Alcohol Tolerance as a Driver of Self-Administration

––– PROJECT SUMMARY ––––––– R21/R33: Alcohol Tolerance as a Driver of Self-Administration ––– PI: Rothenfluh ––– Alcohol use disorder (AUD) is still highly prevalent in the US, and the recent pandemic has made it even more pervasive. Risk factors for the development of AUD include initial resistance to the intoxicating effects of

alcohol, as well as tolerance, where individuals require increasingly larger doses to attain the same behavioral outcomes. Yet, how the initial reaction to alcohol is related to the development of tolerance, and how both of them drive alcohol self-administration is not well understood. This R21/33 application responds to NIAAA PAR-

21-250 “Mechanisms of Alcohol Tolerance”, which aims to ”build a framework for the systematic analysis of the factors that contribute to alcohol sensitivity and tolerance and the mechanisms that regulate tolerance and transition to AUD”. We use Drosophila as a model organism because they show many alcohol-related

behaviors also observed in mammals that involved conserved molecular, genetic, and even neuronal mechanisms. Analyzing over 120 distinct genetic manipulations, we recently showed that initial alcohol resistance is correlated with the development of less tolerance with repeat alcohol exposures. In Aim1, we

propose to similarly, and systematically analyze 49 genes that affect initial resistance/sensitivity and/or tolerance for their development of experience-dependent alcohol self-administration preference. While tolerance to alcohol is mostly determined by reduced effects on the motor system with repeat alcohol

exposure, the ‘reward system’ is also blunted by repeat alcohol. This hedonic tolerance is characterized in humans by experiencing less ‘pleasure’ with various rewards than before drug experience, while rodents become less responsive to normally reinforcing stimuli with hedonic tolerance. Based on our promising

preliminary data, we will develop a robust and convincing assay for hedonic tolerance in Drosophila (Aim2). In order to progress to the R33 phase of the proposal, our MILESTONE is to successfully accomplish Aim2 by clearly defined metrics. Upon achieving this milestone, we aim to investigate genetic, molecular, and neural

mechanisms of hedonic tolerance in Drosophila. In Aim3 we will investigate how the mechanisms and neuronal circuits affecting motor tolerance overlap with hedonic tolerance. Lastly, Aim4 proposes to investigate the molecular and neuronal mechanisms of hedonic tolerance, with both these Aims testing our

overarching hypothesis that molecular mechanisms are (partially) overlapping between motor and hedonic tolerance, but the circuits mediating them are distinct. We will also test how mechanisms of hedonic tolerance affect experience-dependent alcohol preference. Together, these Aims yield much needed insight into the

relevance of tolerance in AUD, especially hedonic tolerance, which has been labeled “key” to understanding AUD.