Receptors In Drosophila Research Articles

Behavioral Sensitization to the Disinhibition Effect of Ethanol Requires the Dopamine/Ecdysone Receptor in Drosophila.

Male flies under the influence of ethanol display disinhibited courtship, which is augmented with repeated ethanol exposures. We have previously shown that dopamine is important for this type of ethanol-induced behavioral sensitization but the underlying mechanism is unknown. Here we report that DopEcR, an insect G-protein coupled receptor that binds to dopamine and steroid hormone ecdysone, is a major receptor mediating courtship sensitization. Upon daily ethanol administration, dumb and damb mutant males defective in D1 (dDA1/DopR1) and D5 (DAMB/DopR2) dopamine receptors, respectively, showed normal courtship sensitization; however, the DopEcR-deficient der males exhibited greatly diminished sensitization. der mutant males nevertheless developed normal tolerance to the sedative effect of ethanol, indicating a selective function of DopEcR in chronic ethanol-associated behavioral plasticity. DopEcR plays a physiological role in behavioral sensitization since courtship sensitization in der males was reinstated when DopEcR expression was induced during adulthood but not during development. When examined for the DopEcR’s functional site, the der mutant’s sensitization phenotype was fully rescued by restored DopEcR expression in the mushroom body (MB) αβ and γ neurons. Consistently, we observed DopEcR immunoreactivity in the MB calyx and lobes in the wild-type Canton-S brain, which was barely detectable in the der brain. Behavioral sensitization to the locomotor-stimulant effect has been serving as a model for ethanol abuse and addiction. This is the first report elucidating the mechanism underlying behavioral sensitization to another stimulant effect of ethanol.

CRISPR-based gene replacement reveals evolutionarily conserved axon guidance functions of Drosophila Robo3 and Tribolium Robo2/3

BackgroundAxon guidance receptors of the Roundabout (Robo) family regulate a number of axon guidance outcomes in bilaterian animals in addition to their canonical role in Slit-dependent midline repulsion. In the fruit fly Drosophila melanogaster, three Robo paralogs (Robo1, Robo2, and Robo3) each have specialized roles in regulating midline crossing and the formation of longitudinal axon pathways in the embryonic ventral nerve cord. The number of robo genes differs in other insects, and it is unknown whether the roles and/or signaling mechanisms of Drosophila Robos are shared in other insect species. To directly compare the axon guidance activities of Robo receptors in Drosophila and the flour beetle Tribolium castaneum, I have used a CRISPR/Cas9-based approach to replace Drosophila robo3 with Tribolium robo2/3.ResultsI show that when expressed from the robo3 locus in Drosophila embryos, Tribolium Robo2/3 (TcRobo2/3) protein is properly translated and localized to axons, where it reproduces the normal expression pattern of Drosophila Robo3. In embryos expressing TcRobo2/3 in place of robo3, two distinct subsets of longitudinal axons are guided properly to their normal positions in the intermediate neuropile, indicating that TcRobo2/3 can promote Robo3-dependent axon guidance decisions in developing Drosophila neurons.ConclusionsThese observations suggest that the mechanism by which Drosophila Robo3 promotes longitudinal pathway formation is evolutionarily conserved in Tribolium, where it is performed by TcRobo2/3. The CRISPR/Cas9-based gene replacement approach described here can be applied to comparative evolutionary developmental studies of other Drosophila genes and their orthologs in other species.

Premature remodeling of fat body and fat mobilization triggered by platelet-derived growth factor/VEGF receptor in Drosophila.

In Drosophila, fat-body remodeling accompanied with fat mobilization is an ecdysone-induced dynamic process that only occurs during metamorphosis. Here, we show that the activated Drosophila platelet-derived growth factor/VEGF receptor (PVR) is sufficient to induce shape changes in the fat body, from thin layers of tightly conjugated polygonal cells to clusters of disaggregated round-shaped cells. These morphologic changes are reminiscent of those seen during early pupation upon initiation of fat-body remodeling. Activation of PVR also triggers an early onset of lipolysis and mobilization of internal storage, as revealed by the appearance of small lipid droplets and up-regulated lipolysis-related genes. We found that PVR displays a dynamic expression pattern in the fat body and peaks at the larval-prepupal transition under the control of ecdysone signaling. Removal of PVR, although it does not prevent ecdysone-induced fat-body remodeling, causes ecdysone signaling to be up-regulated. Our data reveal that PVR is active in a dual-secured mechanism that involves an ecdysone-induced fat-body remodeling pathway and a reinforced PVR pathway for effective lipid mobilization. Ectopic expression of activated c-kit-the mouse homolog of PVR in the Drosophila fat body-also results in a similar phenotype. This may suggest a novel function of c-kit as it relates to lipid metabolism in mammals.-Zheng, H., Wang, X., Guo, P., Ge, W., Yan, Q., Gao, W., Xi, Y., Yang, X. Premature remodeling of fat body and fat mobilization triggered by platelet-derived growth factor/VEGF receptor in Drosophila.

