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Andrew G. Davies, Ph.D. Assistant Professor 1220 East Broad St. Molecular Medicine Research Building Room 3036 P.O. Box 980613 Richmond, Virginia 23298-0613 Phone: (804) 828-2068 Fax: (804) 828-2117 E-mail: agdavies@vcu.edu Publications: selected | PubMed |
Education: University of Melbourne, Australia, 1993
Research interests: Genetics and neurobiology of alcohol intoxication and tolerance
I use the free-living nematode and powerful model genetic organism,
Caenorhabditis elegans, to identify molecular targets of drugs and to
better understand the response of the nervous system to the presence of
these drugs. In particular I have focused on the effects of alcohol on the
nervous system. As occurs with humans, C. elegans display
dose-dependent alterations in behaviors when intoxicated by alcohol. By
concentrating on the depressive effects of alcohol I have been able to
identify multiple genetic mutants that display altered sensitivity to the
behavioral effects of alcohol. Several of the identified mutations affect
a single gene, slo-1, that encodes the C. elegans voltage and
calcium-dependent large conductance potassium (BK) channel.
Electrophysiology and further genetic studies showed that alcohol appears
to activate the SLO-1 potassium channel, an action that would result in
decreased neuronal activity and could explain aspects of the behavioral
depression associated with alcohol intoxication. I am continuing to use
C. elegans genetics to identify other molecular targets of alcohol.
The identification of genes that mediate alcohol’s effects in C.
elegans will provide candidates for genes that play similar roles in
humans. Genes that affect an individual’s acute sensitivity to the drug
may be important in predisposing an individual to alcoholism because there
is a strong correlation between a naïve drinker’s level of tolerance to
alcohol and their likelihood of abusing alcohol later in life.
Further, I am examining the response of the nervous system to alcohol. The
nervous system is not a static target; homeostasis within the nervous
system attempts to maintain normal levels of function even in the presence
of alcohol. One way to examine the changes occurring in the nervous system
during an exposure to alcohol is to examine animals that have recently
been withdrawn from prolonged exposure to alcohol. With C. elegans,
such animals demonstrate behavior that is distinct from their untreated
and intoxicated behaviors. It is likely that the removal of alcohol from
their system has uncovered the compensatory physiological changes that
have occurred in the nervous system to cope with the presence of the
alcohol. One of those changes appears to involve the npr-1 gene or the
pathway in which the gene acts, suggesting that regulation of that pathway
is occurring during prolonged alcohol exposure. The identification of
other pathways that are regulated during alcohol exposure may provide key
insights into the mechanism of tolerance, including a better understanding
of the chronic alcohol tolerance that develops during the development of
alcoholism in humans.
Finally, the approach of using C. elegans to better understand the
targets of alcohol that mediate the behavioral effects of the drug can be
applied to other drugs and compounds. I will take advantage of one of the
strengths of the Department of Pharmacology and Toxicology and will be
initiating a study, using C. elegans genetics, that seeks to
identify novel targets of inhaled solvents.
Bhandari P, Kendler KS, Bettinger JC, Davies AG and Grotewiel, MS (2009) An assay for evoked locomotor behavior in Drosophila reveals a
role for integrins in ethanol sensitivity and rapid ethanol tolerance.
Alcohol. Clin. Exp. Res. 33(10):1794-805.
Kapfhamer D, Bettinger JC, Davies AG, Eastman CL, Smail EA, Heberlein U,
McIntire, SL (2008). Loss of RAB-3/A in Caenorhabditis elegans and
the mouse affects behavioral response to ethanol. Genes Brain Behav. 7:
669-676.
Davies AG, Bettinger JC, Thiele TR, Judy ME, McIntire SL. (2004) Natural
variation in the npr-1 gene modifies ethanol responses of wild strains of
C. elegans. Neuron 42(5):731-743.
Davies AG, McIntire SL. (2004) Using C. elegans to screen for
targets of ethanol and behavior-altering drugs. Biol. Proced. Online
6:113-119.