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

Significant advances in neurotechnology, such as the emergence of 2-photon imaging, have enabled unparalleled access to the complex neural circuits that coordinate behavior in rodents. Integration of these techniques would be groundbreaking for the study of animal models of alcohol use disorder (AUD), which is rooted in longitudinal brain adaptations that could be functionally monitored and manipulated at the level of neural circuits from the onset of alcohol use through dependence. However, 2-photon and related methodologies require or are often facilitated by head-fixation, and a lack of head-fixed models have hindered their integration in the study of AUD. Here we present a head-fixed alcohol self-administration model, and find that head-fixed male and female mice will reliably press an active, but not inactive, lever for an oral alcohol reward. The number of alcohol rewards obtained reliably predicted blood alcohol concentrations, at physiologically relevant levels. Furthermore, we demonstrate that mice can extinguish alcohol self-administration when the alcohol reward is omitted, suggesting active lever pressing behavior was alcohol-directed. Following extinction, presentation of alcohol-related cues or a priming reminder of alcohol itself invigorated reinstatement of alcohol seeking, modeling relapse in a manner that mimics decades of work in freely-moving rodent studies. Overall, our head-fixed alcohol self-administration model allows integration of novel technologies that require or are greatly facilitated by head-fixation, improving our ability to study and understand the neural circuits adaptations and computations that underlie AUD. ### Competing Interest Statement The authors have declared no competing interest.