Mechanism(s) of alcohol action.
Dr. Homanics’ laboratory is focused on understanding the molecular mechanism(s) of action of alcohol. Despite being the most widely used and abused drug, it is largely unknown how alcohol exerts its effects on the brain to cause alcohol-induced behavioral changes. If we could understand alcohol’s mechanism of action, we may ultimately be able to develop safe and effective treatments for preventing / combatting alcohol use disorders and alcoholism.
Two basic approaches are utilized by the Homanics laboratory for investigating alcohol action. The first approach employs genetically engineered mice. Mutant mice are created that harbor precise alterations in genes that encode putative alcohol targets. The mutant mice are tested at the cellular, molecular, and whole animal levels for alterations in alcohol-induced responses. The second approach utilizes molecular biology to investigate the epigenetic effects of alcohol on changes in gene expression.
Trainees in Dr. Homanics’ laboratory have the opportunity to use molecular biology and embryonic stem cell techniques to create genetically engineered mice. Such mice are subsequently analyzed using molecular biology, pharmacology, histology, and numerous whole animal behavioral assays. Studies of the epigenetic effects of alcohol action utilize chromatin immunoprecipitation, quantitative PCR, and western blotting techniques.
Werner, D.F., Swihart, A., Rau, V., Jia, F., Borghese, C.M., McCracken, M.L., Iyer, S., Fanselow, M.S., Oh, I., Sonner, J.M., Eger, E.I., Harrison, N.L., Harris, A.R. and Homanics, G.E. Inhaled anesthetic responses of recombinant receptors and knockin mice harboring α2 (S270H; L277A) GABAA receptor subunits that are resistant to isoflurane. J Pharmacol Exp Ther:). 336:134-144, 2011.
Blednov, Y.A., Borghese, C.M., McCracken, M.L., Beavidez, J., Geil, C.R., Osterndorff-Kahanek, E., Werner, D.F., Iyer, S., Swihart, A., Harrison, N.L., Homanics, G.E. and Harris, R. Loss of ethanol conditioned taste aversion and motor stimulation in knock-in mice with ethanol-insensitive α2-containing GABAA receptors. J Pharmacol Exp Ther. 336: 145-154, 2011.
Werner, D.F., Swihart, A.R., Ferguson, C., Lariviere, W.R., Harrison, N.L. and Homanics, G.E. Alcohol-induced tolerance and physical dependence in mice with ethanol insensitive α1 GABAA receptors. Alcohol Clin Exp Res 33:289-299, 2009.
Chandra, D., Werner, D.F., Olsen, R.W., Harrison, N.L. and Homanics, G.E. Normal acute behavioral responses to moderate/high dose ethanol in GABAA receptor α4 subunit knockout mice. Alcohol Clin Exp Res 32:10-18, 2008.
Glykys, J., Peng, Z., Chandra, D., Homanics, G.E., Houser, C.R. and Mody, I. A novel naturally occuring GABAA receptor partnership with high sensitivity to ethanol. Nat Neurosci 10: 40-48, 2007.
Ferguson, C., Hardy, S.L., Werner, D.F., Hileman, S.M., DeLorey, T.M. and Homanics, G.E. New insight into the role of the β3 subunit of the GABAA-R in development, behavior, body weight regulation, and anesthesia revealed by conditional gene knockout. BMC Neurosci: 85, 2007.