Cue-Induced Ethanol Seeking in Drosophila melanogaster Is Dose-Dependent

Abstract

Alcohol use disorder generates devastating social, medical and economic burdens, making it a major global health issue. The persistent nature of memories associated with intoxication experiences often induces cravings and triggers relapse in recovering individuals. Despite recent advances, the neural and molecular mechanisms underlying these memories are complex and not well understood. This makes finding effective pharmacological targets challenging. The investigation of persistent alcohol-associated memories in the fruit fly, Drosophila melanogaster, presents a unique opportunity to gain a comprehensive understanding of the memories for ethanol reward at the level of genes, molecules, neurons and circuits. Here we characterize the dose-dependent nature of ethanol on the expression of memory for an intoxication experience. We report that the concentration of ethanol, number of ethanol exposures, length of ethanol exposures, and timing between ethanol exposures are critical in determining whether ethanol is perceived as aversive or appetitive, and in how long the memory for the intoxicating properties of ethanol last. Our study highlights that fruit flies display both acute and persistent memories for ethanol-conditioned odor cues, and that a combination of parameters that determine the intoxication state of the fly influence the seemingly complex retention and expression of memories associated with intoxication. Our thorough behavioral characterization provides the opportunity to interrogate the biological underpinnings of these observed preference differences in future studies.

Behavioral features of motivated response to alcohol inDrosophila

“…Our runway-based operant administration data here reveal that flies willingly self-administer ethanol following initial exposure, despite finding the ethanol aversive. Interestingly, the ethanol dose that induced the most striking behavioral responses in the runway task is similar to the one that induced the highest appetitive response in a Pavlovian odor-ethanol association memory task [15]. We found that within each day, initial ethanol administration induced early bouts of thrashing behavior, followed by decreasing velocity and increased levels of pausing, cumulatively supporting aversion.…”

“…Flies exhibit preference for an odor associated with moderate dose ethanol intoxication one to seven days after pairing [14,15]. However, this Pavlovian assay lacks the tracking resolution to quantify behavior during ethanol administration.…”

“…Moreover, aversive experiences can influence perception of rewarding stimuli in Drosophila. This can happen whether different aversive and appetitive stimuli are presented simultaneously [22], whether a single stimulus has both aversive and appetitive properties [14,15], or whether a previous aversive experience alters internal state in the brain, thus affecting future appetitive experiences [23]. The BEER run provides an opportunity to investigate how these valences are integrated and reflect the appropriate output response.…”

Circuits that encode and predict alcohol associated preference

“…Training was performed in the dark with minimal red-light illumination and was preceded by a 20-minute habituation to the training chambers. Training chambers were constructed out of PlexiGlas (30 x 15 x 15 cm) (for details please refer to (Nuñez, Azanchi et al 2018)). During habitation, humidified air (flow rate: 130) was streamed into the chambers.…”

“…Drosophila exhibit sophisticated behaviors in response to changes in their environment, including formation of appetitive memories for food associated with environmental cues (Waddell 2010, Kahsai and Zars 2011, Schleyer, Saumweber et al 2011, Herrero 2012, Fernandez and Kravitz 2013, Heisenberg 2015, Owald, Lin et al 2015. Drosophila also form appetitive memories for the pharmacological properties of alcohol (Kaun, Azanchi et al 2011, Nuñez, Azanchi et al 2018. These alcohol memories are persistent and impel flies to walk over a 120V electric shock in the presence of associated cues.…”