Tribbles ortholog NIPI-3 and bZIP transcription factor CEBP-1 regulate a Caenorhabditis elegans intestinal immune surveillance pathway.

BackgroundMany pathogens secrete toxins that target key host processes resulting in the activation of immune pathways. The secreted Pseudomonas aeruginosa toxin Exotoxin A (ToxA) disrupts intestinal protein synthesis, which triggers the induction of a subset of P. aeruginosa-response genes in the nematode Caenorhabditis elegans.ResultsWe show here that one ToxA-induced C. elegans gene, the Tribbles pseudokinase ortholog nipi-3, is essential for host survival following exposure to P. aeruginosa or ToxA. We find that NIPI-3 mediates the post-developmental expression of intestinal immune genes and proteins and primarily functions in parallel to known immune pathways, including p38 MAPK signaling. Through mutagenesis screening, we identify mutants of the bZIP C/EBP transcription factor cebp-1 that suppress the hypersusceptibility defects of nipi-3 mutants.ConclusionsNIPI-3 is a negative regulator of CEBP-1, which in turn negatively regulates protective immune mechanisms. This pathway represents a previously unknown innate immune signaling pathway in intestinal epithelial cells that is involved in the surveillance of cellular homeostasis. Because NIPI-3 and CEBP-1 are also essential for C. elegans development, NIPI-3 is analogous to other key innate immune signaling molecules such as the Toll receptors in Drosophila that have an independent role during development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0334-6) contains supplementary material, which is available to authorized users.

Innate immunity: Threat level adjustments.

Regulatory variant of peptidoglycan recognition receptors in Drosophila resolve immune responses according to threat level.

Hedgehog Signaling Regulates the Ciliary Transport of Odorant Receptors in Drosophila.

Hedgehog (Hh) signaling is a key regulatory pathway during development and also has a functional role in mature neurons. Here, we show that Hh signaling regulates the odor response in adult Drosophila olfactory sensory neurons (OSNs). We demonstrate that this is achieved by regulating odorant receptor (OR) transport to and within the primary cilium in OSN neurons. Regulation relies on ciliary localization of the Hh signal transducer Smoothened (Smo). We further demonstrate that the Hh- and Smo-dependent regulation of the kinesin-like protein Cos2 acts in parallel to the intraflagellar transport system (IFT) to localize ORs within the cilium compartment. These findings expand our knowledge of Hh signaling to encompass chemosensory modulation and receptor trafficking.

CDK8-Cyclin C Mediates Nutritional Regulation of Developmental Transitions through the Ecdysone Receptor in Drosophila.

The steroid hormone ecdysone and its receptor (EcR) play critical roles in orchestrating developmental transitions in arthropods. However, the mechanism by which EcR integrates nutritional and developmental cues to correctly activate transcription remains poorly understood. Here, we show that EcR-dependent transcription, and thus, developmental timing in Drosophila, is regulated by CDK8 and its regulatory partner Cyclin C (CycC), and the level of CDK8 is affected by nutrient availability. We observed that cdk8 and cycC mutants resemble EcR mutants and EcR-target genes are systematically down-regulated in both mutants. Indeed, the ability of the EcR-Ultraspiracle (USP) heterodimer to bind to polytene chromosomes and the promoters of EcR target genes is also diminished. Mass spectrometry analysis of proteins that co-immunoprecipitate with EcR and USP identified multiple Mediator subunits, including CDK8 and CycC. Consistently, CDK8-CycC interacts with EcR-USP in vivo; in particular, CDK8 and Med14 can directly interact with the AF1 domain of EcR. These results suggest that CDK8-CycC may serve as transcriptional cofactors for EcR-dependent transcription. During the larval–pupal transition, the levels of CDK8 protein positively correlate with EcR and USP levels, but inversely correlate with the activity of sterol regulatory element binding protein (SREBP), the master regulator of intracellular lipid homeostasis. Likewise, starvation of early third instar larvae precociously increases the levels of CDK8, EcR and USP, yet down-regulates SREBP activity. Conversely, refeeding the starved larvae strongly reduces CDK8 levels but increases SREBP activity. Importantly, these changes correlate with the timing for the larval–pupal transition. Taken together, these results suggest that CDK8-CycC links nutrient intake to developmental transitions (EcR activity) and fat metabolism (SREBP activity) during the larval–pupal transition.

