@article {5495, title = {Dopamine modulates acute responses to cocaine, nicotine and ethanol in Drosophila.}, journal = {Current Biology}, volume = {10}, year = {2000}, month = {2000 Feb 24}, pages = {187-94}, abstract = {

Drugs of abuse have a common property in mammals, which is their ability to facilitate the release of the neurotransmitter and neuromodulator dopamine in specific brain regions involved in reward and motivation. This increase in synaptic dopamine levels is believed to act as a positive reinforcer and to mediate some of the acute responses to drugs. The mechanisms by which dopamine regulates acute drug responses and addiction remain unknown.

}, keywords = {Animal, Animals, Behavior, Cocaine, Dopamine, Drosophila, Ethanol, Male, Nicotine}, issn = {0960-9822}, author = {Bainton, R J and Tsai, L T and Singh, C M and Moore, M S and Neckameyer, W S and Heberlein, U} } @article {5494, title = {Functional ethanol tolerance in Drosophila.}, journal = {Neuron}, volume = {28}, year = {2000}, month = {2000 Oct}, pages = {261-71}, abstract = {

In humans, repeated alcohol consumption leads to the development of tolerance, manifested as a reduced physiological and behavioral response to a particular dose of alcohol. Here we show that adult Drosophila develop tolerance to the sedating and motor-impairing effects of ethanol with kinetics of acquisition and dissipation that mimic those seen in mammals. Importantly, this tolerance is not caused by changes in ethanol absorption or metabolism. Rather, the development of tolerance requires the functional and structural integrity of specific central brain regions. Mutants unable to synthesize the catecholamine octopamine are also impaired in their ability to develop tolerance. Taken together, these data show that Drosophila is a suitable model system in which to study the molecular and neuroanatomical bases of ethanol tolerance.

}, keywords = {Animal, Animals, Behavior, Biological, Central Nervous System, Dose-Response Relationship, Drosophila, Drug, Drug Tolerance, Ethanol, Inhalation Exposure, Male, Models, Motor Activity, Mutation, Octopamine}, issn = {0896-6273}, author = {Scholz, H and Ramond, J and Singh, C M and Heberlein, U} } @article {46643, title = {Genetic control of acute ethanol-induced behaviors in Drosophila.}, journal = {Alcoholism, Clinical and Experimental Research}, volume = {24}, year = {2000}, month = {2000 Aug}, pages = {1127-36}, abstract = {

BACKGROUND: In most organisms in which acute ethanol exposure has been studied, it leads to similar changes in behavior. Generally, low ethanol doses activate the central nervous system, whereas high doses are sedative. Sensitivity to the acute intoxicating effects of ethanol is in part under genetic control in rodents and humans, and reduced sensitivity in humans predicts the development of alcoholism (Crabbe et al., 1994; Schuckit, 1994). We have established Drosophila melanogaster as a model organism to study the mechanisms that regulate acute sensitivity to ethanol.

METHODS: We measured the effects of ethanol vapor on Drosophila locomotor behaviors by using three different assays. Horizontal locomotion was quantified in a locomotor chamber, turning behavior was assayed in narrow tubes, and ethanol-induced loss of postural control was measured in an inebriometer. Mutants with altered sensitivity to the acute effects of ethanol were generated by treatment with ethyl methane sulfonate and isolated by selection in the inebriometer. We ascertained the effects of these mutations on ethanol pharmacokinetics by measuring ethanol levels in extracts of flies at various times during and after ethanol exposure.

RESULTS: Among nearly 30,000 potentially mutant flies tested, we isolated 19 mutant strains with reduced and 4 strains with increased sensitivity to the acute effects of ethanol as measured in the inebriometer. Of these mutants, four showed changes in ethanol absorption. Two mutants, named barfly and tipsy to reflect their reduced and increased ethanol sensitivity in the inebriometer, respectively, were analyzed for locomotor behaviors. Both mutants exhibited ethanol-induced hyperactivity that was indistinguishable from wild type. However, barfly and tipsy displayed reduced and increased sensitivity to the sedative effects of ethanol, respectively. Finally, both mutants showed an increased rate of ethanol-induced turning behavior.

