Functional Ethanol Tolerance in Drosophila

Scholz, Henrike; Ramond, Jennifer; Singh, Carol M.; Heberlein, Ulrike

doi:10.1016/s0896-6273(00)00101-x

Cited by 204 publications

(324 citation statements)

References 48 publications

(2 reference statements)

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“…Previous work by others has established Drosophila as a useful model organism for studies of ethanol (20), including the mechanisms of ethanol tolerance (23). Exposure to ethanol (C) dsRNA-II (as in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to their physiological function, the GABA B receptors may play a role in the behavioral actions of addictive compounds such as ethanol (16)(17)(18)(19). Although Drosophila has been used to study the mechanisms of action of alcohol (20)(21)(22)(23), as yet, this model has not been used to characterize the involvement of GABA B receptors. show high sequence homology to mammalian GABA B R1 and GABA B R2, respectively; the subunit D-GABA B R3 seems to be an insectspecific subtype with no known mammalian counterpart and no known function.…”

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confidence: 99%

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γ-Aminobutyric acid B receptor 1 mediates behavior-impairing actions of alcohol in Drosophila : Adult RNA interference and pharmacological evidence

Dzitoyeva

Dimitrijević

Manev

2003

Proc. Natl. Acad. Sci. U.S.A.

113

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In addition to their physiological function, metabotropic receptors for neurotransmitter ␥-aminobutyric acid (GABA), the GABAB receptors, may play a role in the behavioral actions of addictive compounds. Recently, GABAB receptors were cloned in fruit flies (Drosophila melanogaster), indicating that the advantages of this experimental model could be applied to GABAB receptor research. RNA interference (RNAi) is an endogenous process triggered by double-stranded RNA and is being used as a tool for functional gene silencing and functional genomics. Here we show how cell-nonautonomous RNAi can be induced in adult fruit flies to silence a subtype of GABAB receptors, GABABR1, and how RNAi combined with pharmacobehavioral techniques (including intraabdominal injections of active compounds and a computer-assisted quantification of behavior) can be used to functionally characterize these receptors. We observed that injection of double-stranded RNA complementary to GABABR1 into adult Drosophila selectively destroys GABABR1 mRNA and attenuates the behavioral actions of the GABAB agonist, 3-aminopropyl-(methyl)phosphinic acid. Moreover, both GABABR1 RNAi and the GABAB antagonist CGP 54626 reduced the behavior-impairing effects of ethanol, suggesting a putative role for the Drosophila GABAB receptors in alcohol's mechanism of action. The Drosophila model we have developed can be used for further in vivo functional characterization of GABAB receptor subunits and their involvement in the molecular and systemic actions of addictive substances.fruit fly ͉ GABAB receptors ͉ ethanol ͉ CGP 54626 ͉ 3-APMPA F ruit flies are used for research primarily because of the homology of Drosophila genes to those of mammals and because Drosophila is amenable to genetic manipulation including gene silencing through a process known as RNA interference (RNAi) (1-7). Typically, RNAi is triggered by double-stranded RNA (dsRNA), which is first processed by an RNase, Dicer (8), into 21-to 23-nt fragments. These fragments form a silencing complex that binds specifically to the dsRNA-complementary endogenous mRNA and leads to the destruction of the mRNA (1, 9). Injecting adult Drosophila intraabdominally with dsRNA results in the cell-nonautonomous silencing of the complementary endogenous mRNA throughout the body, including the CNS (10). Because this method does not interfere in the normal development of the animal but can replicate typical phenotypes produced by gene mutations (11), here we have used adult RNAi to silence ␥-aminobutyric acid (GABA) B receptors.The slow inhibitory GABA synaptic neurotransmission is mediated by the metabotropic G protein-coupled and cAMPlinked GABA B receptors (12, 13) that have been cloned in humans (14) and also recently in Drosophila (15). In addition to their physiological function, the GABA B receptors may play a role in the behavioral actions of addictive compounds such as ethanol (16)(17)(18)(19). Although Drosophila has been used to study the mechanisms of action of alcohol (20)(21)(22)(23), as yet, this model ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

γ-Aminobutyric acid B receptor 1 mediates behavior-impairing actions of alcohol in Drosophila : Adult RNA interference and pharmacological evidence

Dzitoyeva

Dimitrijević

Manev

2003

Proc. Natl. Acad. Sci. U.S.A.

