Rapid appearance of negative emotion during oral fentanyl self-administration in male and female rats

Abstract

Opioid use disorder has become an epidemic in the United States, fueled by the widespread availability of fentanyl, which produces rapid and intense euphoria followed by severe withdrawal and emotional distress. We developed a new preclinical model of fentanyl seeking in outbred male and female rats using volitional oral self-administration that can be readily applied in labs without intravascular access. Using a traditional two lever operant procedure, rats learned to take oral fentanyl vigorously, escalated intake across sessions, and readily reinstated responding to conditioned cues after extinction. Oral self-administration also revealed individual and sex differences that are essential to studying substance use risk propensity. During a behavioral economics task, rats displayed inelastic demand curves and maintained stable intake across a wide range of fentanyl concentrations. Oral SA was also neatly patterned, with distinct " loading" and " maintenance" phases of responding within each session. Using our software DeepSqueak, we analyzed thousands of ultrasonic vocalizations (USVs), which are innate expressions of current emotional state in rats. Rats produced 50 kHz USVs during loading then shifted quickly to 22 kHz calls despite ongoing maintenance oral fentanyl taking, reflecting a transition to negative reinforcement. Using fiber photometry, we found that the lateral habenula differentially processed drug-cues and drug-consumption depending on affective state, with potentiated modulation by drug cues and consumption during the negative affective maintenance phase. Together, these results indicate a rapid progression from positive to negative reinforcement occurs even within an active drug taking session, revealing a within-session opponent process. Significance StatementThe United States opioid epidemic is defined by rampant and treatment resistant fentanyl use. Better understanding of neural substrates underlying this phenomenon is essential to slowing the opioid crisis. Intravenous and vapor self-administration (SA) are the standard models for studying fentanyl use in rodents, however they many carry pragmatic downsides. Here, we used a novel oral fentanyl self-administration model that provides key translational and technical benefits and can be readily applied in other labs to study the neurobiology of fentanyl SA. This method captured individual and sex differences necessary for studying substance use risk propensity and uncovered a rapid shift in affective state in rats, suggesting and shift from positive to negative reinforcement within each fentanyl taking session.