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A control system analysis of the dynamic response of N-methyl-D-aspartate glutamate receptors to alcoholism and alcohol withdrawal
Theoretical Biology and Medical Modelling (2015)
  • Carlos A Gutierrez, Rowan University
  • Mary M Staehle, Rowan University
Background: N-methyl-D-Aspartate (NMDA) and its receptors (NMDAR) play a critical
role in glutamatergic neurotransmission. Ethanol molecules inhibit these receptors, and
if the brain is exposed to ethanol chronically, NMDA-induced glutamatergic changes
can result in physical dependence to ethanol in order to sustain normal brain function.
In these cases, removal of ethanol from the system results in excitotoxic withdrawal.
One compensatory mechanism the brain uses to regulate extracellular glutamate
concentration is modulating the number of NMDARs at the synapse. Previous work has
shown that the number of functional NMDARs at the synapse can be changed by three
mechanisms: additional receptors can be synthesized and inserted, receptors can be
recruited to the synapse from extrasynaptic regions, or the functionality of existing
receptors can be modified.
Methods: In this study, we consider the dynamic relocation control of NMDARs in
response to chronic alcoholism and withdrawal. Specifically, we (1) propose and
construct a mathematical model of the relocation control as a negative feedback
system with an explicit set point, (2) investigate the effect of various ethanol
consumption and withdrawal profiles on the NMDAR population, and (3) propose and
calculate quantitative measures for the extent of withdrawal based on modeled
NMDAR populations.
Results: A relocation-only model with an explicit set point was developed. The
model was shown to apply across a wide range of controller parameters. The
results suggest that withdrawal severity does not depend upon the dynamics
involved in the development of dependence, and that regulating the blood alcohol
level throughout the progression of withdrawal can minimize excitotoxic
withdrawal symptoms.
Conclusions: The negative feedback control system produced characteristic behaviors
of NMDAR populations in response to simulations of alcohol dependence and abrupt
withdrawal. The model can also predict the severity of excitotoxic withdrawal following
various alcohol consumption and/or withdrawal patterns in order to generate testable
hypotheses regarding ameliorating withdrawal.
  • : Alcohol dependence,
  • Alcohol withdrawal,
  • Control system modeling,
  • NMDA receptors,
  • Glutamatergic signaling
Publication Date
January 12, 2015
Publisher Statement
© 2015 Gutierrez and Staehle; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
Citation Information
Carlos A Gutierrez and Mary M Staehle. "A control system analysis of the dynamic response of N-methyl-D-aspartate glutamate receptors to alcoholism and alcohol withdrawal" Theoretical Biology and Medical Modelling Vol. 12 Iss. 1 (2015) p. 8 - 8
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