(487e) Modeling the Control of An Excitatory Neurotransmitter Receptor during Alcoholism and Alcohol Withdrawal

In 1998, it was estimated that 14 million Americans were affected by alcohol abuse and the annual economic impact of the associated healthcare and productivity losses totaled $100 billion dollars [1]. Over the last decade, there has been no improvement in the epidemic, according to a Centers for Disease Control report indicating an average of 35,915 chronic alcohol-related deaths per year between 2001 and 2005, along with a steady rise in the number of alcohol-related morbidity hospital discharges [2]. Despite its prevalence and many decades of alcohol research, however, we do not completely understand the neurological basis, epidemiology, optimal treatment regimen, and progression of alcoholism.

Previous alcohol research has elucidated the prominent role of the brain during alcoholism and alcohol withdrawal. Furthermore, numerous studies have suggested that many of the physiological and emotional consequences of alcoholism and alcohol withdrawal may be due to the deregulation of neurotransmitter systems in the brain. Ethanol molecules block a particular type of glutamate receptor (glutamate is the brain's primary excitatory neurotransmitter), the N-methyl-D-aspartate (NMDA) receptor, and thereby abolish its glutamatergic response [3]. Clinical studies with NMDA receptor agonists and antagonists have solidified the importance of NMDA receptors in alcoholism and alcohol withdrawal: NMDA receptor antagonists (like ethanol itself) lessen alcohol withdrawal symptoms while NMDA receptor agonists increase the severity of these symptoms [4, 5]. Additional clinical studies have shown an increase in glutamatergic excitation during withdrawal [6], which is indicative of a larger than normal NMDA receptor response.

We hypothesize that the level of glutamatergic response from NMDA receptors is regulated during chronic alcoholism via the control of available, non-ethanol-blocked NMDA receptors. While blood alcohol levels are non-zero, ethanol molecules bind and block NMDA receptors, thereby decreasing the glutamatergic response. Experimental results suggest that there is compensatory control action to maintain steady glutamatergic response achieved either via generation of new NMDA receptors or via recruitment of NMDA receptors to the synapse (where neurotransmission occurs) from a nearby reserve pool. Upon alcohol withdrawal, however, the ethanol molecules dissociate from blocked NMDA receptors, producing additional unblocked receptors at the synapse, and resulting in a marked increase in glutamatergic excitation, which could explain many of the physiological and emotional effects observed clinically during alcohol withdrawal.

We have developed three separate computational models of this isolated hypothesized control system. All three models examine the effect of a typical chronic alcohol intake pattern on both NMDA receptor levels and glutamatergic response during alcoholism and alcohol withdrawal. In the first model, we include only new NMDA receptor generation via protein synthesis as the control action. In the second model, we include only receptor relocalization from a reserve pool to the synapse as the means of control action. Finally, in the third model, we include both mechanisms. In all three models, we are able to capture both the expected NMDA receptor dynamics during alcoholism and the expected glutamatergic increase during withdrawal. In this presentation, we will discuss the model development and parameterization, as well as the differences in sensitivity and stability characteristics of the three models. While we do not expect that NMDA receptor control alone completely describes the organism-wide effects of alcoholism and alcohol withdrawal, the widespread effects of glutamatergic regulation in the brain could explain many of the clinical symptoms, and future work with these models will include the incorporation of additional molecular details to obtain a more comprehensive model that can then be utilized to postulate alternative alcohol withdrawal treatments.

1. Rich, B., Ed. (1998). The Dana Brain Daybook: What's New in Neuroscience. 2(1).

2. Centers for Disease Control, Alcohol-Attributable Deaths Report, Average for United States 2001-2005, http://www.cdc.gov/Alcohol

3. Grant, K.A. and D.M. Lovinger (1995). Cellular and behavioral neurobiology of alcohol: receptor-mediated neuronal processes. Clinical Neuroscience, 3, 155-164.

4. Krupitsky, E.M., A.A. Rudenko, A.M. Burakov, T.Y. Slavina, A.A. Grinenko, B. Pittman, R. Gueorguieva, I.L. Petrakis, E.E. Zvartau, J.H. Krystal (2007). Antiglutamatergic strategies for ethanol detoxification: comparison with placebo and Diazepam. Alcoholism: Clinical and Experimental Research, 31(4), 604-611.

5. Krystal, J.H., I.L. Petrakis, G. Mason, L. Trevisan, D.C. D'Souza (2003). N-methyl-D-aspartate glutamate receptors and alcoholism: reward, dependence, treatment, and vulnerability. Pharmacology & Therapeutics, 99, 79-94.

6. Rosetti, Z.L., S. Carboni, F. Fadda (1999). Glutamate induced increase of extracellular glutamate through N-methyl-D-aspartate receptors in ethanol withdrawal. Neuroscience, 93(3), 1135-1140.