A Control System Hypothesis of the N-methyl-D-aspartate Glutamate Receptor's Role in Alcoholism and Alcohol Withdrawal

Abstract

Alcoholism and alcohol withdrawal, complicated physiological conditions with significant consequences for physical and emotional health, have been the focus of extensive studies in various scientific disciplines for centuries. In America alone, alcoholism is known to affect 14 million people; it accounts for an estimated annual cost of $100 billion in healthcare and related productivity losses, and according to the Centers for Disease Control, there were 34,833 chronic alcohol-related deaths in 2001.Various experimental studies have strongly suggested that many of the physiological consequences of alcoholism and alcohol withdrawal may be associated with alcohol-induced inhibition of N-methyl-D-aspartate (NMDA) glutamate receptors, but the mechanisms are not completely known. (Glutamate is an important excitatory neurotransmitter and its NMDA receptors are expressed widely throughout the brain.) In this paper, we postulate the following hypothesis: that the level of unblocked NMDA receptors is controlled in alcoholism to maintain at a constant level, the amount of glutamate release and extent of glutamatergic excitation; that ethanol blocks these receptors, and additional receptors are generated to compensate for the loss; we then develop and analyze a control system model predicated on this hypothesis. Our model shows, among other things, that upon cessation of alcohol consumption, no additional generation of NMDA receptors occurs, but the number of unblocked NMDA receptors increases dramatically, leading to the excitotoxicity observed clinically. This first attempt at a control system representation of the NMDA receptor's role is thus able to capture the essence of some key organism-wide responses observed in alcoholism and alcohol withdrawal. Future work will involve incorporating additional molecular details to obtain a more accurate model which can then be potentially useful in postulating treatment regimens for alcohol withdrawal.