113

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“…The white gene is at 3B2-3C2 (Pirotta et al 1983) and is complemented by the Dp(1:Y)w+ chromosome based on eye color. The mini-white gene in the cantonized tetanus toxin light chain GAL4-UAS effector line CYO34-1 (Scholz et al 2000) was also tested for behavioral rescue of wCS13 mutant flies. Additionally, the bw 1 and st 1 mutations were outcrossed to wild-type flies for greater than six generations (Dreesen et al 1988;Tearle et al 1989).…”

Section: Genetic Manipulations and Culture Conditionsmentioning

confidence: 99%

Genetic dissociation of acquisition and memory strength in the heat-box spatial learning paradigm in Drosophila

Diegelmann¹,

Zars²,

Zars³

2006

Learn. Mem.

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Memories can have different strengths, largely dependent on the intensity of reinforcers encountered. The relationship between reinforcement and memory strength is evident in asymptotic memory curves, with the level of the asymptote related to the intensity of the reinforcer. Although this is likely a fundamental property of memory formation, relatively little is known of how memory strength is determined. Memory performance at different levels in Drosophila can be measured in an operant heat-box conditioning paradigm. In this spatial learning paradigm, flies learn and remember to avoid one-half of a dark chamber associated with a temperature outside of the preferred range. The reinforcement temperature has a strong effect on the level of learning in wild-type flies, with higher temperatures inducing stronger memories. Additionally, two mutations alter memory-acquisition curves, either changing acquisition rate or asymptotic memory level. The rutabaga mutation, affecting a type-1 adenylyl cyclase, decreases the acquisition rate. In contrast, the white mutation, modifying an ABC transporter, limits asymptotic memory. The white mutation does not negatively affect classical olfactory conditioning but actually improves performance at low reinforcement levels. Thus, memory acquisition/memory strength and classical olfactory/operant spatial memories can be genetically dissociated. A conceptual model of operant conditioning and the levels at which rutabaga and white influence conditioning is proposed.Memories are formed from unexpected experiences. Eventually, a sensory cue or behavior predicts positive or negative consequences. Importantly, memory strength depends on the intensity of those reinforcing stimuli such that weak reinforcers support memories of limited magnitude. This relationship is evident in asymptotic acquisition curves where the asymptote level is related to the intensity of the reinforcer. This has been found in operant and classical conditioning paradigms with both positive and negative reinforcers in many species (Herrnstein 1997), including several species of insects (e.g., in rewarded classical and operant conditioning in the honeybee and negatively associated olfactory classical conditioning in Drosophila) (Menzel and Erber 1972;Bitterman et al. 1983;Tully and Quinn 1985;Loo and Bitterman 1992). The repeated finding of the positive relationship between reinforcement intensity and memory strength indicates that this is a fundamental property of learning.The biogenic amines (e.g., serotonin, dopamine, and octopamine) can function as teaching signals. These are the molecules that, together with sensory-based depolarization, feed into the cAMP/PKA and NMDA-receptor pathways. The biochemical changes in this pathway support synaptic plasticity and memory formation. In the Aplysia model of heterosynaptic plasticity, serotonin mediates the tail shock and is a sufficient teaching signal with in vitro synaptic plasticity tests (Martin et al. 1997;Kandel 2001). Dopamine is also critical in memory formation....

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“…Extensive studies of the neuroadaptations accompanying tolerance development have shown genetic influences to be strong (Kalant et al 1971;Kalant 1998). Recent studies using the powerful genetic manipulations available in invertebrate species have extended the range of genetic influences thought to be responsible (Scholz et al 2000;Cowmeadow et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Neurogenetic studies of alcohol addiction

Crabbe

2008

Phil. Trans. R. Soc. B

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Neurogenetic studies of alcohol dependence have relied substantially on genetic animal models, particularly rodents. Studies of inbred strains, selectively bred lines and mutants bearing genes whose function has been targeted for over or under expression are reviewed. Studies focused on gene expression changes are the most recent contributors to this literature, and some genetic effects may work through epigenetic mechanisms. In a few instances, interesting parallels have been revealed between genetic risk in humans and studies in non-human animal models. Future approaches are likely to be increasingly complex.

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Functional Ethanol Tolerance in Drosophila

Cited by 204 publications

References 48 publications

γ-Aminobutyric acid B receptor 1 mediates behavior-impairing actions of alcohol in Drosophila : Adult RNA interference and pharmacological evidence

γ-Aminobutyric acid B receptor 1 mediates behavior-impairing actions of alcohol in Drosophila : Adult RNA interference and pharmacological evidence

Genetic dissociation of acquisition and memory strength in the heat-box spatial learning paradigm in Drosophila

Neurogenetic studies of alcohol addiction

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