@article {46599, title = {The evolution of Drosophila melanogaster as a model for alcohol research.}, journal = {Annual Reviews of Neuroscience}, volume = {36}, year = {2013}, month = {2013 Jul 8}, pages = {121-38}, abstract = {

Animal models have been widely used to gain insight into the mechanisms underlying the acute and long-term effects of alcohol exposure. The fruit fly Drosophila melanogaster encounters ethanol in its natural habitat and possesses many adaptations that allow it to survive and thrive in ethanol-rich environments. Several assays to study ethanol-related behaviors in flies, ranging from acute intoxication to self-administration and reward, have been developed in the past 20 years. These assays have provided the basis for studying the physiological and behavioral effects of ethanol and for identifying genes mediating these effects. In this review we describe the ecological relationship between flies and ethanol, the effects of ethanol on fly development and behavior, the use of flies as a model for alcohol addiction, and the interaction between ethanol and social behavior. We discuss these advances in the context of their utility to help decipher the mechanisms underlying the diverse effects of ethanol, including those that mediate ethanol dependence and addiction in humans.

}, keywords = {Alcoholism, Animals, Biological Evolution, Disease Models, Animal, Drosophila melanogaster, Ethanol, Humans, Reward, Self Administration}, issn = {1545-4126}, doi = {10.1146/annurev-neuro-062012-170256}, author = {Devineni, Anita V and Heberlein, Ulrike} } @article {46597, title = {The novel gene tank, a tumor suppressor homolog, regulates ethanol sensitivity in Drosophila.}, journal = {The Journal of Neuroscience}, volume = {33}, year = {2013}, month = {2013 May 8}, pages = {8134-43}, abstract = {

In both mammalian and insect models of ethanol intoxication, high doses of ethanol induce motor impairment and eventually sedation. Sensitivity to the sedative effects of ethanol is inversely correlated with risk for alcoholism. However, the genes regulating ethanol sensitivity are largely unknown. Based on a previous genetic screen in Drosophila for ethanol sedation mutants, we identified a novel gene, tank (CG15626), the homolog of the mammalian tumor suppressor EI24/PIG8, which has a strong role in regulating ethanol sedation sensitivity. Genetic and behavioral analyses revealed that tank acts in the adult nervous system to promote ethanol sensitivity. We localized the function of tank in regulating ethanol sensitivity to neurons within the pars intercerebralis that have not been implicated previously in ethanol responses. We show that acutely manipulating the activity of all tank-expressing neurons, or of pars intercerebralis neurons in particular, alters ethanol sensitivity in a sexually dimorphic manner, since neuronal activation enhanced ethanol sedation in males, but not females. Finally, we provide anatomical evidence that tank-expressing neurons form likely synaptic connections with neurons expressing the neural sex determination factor fruitless (fru), which have been implicated recently in the regulation of ethanol sensitivity. We suggest that a functional interaction with fru neurons, many of which are sexually dimorphic, may account for the sex-specific effect induced by activating tank neurons. Overall, we have characterized a novel gene and corresponding set of neurons that regulate ethanol sensitivity in Drosophila.

}, keywords = {Adaptor Proteins, Signal Transducing, Analysis of Variance, Animals, Animals, Genetically Modified, Apoptosis Regulatory Proteins, Behavior, Animal, Central Nervous System Depressants, Dose-Response Relationship, Drug, Drosophila, Drosophila Proteins, Ethanol, Gene Expression Regulation, Green Fluorescent Proteins, Humans, Molecular Biology, Mutation, Nuclear Proteins, RNA Interference, TRPC Cation Channels, Tumor Suppressor Proteins}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.3695-12.2013}, author = {Devineni, Anita V and Eddison, Mark and Heberlein, Ulrike} } @article {46604, title = {Acute ethanol responses in Drosophila are sexually dimorphic.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {109}, year = {2012}, month = {2012 Dec 18}, pages = {21087-92}, abstract = {

In mammalian and insect models of ethanol intoxication, low doses of ethanol stimulate locomotor activity whereas high doses induce sedation. Sex differences in acute ethanol responses, which occur in humans, have not been characterized in Drosophila. In this study, we find that male flies show increased ethanol hyperactivity and greater resistance to ethanol sedation compared with females. We show that the sex determination gene transformer (tra) acts in the developing nervous system, likely through regulation of fruitless (fru), to at least partially mediate the sexual dimorphism in ethanol sedation. Although pharmacokinetic differences may contribute to the increased sedation sensitivity of females, neuronal tra expression regulates ethanol sedation independently of ethanol pharmacokinetics. We also show that acute activation of fru-expressing neurons affects ethanol sedation, further supporting a role for fru in regulating this behavior. Thus, we have characterized previously undescribed sex differences in behavioral responses to ethanol, and implicated fru in mediating a subset of these differences.

