Alcohol use disorders (AUDs) are a major problem in medicine and society, and the few available treatment strategies have so far met with limited success. It is well established that genetic, psychosocial, and environmental factors contribute to an increased risk for AUDs. Our laboratory has pioneered the development of Drosophila as a model system for the identification of genes and molecular pathways that regulate simple ethanol-induced behaviors, such as intoxication and the development of tolerance, and many of the underlying molecular mechanisms have been found to be conserved between flies and mammals. Here, we propose to investigate the mechanisms underlying more complex behaviors - ethanol consumption, preference, relapse, and reward - in Drosophila.
The Specific aims of this proposal are: 1) to characterize in detail, using newly developed software, the behavior of flies during ethanol self-administration and relapse, and study the influences of experience as well as social and environmental context;2) to define the neuromodulators and neural circuits engaged during these behaviors;3) to establish whether genes that regulate acute ethanol intoxication also mediate ethanol consumption, relapse and reward, and identify novel genes that regulate these behaviors;and 4) to identify potential pharmacotherapies for AUDs by screening a large collection of FDA-approved drugs for their efficacy in curbing ethanol consumption and relapse. The ease, potential for high throughput, and relatively low expense of Drosophila studies make the fly a powerful system to investigate the molecular and neural mechanisms underlying ethanol preference, relapse and reward. These mechanisms will provide novel insights into these complex behaviors, which can be translated to rodent models, provide candidate genes for the genetics of AUDs in humans, and ultimately, suggest potential targets for pharmacotherapy.
We will identify novel mechanisms underlying ethanol self-administration, relapse, and reward in flies, mechanisms which can be then be translated rapidly to preclinical rodent models, provide candidate genes for the human genetics of alcohol use disorders, and suggest new pharmacotherapies for this immense medical and social problem.
|Yang, Cindy F; Shah, Nirao M (2014) Representing sex in the brain, one module at a time. Neuron 82:261-78|
|McClure, Kimberly D; Heberlein, Ulrike (2013) A small group of neurosecretory cells expressing the transcriptional regulator apontic and the neuropeptide corazonin mediate ethanol sedation in Drosophila. J Neurosci 33:4044-54|
|Kapfhamer, D; Taylor, S; Zou, M E et al. (2013) Taok2 controls behavioral response to ethanol in mice. Genes Brain Behav 12:87-97|
|Shohat-Ophir, G; Kaun, K R; Azanchi, R et al. (2012) Sexual deprivation increases ethanol intake in Drosophila. Science 335:1351-5|
|Eddison, Mark; Belay, Amsale T; Sokolowski, Marla B et al. (2012) A genetic screen for olfactory habituation mutations in Drosophila: analysis of novel foraging alleles and an underlying neural circuit. PLoS One 7:e51684|
|Maiya, Rajani; Lee, Seonok; Berger, Karen H et al. (2012) DlgS97/SAP97, a neuronal isoform of discs large, regulates ethanol tolerance. PLoS One 7:e48967|
|Joseph, Ryan M; Heberlein, Ulrike (2012) Tissue-specific activation of a single gustatory receptor produces opposing behavioral responses in Drosophila. Genetics 192:521-32|
|Devineni, Anita V; Heberlein, Ulrike (2012) Acute ethanol responses in Drosophila are sexually dimorphic. Proc Natl Acad Sci U S A 109:21087-92|
|Kapfhamer, David; King, Ian; Zou, Mimi E et al. (2012) JNK pathway activation is controlled by Tao/TAOK3 to modulate ethanol sensitivity. PLoS One 7:e50594|
|Kaun, Karla R; Azanchi, Reza; Maung, Zaw et al. (2011) A Drosophila model for alcohol reward. Nat Neurosci 14:612-9|
Showing the most recent 10 out of 32 publications