142 - Effects of Acute Treatment with the Glucagon-like peptide-1 Receptor Agonist, Liraglutide, on Cue-induced and Drug-induced Reinstatement of Fentanyl Seeking in Male and Female Rats

Poster Board Number: 142
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Abstract Body : Opioid Use Disorder (OUD) is a chronic relapsing disorder that has negative impacts on the individual, the family, and the community. In 2021, opioids contributed to 80% of all drug overdose deaths in the US. This rise in opioid-related deaths coincides with a significant rise in the use of fentanyl, a synthetic opioid that is 150 times more potent than morphine, spares no demographic, and costs the nation $78.5 billion annually. Thus, it is imperative to better understand the underlying mechanisms of OUD to identify new treatment targets. Using animal models, studies have shown that rats readily self-administer heroin and fentanyl and actively seek the drug following exposure to drug-related cues, the drug itself, or stress. We have shown that treatment with the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, can reduce heroin taking and seeking behavior in rats. Here, we test whether the GLP-1R agonist can reduce fentanyl seeking in rats with a history of fentanyl self-administration and investigate whether estrous phase may influence these effects in females. The subjects were 24 naïve male and 28 naïve female Sprague Dawley rats. All rats were implanted with indwelling jugular catheters for the intravenous delivery of a fentanyl solution. Rats were trained in operant chambers to self-administer fentanyl (2.5 ug/kg) for 6 hours per day for 14 days. On Day 15, rats received a 6h pretreatment with either 0.3 mg/kg liraglutide s.c. or saline s.c. and then underwent a 4h extinction/reinstatement test. Throughout the study, female rats received daily vaginal lavage to track estrous phase. The results showed that both male and female rats readily self-administered fentanyl, with marked individual differences in drug-taking behavior. Thus, as with other drugs of abuse tested, some male and female rats self-administered more fentanyl than did others. When challenged in the extinction/reinstatement test, vulnerable rats treated 6 h earlier with saline exhibited high cue-induced fentanyl seeking and high drug-induced reinstatement of fentanyl seeking behavior. In contrast, rats treated 6 h prior to test with the GLP-1R agonist, liraglutide, exhibited attenuated cue-induced fentanyl seeking and drug-induced reinstatement of fentanyl seeking. These protective effects were on par with those obtained following treatment with the currently approved partial opioid agonist, buprenorphine. Finally, while evident in both male and female rats, the protective effect of the GLP-1R agonist (particularly on cue-induced seeking) was most robust in males. The effect of phase of the estrous cycle on fentanyl taking, fentanyl seeking, and protection by treatment with the GLP-1R agonist, liraglutide, is examined. Overall, this study revealed that there are robust individual differences in fentanyl taking and seeking behavior, and that acute treatment with the GLP-1R agonist, liraglutide, blocks both cue-induced fentanyl seeking and drug-induced reinstatement of fentanyl seeking in both male and female rats. The present results further substantiate the conclusion that GLP-1R agonists, satiety agents already approved for the treatment of obesity and type two diabetes, may serve as effective non-opioids for the treatment of OUD in humans. Support for this research was provided by NIH grant UG3 DA050325.