Chemicals and chemoreceptors: ecologically relevant signals driving behavior in Drosophila

Insects encounter a vast repertoire of chemicals in their natural environment, which can signal positive stimuli like the presence of a food source, a potential mate, or a suitable oviposition site as well as negative stimuli such as competitors, predators, or toxic substances reflecting danger. The presence of specialized chemoreceptors like taste and olfactory receptors allow animals to detect chemicals at short and long distances and accordingly, trigger proper behaviors towards these stimuli. Since the first description of olfactory and taste receptors in Drosophila fifteen years ago, our knowledge on the identity, properties, and function of specific chemoreceptors has increased exponentially. In the last years, multidisciplinary approaches combining genetic tools with electrophysiological techniques, behavioral recording, evolutionary analysis, and chemical ecology studies are shedding light on our understanding on the ecological relevance of specific chemoreceptors for the survival of Drosophila in their natural environment. In this review we discuss the current knowledge on chemoreceptors of both the olfactory and taste systems of the fruitfly. We focus on the relevance of particular receptors for the detection of ecologically relevant cues such as pheromones, food sources, and toxic compounds, and we comment on the behavioral changes that the detection of these chemicals induce in the fly. In particular, we give an updated outlook of the chemical communication displayed during one of the most important behaviors for fly survival, the courtship behavior. Finally, the ecological relevance of specific chemicals can vary depending on the niche occupied by the individual. In that regard, in this review we also highlight the contrast between adult and larval systems and we propose that these differences could reflect distinctive requirements depending on the change of ecological niche occupied by Drosophila along its life cycle.

Expression analysis of octopamine and tyramine receptors in Drosophila

The monoamines octopamine and tyramine, which are the invertebrate counterparts of epinephrine and norepinephrine, transmit their action through sets of G protein-coupled receptors. Four different octopamine receptors (Oamb, Octß1R, Octß2R, Octß3R) and 3 different tyramine receptors (TyrR, TyrRII, TyrRIII) are present in the fruit fly Drosophila melanogaster. Utilizing the presumptive promoter regions of all 7 octopamine and tyramine receptors, the Gal4/UAS system is utilized to elucidate their complete expression pattern in larvae as well as in adult flies. All these receptors show strong expression in the nervous system but their exact expression patterns vary substantially. Common to all octopamine and tyramine receptors is their expression in mushroom bodies, centers for learning and memory in insects. Outside the central nervous system, the differences in the expression patterns are more conspicuous. However, four of them are present in the tracheal system, where they show different regional preferences within this organ. On the other hand, TyrR appears to be the only receptor present in the heart muscles and TyrRII the only one expressed in oenocytes. Skeletal muscles express octß2R, Oamb and TyrRIII, with octß2R being present in almost all larval muscles. Taken together, this study provides comprehensive information about the sites of expression of all octopamine and tyramine receptors in the fruit fly, thus facilitating future research in the field.

Toll-Dorsal Pathway Regulates Immunity as well as Dorso-Ventral Patterning in Drosophila

The identification of the Toll receptor in Drosophila was a major discovery which restructured the paradigm in immunityas well as developmental biology . Toll homologues are present in mammals where they regulate only immunity . However ,in flies, same Toll pathway controls two disparate biological processes like embryonic dorso-ventral patterning and humoralimmune response. Toll activation by Spatzle is preceded by a proteolytic cascade which is dif ferently regulated in immunityand embryonic development. Signalling downstream to Toll is similar in both processes and eventually leads to theactivation of Drosophila homologues of NF-κB proteins; Dorsal and DIF. Toll pathway, in the early embryo results ingraded expression of Dorsal protein leading to Dorso-V entral axis patterning. On the other hand, activation of Toll-Dorsalpathway in the fat-body leads to induction of antibacterial proteins in larval and adult stages. Here, we review the currentstatus of our knowledge of Dorsal pathway in embryonic development and immunity with special emphasis to regulationof target gene/s of the two pathways by Dorsal.Key W ords : Dorsal; Toll; DNA Geometr y; Dorso-Ventral Patterning; Insect Immunity

