Scientific research has concluded that both nature (genetics) and nurture (environment) contribute to the development of alcoholism, a disease that affects nearly 14 million people in the United States. Medical studies have also shown that the offspring of alcoholic parents are less sensitive to the effects of alcohol and are at higher risk for the development of alcoholism. Thus, low sensitivity to alcohol may be a biological marker for alcoholism. Finding genes and determining how these genes work to develop alcoholism are important foci of research today. Because of methodological and ethical issues in human studies, a mouse model of high sensitivity (LS) and low sensitivity (SS) to the hypnotic/ataxic effect of alcohol was developed to facilitate the scientific research of genes and brain mechanisms that pre-determine the sensitivity of alcohol intoxication. At a given dose of alcohol, inbred LS mice (ILS) sleep about ten times longer than inbred SS mice (ISS), which makes these two strains valuable tools for studying the alcohol actions in the brain. Consumption of alcohol can cause the loss of fine motor behavior, suggesting that alcohol interacts at neuronal sites in the cerebellum where fine motor control is disrupted. Alcohol inhibition of Purkinje cell activity via GABA receptors was shown to correlate with loss of balance in mice. Since the deep cerebellar nuclei (DCN) neurons are the major output pathway from the cerebellum, we postulate that alcohol may reduce excitatory glutamatergic (NMDA and/or AMPA) receptor-mediated currents, and may enhance inhibitory GABAergic (GABAA) currents in DCN neurons. These actions involving nerve cells in the cerebellum may contribute to the differential alcohol triggered behavioral impairments between alcohol sensitive ILS mice and alcohol insensitive ISS mice. The combination of our proposed and ongoing genetic studies may aid the identification of more sensitive drug targets and the development of novel drugs for rational therapeutic approaches to alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Small Research Grants (R03)
Project #
5R03AA015086-02
Application #
7046847
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Twombly, Dennis
Project Start
2005-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$73,778
Indirect Cost
Name
University of Colorado Denver
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045