The rewarding properties of drugs contribute to the development of abuse and addiction. Here we present a new assay to investigate the motivational properties of ethanol in the genetically tractable model, Drosophila melanogaster. Flies learn to associate cues with ethanol intoxication and, although transiently aversive, the experience leads to a long-lasting attraction for the ethanol-paired cue, implying that intoxication is rewarding. Temporally blocking transmission in dopaminergic neurons revealed that flies require activation of these neurons to express, but not develop, conditioned preference for ethanol-associated cues. Moreover, flies acquire, consolidate, and retrieve these rewarding memories using distinct sets of neurons of the mushroom body. Finally, mutations in scabrous, encoding a fibrinogen-related peptide that regulates Notch signaling, disrupt the formation of memories for ethanol reward. Our results thus establish that Drosophila can be useful in understanding the molecular, genetic and neural mechanisms underling the rewarding properties of ethanol.

These results demonstrate that social context exerts a regulatory influence on the expression of chemical signals, while modulating sexual behavior in the fruit fly.

The brain's reward systems evolved to reinforce behaviors required for species survival, including sex, food consumption, and social interaction. Drugs of abuse co-opt these neural pathways, which can lead to addiction. Here, we use Drosophila melanogaster to investigate the relationship between natural and drug rewards. In males, mating increased Neuropeptide F (NPF) levels, whereas sexual deprivation reduced NPF. Activation or inhibition of the NPF system in turn enhanced or reduced ethanol preference. These results thus link sexual experience, NPF system activity, and ethanol consumption. Artificial activation of NPF neurons was in itself rewarding and precluded the ability of ethanol to act as a reward. We propose that activity of the NPF/NPF receptor axis represents the state of the fly reward system and modifies behavior accordingly.

Chemical communication mediates social interactions in insects. For the fruit fly, D. melanogaster, the chemical display is a key fitness trait because it leads to mating. An exchange of cues that resembles a dialogue between males and females is enacted by pheromones, chemical signals that pass between individual flies to alter physiology and behavior. Chemical signals also affect the timing of locomotor activity and sleep. We investigated genetic and environmental determinants of chemical communication. To evaluate the role of the social environment, we extracted a chemical blend from individual males selected from groups composed of one genotype and compared these extracts to those from groups of mixed genotypes. To evaluate the role of the physical environment, these comparisons were performed under a light-dark cycle or in constant darkness. Here, we show that chemical signaling is affected by the social environment, light-dark cycle, and genotype as well as the complex interplay of these variables. Gene-by-environment interactions produce highly significant effects on chemical signaling. We also examined individual responses within the groups. Strikingly, the response of one wild-type fly to another is modulated by the genotypic composition of his neighbors. Chemical signaling in D. melanogaster may be a "fickle" trait that depends on the individual's social background.

The neural circuits that mediate behavioral choice evaluate and integrate information from the environment with internal demands and then initiate a behavioral response. Even circuits that support simple decisions remain poorly understood. In Drosophila melanogaster, oviposition on a substrate containing ethanol enhances fitness; however, little is known about the neural mechanisms mediating this important choice behavior. Here, we characterize the neural modulation of this simple choice and show that distinct subsets of dopaminergic neurons compete to either enhance or inhibit egg-laying preference for ethanol-containing food. Moreover, activity in α′β′ neurons of the mushroom body and a subset of ellipsoid body ring neurons (R2) is required for this choice. We propose a model where competing dopaminergic systems modulate oviposition preference to adjust to changes in natural oviposition substrates.I n nature, rotting fruit is the social hub for the fruit fly Drosophila melanogaster. Flies use fermenting fruit as a food source (1) and a site for oviposition (2). The choice of a suitable oviposition substrate is an ecologically important decision with a direct impact on species fitness. However, other than having a clear preference for fermenting fruit, how females choose oviposition sites in nature is largely unknown.One of the main metabolites of fermentation is ethanol, which is present in ripe fleshy fruits (3). Although ethanol concentrations in the fruit are rather low [≤5% (vol/vol)] (4), plumes containing ethanol vapor can act as long-distance signals to attract flies to rotting fruit (3, 5). When given the choice, female flies prefer to lay their eggs on media containing low concentrations of ethanol (up to 5%) (6), which leads to enhanced fitness of the developing larva and the adult fly.D. melanogaster's resistance to ethanol toxicity may have evolved to allow inhabitation of ethanol-containing environments (7). For example, adult flies allowed to mate on ethanolcontaining media improve mating success and fecundity (8). Although rearing larvae on food containing relatively high ethanol concentrations delays development and decreases survival (9-11), larvae reared on low concentrations of ethanol develop into heavier adults (7,12). This weight increase may be a result of D. melanogaster larvae metabolizing ethanol and using it as a food source (12). Ingestion of ethanol during the larval stage has additional benefits, such as protection from natural parasites such as endoparasitoid wasps (13).Studies on the neural circuits underlying the oviposition program and choice of oviposition substrates have been initiated only recently in D. melanogaster (14, 15). Ethanol is a particularly intriguing stimulus for oviposition preference, because it has, depending on concentration, both beneficial and detrimental effects on developing larvae. In flies, the function of dopaminergic neurons has been implicated in responses to both rewarding and aversive stimuli (16-19), making it a candidate neuromodulator to signa...