Insulin/IGF signaling and its regulation in Drosophila

Taking advantage of Drosophila as a genetically tractable experimental animal much progress has been made in our understanding of how the insulin/IGF signaling (IIS) pathway regulates development, growth, metabolism, stress responses and lifespan. The role of IIS in regulation of neuronal activity and behavior has also become apparent from experiments in Drosophila. This review briefly summarizes these functional roles of IIS, and also how the insulin producing cells (IPCs) are regulated in the fly. Furthermore, we discuss functional aspects of the spatio-temporal production of eight different insulin-like peptides (DILP1-8) that are thought to act on one known receptor (dInR) in Drosophila.

Pre- and Postsynaptic Role of Dopamine D2 Receptor DD2R in Drosophila Olfactory Associative Learning.

Dopaminergic neurons in Drosophila play critical roles in diverse brain functions such as motor control, arousal, learning, and memory. Using genetic and behavioral approaches, it has been firmly established that proper dopamine signaling is required for olfactory classical conditioning (e.g., aversive and appetitive learning). Dopamine mediates its functions through interaction with its receptors. There are two different types of dopamine receptors in Drosophila: D1-like (dDA1, DAMB) and D2-like receptors (DD2R). Currently, no study has attempted to characterize the role of DD2R in Drosophila learning and memory. Using a DD2R-RNAi transgenic line, we have examined the role of DD2R, expressed in dopamine neurons (i.e., the presynaptic DD2R autoreceptor), in larval olfactory learning. The function of postsynaptic DD2R expressed in mushroom body (MB) was also studied as MB is the center for Drosophila learning, with a function analogous to that of the mammalian hippocampus. Our results showed that suppression of presynaptic DD2R autoreceptors impairs both appetitive and aversive learning. Similarly, postsynaptic DD2R in MB neurons appears to be involved in both appetitive and aversive learning. The data confirm, for the first time, that DD2R plays an important role in Drosophila olfactory learning.

The Great Wall Symposium.

The third Great Wall Symposium recently held in Paris, France, featured the latest advances in the field of peptidoglycan metabolism. We hosted two Keynote lectures by Kevin D. Young and Alexander Tomasz, as well as 24 speakers in six different sessions. The meeting attracted a great deal of interest from the scientific community, which has expanded dramatically in the last decade. The remerged interest in the field of peptidoglycan research occurred around the year 2000 with two important discoveries: (1) the characterization of bacterial cytoskeleton and their role in cell wall synthesis, and (2) the discovery of innate immune receptors in Drosophila (through peptidoglycan recognition proteins) and in mammals (through the Nod proteins) involved in sensing of peptidoglycan. As a consequence of the rediscovered interest in peptidoglycan by microbiologists, cell biologists, and immunologists, a first meeting exclusively focused on peptidoglycan research was organized in Baeza, Spain, October 4–6, 2010. This first small meeting answered the real need for a discussion platform of the peptidoglycan community, and a second meeting followed a year later in Lisbon, Portugal, September 28–30, 2011. To avoid overlapping with the Bacterial Cell Surface Gordon Conference, it was decided that this meeting would be organized every two years alternating with the Gordon Conference. In addition, given the fact that the Gordon conference is organized in the United States, the scientific community felt that this meeting should stay in Europe to favor diversity and opportunity for young scientists to meet with senior members of the field. The number of participants (128 in total) increased again with regard to the first and second meeting and was limited by the venue capacity. The meeting has rapidly become a reference in the field and a collective decision was made to pursue the adventure in two years in Florence, Italy, at the Villa Finaly on September 21–24, 2015. Microbial Drug Resistance has been an active promoter of the advances that have been made in the field of peptidoglycan metabolism during the last two decades, first with a special issue of the last Cell Wall meeting before the Great Wall Symposium era that took place at Lago de Garda, Italy, in 1995. Following this tradition, Alexander Tomasz has organized a special issue on the science presented at the Great Wall Symposium. A first special issue was published in June 2012 on the work presented at the second symposium. To maintain the visibility of the field, a second special issue on the third meeting is presented in this special issue, creating a great opportunity for young scientists to present their work to the scientific community.