CONCLUSIONS: The effects of acute ethanol exposure on Drosophila locomotor behaviors are remarkably similar to those described for mammals. The analysis of mutants with altered sensitivity to ethanol revealed that the genetic pathways which regulate these responses are complex and that single genes can affect hyperactivity, turning, and sedation independently.

}, keywords = {Absorption, Animals, Behavior, Animal, Drosophila melanogaster, Drug Resistance, Ethanol, Kinetics, Motor Activity, Mutation}, issn = {0145-6008}, author = {Singh, C M and Heberlein, U} } @article {5496, title = {Ethanol intoxication in Drosophila: genetic and pharmacological evidence for regulation by the cAMP signaling pathway.}, journal = {Cell}, volume = {93}, year = {1998}, month = {1998 Jun 12}, pages = {997-1007}, abstract = {

Upon exposure to ethanol, Drosophila display behaviors that are similar to ethanol intoxication in rodents and humans. Using an inebriometer to measure ethanol-induced loss of postural control, we identified cheapdate, a mutant with enhanced sensitivity to ethanol. Genetic and molecular analyses revealed that cheapdate is an allele of the memory mutant amnesiac. amnesiac has been postulated to encode a neuropeptide that activates the cAMP pathway. Consistent with this, we find that enhanced ethanol sensitivity of cheapdate can be reversed by treatment with agents that increase cAMP levels or PKA activity. Conversely, genetic or pharmacological reduction in PKA activity results in increased sensitivity to ethanol. Taken together, our results provide functional evidence for the involvement of the cAMP signal transduction pathway in the behavioral response to intoxicating levels of ethanol.

}, keywords = {Adenylate Cyclase, Alleles, Amino Acid Sequence, Animal, Animals, Base Sequence, Behavior, Cloning, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Drosophila melanogaster, Drosophila Proteins, Enzyme Activation, Enzyme Inhibitors, Ethanol, Forskolin, Genes, Genetic Complementation Test, Genetically Modified, Insect, Male, Messenger, Molecular, Molecular Sequence Data, Mutation, Neuropeptides, RNA, Signal Transduction}, issn = {0092-8674}, author = {Moore, M S and DeZazzo, J and Luk, A Y and Tully, T and Singh, C M and Heberlein, U} } @article {46654, title = {Growth and differentiation in the Drosophila eye coordinated by hedgehog.}, journal = {Nature}, volume = {373}, year = {1995}, month = {1995 Feb 23}, pages = {709-11}, abstract = {

Differentiation of the Drosophila retina is asynchronous: it starts at the posterior margin of the eye imaginal disc and progresses anteriorly over two days. During this time the disc continues to grow, increasing in size by approximately eightfold. An indentation in the epithelium, the morphogenetic furrow, marks the front edge of the differentiation wave. Anterior progression of the furrow is thought to be driven by signals emanating from differentiating photoreceptor cells in the posterior eye disc. A good candidate for such a signal is the product of the hedgehog (hh) gene; it is expressed, and presumably secreted, by differentiating photoreceptors and its function is required for continued furrow movement. Here we show that ectopic expression of hedgehog sets in motion ectopic furrows in the anterior eye disc. In addition to changes in cell shape, these ectopic furrows are associated with a tightly orchestrated series of events, including proliferation, cell cycle synchronization and pattern formation, that parallel normal furrow progression. We propose that the morphogenetic furrow coincides with a transient boundary that coordinates growth and differentiation of the eye disc, and that hedgehog is necessary and sufficient to propagate this boundary across the epithelium.

}, keywords = {Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Cycle, Cell Cycle Proteins, DNA-Binding Proteins, Drosophila, Drosophila Proteins, Embryonic Induction, Eye, Hedgehog Proteins, Helix-Loop-Helix Motifs, Insect Hormones, Insect Proteins, Nerve Tissue Proteins, Phosphoprotein Phosphatases, Protein Tyrosine Phosphatases, Proteins, Repressor Proteins, Signal Transduction, Transcription Factors}, issn = {0028-0836}, doi = {10.1038/373709a0}, author = {Heberlein, U and Singh, C M and Luk, A Y and Donohoe, T J} }