recently, it has been found that PCP, ketamine, and many other drugs that have NMDA antagonist properties cause pathomorphological changes in cerebrocortical neu rons of the adult rat brain, and it has been clearly demonstrated that these changes can be completely prevented if a GABAmimetic drug is administered together with the NMDA antagonist. In light of this information, the fact that ethanol has strong GABA-mimetic activity as well as NMDA antagonist activity should cause it to behave as if it did not have psychotomimetic and neurotoxic properties because ethanol's potential to cause these adverse effects due to its blocking action at NMDA receptors would be cancelled out by its counterbalancing action at GA-BAA receptors. It is interesting to note that in the ketamine anesthesia situation the psychotic reactions were often not completely prevented because it was the practice to administer the GABAmimetic drug toward the end of the anesthesia period or in the recovery room after the brain changes conducive to psychotic behaviors had already occurred. The door was being closed after the horse was already out of the barn. In contrast, in animal experiments, the GABAmimetic drug has been administered in advance or at the same time as the NMDA antagonist, and this results in complete prevention of the neurotoxic effects of the NMDA antagonist. Thus, since ethanol has the GABAmimetic property built-in, its user is always protected against the expression of its psychotomi-metic or neurotoxic potential.
The psychosis produced by NMDA antagonist drugs closely resembles a schizophrenic psychosis and this has given rise to a currently popular hypothesis that hypofunction of the NMDA glutamate receptor system may contribute to the pathophysiol-ogy of schizophrenia. Previously, the emphasis in schizophrenia research was on the dopamine system, the hypothesis being that hyperactivity of this system may be responsible for schizophrenic symptomatology. These two hypotheses are not mutually exclusive. There is evidence that dopamine is an inhibitory regulator of the release of glutamate at NMDA glutamate receptors. Thus, if the dopamine system were hyperactive, this would result in hyperinhibition of glutamate release at NMDA receptors which would produce an NMDA receptor hypofunctional state that could explain the symptoms of schizophrenia. Ethanol hallucinosis occurs in people who are not withdrawing from alcohol but rather are chronically ingesting alcohol on a steady basis. Under this condition, the NMDA transmitter system is being blocked and hence is hypofunctional, and the dopamine system is believed to be in a hyperactive state. Thus, it is reasonable to propose that dopamine hyperactivity, NMDA receptor hypoactivity, or both may be responsible for the symptoms of alcoholic hallucinosis. Because alcoholic hallucinosis is a relatively rare condition, it seems likely that it occurs only in individuals who harbor a genetic predisposition to manifest psychotic symptoms, perhaps due to dysfunction of one or more of the transmitter systems with which ethanol interacts. The genetic predisposition may not be strong enough by itself to trigger psychotic symptoms, but ethanol's interaction with the genetically defective transmitter system(s) may be enough to tip the balance and cause the genetic predisposition to be expressed as a clinical illness. However, in the absence of a genetic predisposition, the GABAmimetic properties ofethanol may be strong enough to prevent propsychotic mechanisms from breaking through.
Was this article helpful?