Erratum to: Two types of muscarinic acetylcholine receptors in Drosophila and other arthropods

Erratum to: Two types of muscarinic acetylcholine receptors in Drosophila and other arthropods

The Insulin Receptor Is Required for the Development of the Drosophila Peripheral Nervous System

The Insulin Receptor (InR) in Drosophila presents features conserved in its mammalian counterparts. InR is required for growth; it is expressed in the central and embryonic nervous system and modulates the time of differentiation of the eye photoreceptor without altering cell fate. We show that the InR is required for the formation of the peripheral nervous system during larval development and more particularly for the formation of sensory organ precursors (SOPs) on the fly notum and scutellum. SOPs arise in the proneural cluster that expresses high levels of the proneural proteins Achaete (Ac) and Scute (Sc). The other cells will become epidermis due to lateral inhibition induced by the Notch (N) receptor signal that prevents its neighbors from adopting a neural fate. In addition, misexpression of the InR or of other components of the pathway (PTEN, Akt, FOXO) induces the development of an abnormal number of macrochaetes that are Drosophila mechanoreceptors. Our data suggest that InR regulates the neural genes ac, sc and sens. The FOXO transcription factor which is localized in the cytoplasm upon insulin uptake, displays strong genetic interaction with the InR and is involved in Ac regulation. The genetic interactions between the epidermal growth factor receptor (EGFR), Ras and InR/FOXO suggest that these proteins cooperate to induce neural gene expression. Moreover, InR/FOXO is probably involved in the lateral inhibition process, since genetic interactions with N are highly significant. These results show that the InR can alter cell fate, independently of its function in cell growth and proliferation.

Association of NPY Receptor 2 Polymorphism with Alcohol Dependence

Einleitung: Alcohol dependence (AD) contributes substantially to the global burden of disease. It's etiology involves both environmental and genetic factors with an estimated heritability of around 50%. Several lines of evidence suggest that the neuropeptide Y system plays a role in ethanol consumption: NPY knock-out mice consumed more alcohol than the wild-type, and NPY infusion reduced ethanol intake in rats. A recent study reported that activation/inhibition of the NPF system reduced/strengthened ethanol preference in drosophila. NPF receptors in drosophila are homologs of human NPY receptors. Following this rationale, we tested the genes encoding NPY and its receptors for association with AD in a large GWAS on AD.

Two types of muscarinic acetylcholine receptors in Drosophila and other arthropods.

Muscarinic acetylcholine receptors (mAChRs) play a central role in the mammalian nervous system. These receptors are G protein-coupled receptors (GPCRs), which are activated by the agonists acetylcholine and muscarine, and blocked by a variety of antagonists. Mammals have five mAChRs (m1-m5). In this study, we cloned two structurally related GPCRs from the fruit fly Drosophila melanogaster, which, after expression in Chinese hamster ovary cells, proved to be muscarinic acetylcholine receptors. One mAChR (the A-type; encoded by gene CG4356) is activated by acetylcholine (EC50, 5×10(-8)M) and muscarine (EC50, 6×10(-8)M) and blocked by the classical mAChR antagonists atropine, scopolamine, and 3-quinuclidinyl-benzilate (QNB), while the other (the B-type; encoded by gene CG7918) is also activated by acetylcholine, but has a 1,000-fold lower sensitivity to muscarine, and is not blocked by the antagonists. A- and B-type mAChRs were also cloned and functionally characterized from the red flour beetle Tribolium castaneum. Recently, Haga et al. (Nature 2012, 482: 547-551) published the crystal structure of the human m2 mAChR, revealing 14 amino acid residues forming the binding pocket for QNB. These residues are identical between the human m2 and the D. melanogaster and T. castaneum A-type mAChRs, while many of them are different between the human m2 and the B-type receptors. Using bioinformatics, one orthologue of the A-type and one of the B-type mAChRs could also be found in all other arthropods with a sequenced genome. Protostomes, such as arthropods, and deuterostomes, such as mammals and other vertebrates, belong to two evolutionarily distinct lineages of animal evolution that split about 700 million years ago. We found that animals that originated before this split, such as cnidarians (Hydra), had two A-type mAChRs. From these data we propose a model for the evolution of mAChRs.