}, keywords = {Alcoholic Intoxication, Animals, Central Nervous System Stimulants, Crosses, Genetic, Disease Models, Animal, Drosophila melanogaster, Ethanol, Female, Gene Expression Regulation, Male, Models, Statistical, Neurons, Sex Characteristics, Sex Factors}, issn = {1091-6490}, doi = {10.1073/pnas.1218850110}, author = {Devineni, Anita V and Heberlein, Ulrike} } @article {4522, title = {Drosophila melanogaster as a model to study drug addiction.}, journal = {Human Genetics}, volume = {131}, year = {2012}, month = {2012 Feb 17}, pages = {959-75}, abstract = {

Animal studies have been instrumental in providing knowledge about the molecular and neural mechanisms underlying drug addiction. Recently, the fruit fly Drosophila melanogaster has become a valuable system to model not only the acute stimulating and sedating effects of drugs but also their more complex rewarding properties. In this review, we describe the advantages of using the fly to study drug-related behavior, provide a brief overview of the behavioral assays used, and review the molecular mechanisms and neural circuits underlying drug-induced behavior in flies. Many of these mechanisms have been validated in mammals, suggesting that the fly is a useful model to understand the mechanisms underlying addiction.

}, issn = {1432-1203}, doi = {10.1007/s00439-012-1146-6}, author = {Kaun, Karla R and Devineni, Anita V and Heberlein, Ulrike} } @article {46611, title = {The genetic relationships between ethanol preference, acute ethanol sensitivity, and ethanol tolerance in Drosophila melanogaster.}, journal = {Fly (Austin)}, volume = {5}, year = {2011}, month = {2011 Jul-Sep}, pages = {191-9}, abstract = {

The relationship between alcohol consumption, sensitivity, and tolerance is an important question that has been addressed in humans and rodent models. Studies have shown that alcohol consumption and risk of abuse may correlate with (1) increased sensitivity to the stimulant effects of alcohol, (2) decreased sensitivity to the depressant effects of alcohol, and (3) increased alcohol tolerance. However, many conflicting results have been observed. To complement these studies, we utilized a different organism and approach to analyze the relationship between ethanol consumption and other ethanol responses. Using a set of 20 Drosophila melanogaster mutants that were isolated for altered ethanol sensitivity, we measured ethanol-induced hyperactivity, ethanol sedation, sedation tolerance, and ethanol consumption preference. Ethanol preference showed a strong positive correlation with ethanol tolerance, consistent with some rodent and human studies, but not with ethanol hyperactivity or sedation. No pairwise correlations were observed between ethanol hyperactivity, sedation, and tolerance. The evolutionary conservation of the relationship between tolerance and ethanol consumption in flies, rodents, and humans indicates that there are fundamental biological mechanisms linking specific ethanol responses.

}, keywords = {Alcohol Drinking, Alcoholic Intoxication, Animals, Central Nervous System Depressants, Drosophila melanogaster, Drosophila Proteins, Ethanol, Food Preferences, Hyperkinesis, Male, Transcription Factors}, issn = {1933-6942}, author = {Devineni, Anita V and McClure, Kimberly D and Guarnieri, Douglas J and Corl, Ammon B and Wolf, Fred W and Eddison, Mark and Heberlein, Ulrike} } @article {46615, title = {Addiction-like behavior in Drosophila.}, journal = {Communicative \& Integrative Biology}, volume = {3}, year = {2010}, month = {2010 Jul}, pages = {357-9}, abstract = {

