A Model of Ethanol Self-Administration in Head-Fixed Mice

Abstract

BackgroundSignificant advances in neurotechnology, such as the application of two-photon (2P) imaging of biosensors in vivo, have enabled unparalleled longitudinal and high-resolution access to neural circuits that coordinate behavior in rodents. Integration of these techniques would be groundbreaking for the study of alcohol use disorder (AUD). AUD is rooted in significant neural adaptations that could be functionally monitored and manipulated at the single-cell level across development of dependence in rodents. However, 2P imaging and related methodologies often require or are facilitated by head-fixation, and a lack of head-fixed models have hindered their integration for the study of alcohol dependence. MethodsWe developed a head-fixed model in which animals learned to self-administer ethanol across [~]14 days. Active lever responding resulted in a tone cue and ethanol reward, whereas responding on the inactive lever resulted in neither cue nor ethanol reward. Following acquisition, animals extinguished lever pressing across a minimum of 10 days. And finally, animals were tested separately for both cue- and ethanol-induced reinstatement of lever pressing. ResultsHere we show, for the first time, that in our head-fixed ethanol self-administration model male and female mice reliably pressed an active, but not inactive, lever for an oral ethanol reward. Ethanol rewards positively correlated with blood ethanol concentrations, at pharmacologically relevant levels. Furthermore, mice extinguished ethanol self-administration when the ethanol reward and cue were omitted, suggesting active lever pressing was ethanol directed. Following extinction, presentation of the ethanol-associated cue or priming with ethanol itself invigorated reinstatement of ethanol seeking, modeling relapse in a manner that replicates decades of work in freely-moving rodent studies. ConclusionsOverall, our head-fixed ethanol self-administration model will allow for incorporation of novel technologies that require or are greatly facilitated by head-fixation, improving our ability to study and understand the neural adaptations and computations that underlie alcohol dependence.