Wengen, the Sole Tumour Necrosis Factor Receptor in Drosophila, Collaborates with Moesin to Control Photoreceptor Axon Targeting during Development

Photoreceptor neurons (R cells) in the Drosophila eye define a map of visual space by connecting to targets in distinct layers of the optic lobe, with R1-6 cells connecting to the lamina (the first optic ganglion) and R7 and R8 cells connecting to the medulla (the second optic ganglion). Here, we show that Wengen (Wgn) directly binds Moesin (Moe) through a cytosolic membrane proximal domain and this interaction is important for mediating two distinct aspects of axonal targeting. First, we show that loss of wgn or moe function disrupts cell autonomous R8 axon targeting. Second, we report that wgn or moe mutants show defects in R2–R5 targeting that result from disruption of non-cell autonomous effects, which are secondary to the cell autonomous R8 phenotype. Thus, these studies reveal that the Wgn-Moe signaling cascade plays a key role in photoreceptor target field innervations through cell autonomous and non-cell autonomous mechanisms.

Neuropeptide-Gated Perception of Appetitive Olfactory Inputs in Drosophila Larvae

Understanding how smell or taste translates into behavior remains challenging. We have developed a behavioral paradigm in Drosophila larvae to investigate reception and processing of appetitive olfactory inputs in higher-order olfactory centers. We found that the brief presentation of appetitive odors caused fed larvae to display impulsive feeding of sugar-rich food. Deficiencies in the signaling of neuropeptide F (NPF), the fly counterpart of neuropeptide Y (NPY), blocked appetitive odor-induced feeding by disrupting dopamine (DA)-mediated higher-order olfactory processing. We have identified a small number of appetitive odor-responsive dopaminergic neurons (DL2) whose activation mimics the behavioral effect of appetitive odor stimulation. Both NPF and DL2 neurons project to the secondary olfactory processing center; NPF and its receptor NPFR1 mediate a gating mechanism for reception of olfactory inputs in DL2 neurons. Our findings suggest that eating for reward value is an ancient behavior and that fly larvae are useful for studying neurobiology and the evolution of olfactory reward-driven behavior.

Dopamine D2 Receptor as a Cellular Component Controlling Nocturnal Hyperactivities in Drosophila melanogaster

Dysfunctional regulation of brain dopamine (DA) functions has been found in patients with drug addiction and various neurological disorders that frequently accompany disturbance in sleep behavior. In this study, the roles of the dopaminergic nervous system on the regulation of daily locomotor activity rhythm were investigated in Drosophila melanogaster. Reduced synaptic DA release by expressing tetanus toxin gradually attenuated peak activity levels by altering activity patterns, particularly under constant darkness. Besides, flies with a mutant dopamine transporter fumin (fmn), in which the synaptic DA levels were elevated, displayed increased activities in both daytime and nighttime, but did more so at nighttime, suggesting that DA function is involved in regulation of fruit fly's nocturnal locomotor activities. Furthermore, flies treated with bromocriptine, an agonist of Drosophila dopamine D2 receptor (dD2R), exhibited nocturnal locomotor hyperactivity in a dose-dependent manner and this effect was inhibited in dD2R knockdown flies. When mutant flies null for period (per), timeless (tim), dClock (dClk), or cycle (cyc) were treated with bromocriptine, only cycle-null flies (cyc01) did not show induced nocturnal hyperactivities, suggesting that cyc might play a role in bromocriptine-induced nocturnal hyperactivities. Elevation of experimental temperature also increased nocturnal activities at the expense of daytime activities. The heat-induced increase in nocturnal activities gradually returned to basal levels at continuously elevated temperature. Inhibition of DA synthesis did not suppress heat-induced early development of nocturnal hyperactivity but prevented gradual decrement of initially elevated nocturnal activities, suggesting that DA impinges on certain adaptive roles in response to changes in environmental temperature. These results overall suggest that controlling dopaminergic transmission is important for daily locomotor behavior and bromocriptine-induced nocturnal hyperactivity which is mediated through dD2R receptor and CYC functions. In parallel to these results, excessive activation of dopaminergic neurotransmission, the primary cause of schizophrenia, is associated with abnormally elevated nocturnal locomotor activities through D2-type receptor in Drosophila. The results suggest that fruit flies are an excellent model system to provide some answers to previously unexplainable observations regarding the compromised dopaminergic nervous system and the related therapeutic agents. (Author correspondence: kmkim@jnu.ac.kr)