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Andrew G. Davies,
Ph.D. 410 North 12th Street Robert Blackwell Smith Building P.O. Box 980613 Richmond, Virginia 23298-0613 Phone: (804) 828-2068 Fax: (804) 828-2117 E-mail: agdavies@vcu.edu Publications: selected | PubMed Lab: Video: |
Education: University of Melbourne, Australia, 1993
Research interests: 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been withdrawn from prolonged exposure to alcohol.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 other existing
strengths of the Department of Pharmacology and Toxicology and will be
initiating studies, using C. elegans genetics, that seek to
characterize genes involved in the behavioral effects of cannabinoids
and nicotine.
Davies AG, Pierce-Shimomura JT, Kim H, VanHoven MK, Thiele TR, Bonci A, Bargmann CI, McIntire SL. (2003) A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans. Cell 115(6):655-666
Davies AG, McIntire SL. (2004) Using C. elegans to screen for targets of ethanol and behavior-altering drugs. Biol. Proced. Online 6:113-119.
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.
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 (2008) Genes Brain Behav. 7(6):669-676.