Alcohol abuse is a pervasive problem known to be influenced by genetic factors, yet our understanding of the mechanisms underlying alcohol addiction is far from complete. Drosophila melanogaster has been established as a model for studying the molecular mechanisms that mediate the acute and chronic effects of alcohol. However, the Drosophila model has not yet been extended to include more complex alcohol-related behaviors such as self-administration. We recently established a paradigm to characterize ethanol consumption and preference in flies. We demonstrated that flies prefer to consume ethanol-containing food over regular food, and this preference exhibits several features of alcohol addiction: flies increase ethanol consumption over time, they consume ethanol to pharmacologically relevant concentrations, they will overcome an aversive stimulus in order to consume ethanol, and they exhibit relapse after a period of ethanol deprivation. Thus, ethanol preference in flies provides a new model for studying important aspects of addiction and their underlying mechanisms. One mutant that displayed decreased ethanol preference, krasavietz, may represent a first step toward uncovering those mechanisms.

}, issn = {1942-0889}, author = {Devineni, Anita V and Heberlein, Ulrike} } @article {5486, title = {Oviposition preference for and positional avoidance of acetic acid provide a model for competing behavioral drives in Drosophila.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {106}, year = {2009}, month = {2009 Jul 7}, pages = {11352-7}, abstract = {

Selection of appropriate oviposition sites is essential for progeny survival and fitness in generalist insect species, such as Drosophila melanogaster, yet little is known about the mechanisms regulating how environmental conditions and innate adult preferences are evaluated and balanced to yield the final substrate choice for egg-deposition. Female D. melanogaster are attracted to food containing acetic acid (AA) as an oviposition substrate. However, our observations reveal that this egg-laying preference is a complex process, as it directly opposes an otherwise strong, default behavior of positional avoidance for the same food. We show that 2 distinct sensory modalities detect AA. Attraction to AA-containing food for the purpose of egg-laying relies on the gustatory system, while positional repulsion depends primarily on the olfactory system. Similarly, distinct central brain regions are involved in AA attraction and repulsion. Given this unique situation, in which a single environmental stimulus yields 2 opposing behavioral outputs, we propose that the interaction of egg-laying attraction and positional aversion for AA provides a powerful model for studying how organisms balance competing behavioral drives and integrate signals involved in choice-like processes.

}, keywords = {Acetic Acid, Animal, Animal Feed, Animals, Avoidance Learning, Biological, Brain, Drosophila melanogaster, Female, Hydrogen-Ion Concentration, Models, Neurons, Olfactory Pathways, Oviposition, Sexual Behavior, Taste}, issn = {1091-6490}, doi = {10.1073/pnas.0901419106}, author = {Joseph, Ryan M and Devineni, Anita V and King, Ian F G and Heberlein, Ulrike} } @article {4526, title = {Preferential ethanol consumption in Drosophila models features of addiction.}, journal = {Current Biology}, volume = {19}, year = {2009}, month = {2009 Dec 29}, pages = {2126-32}, abstract = {

Alcohol addiction is a common affliction with a strong genetic component [1]. Although mammalian studies have provided significant insight into the molecular mechanisms underlying ethanol consumption [2], other organisms such as Drosophila melanogaster are better suited for unbiased, forward genetic approaches to identify novel genes. Behavioral responses to ethanol, such as hyperactivity, sedation, and tolerance, are conserved between flies and mammals [3, 4], as are the underlying molecular pathways [5-9]. However, few studies have investigated ethanol self-administration in flies [10]. Here we characterize ethanol consumption and preference in Drosophila. Flies prefer to consume ethanol-containing food over regular food, and this preference increases over time. Flies are attracted to the smell of ethanol, which partially mediates ethanol preference, but are averse to its taste. Preference for consuming ethanol is not entirely explained by attraction to either its sensory or caloric properties. We demonstrate that flies can exhibit features of alcohol addiction. First, flies self-administer ethanol to pharmacologically relevant concentrations. Second, flies will overcome an aversive stimulus in order to consume ethanol. Third, flies rapidly return to high levels of ethanol consumption after a period of imposed abstinence. Thus, ethanol preference in Drosophila provides a new model for studying aspects of addiction.

}, keywords = {Alcohol Drinking, Alcoholism, Analysis of Variance, Animal, Animals, Disease Models, Drosophila melanogaster, Drosophila Proteins, Ethanol, Eukaryotic Initiation Factor-5, Food Preferences, Smell, Taste}, issn = {1879-0445}, doi = {10.1016/j.cub.2009.10.070}, author = {Devineni, Anita V and Heberlein, Ulrike} }