Effect of acute treatment with the glucagon-like peptide-1 receptor agonist, liraglutide, and estrus phase on cue- and drug-induced fentanyl seeking in female rats

Dec 24, 2024Behavioural pharmacology

How a diabetes drug and reproductive cycle phase affect fentanyl craving triggered by cues and drug in female rats

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Abstract

Female rats self-administered fentanyl (1.85 μg/infusion) with significant individual differences in behavior.

Rats in the estrus phase showed increased fentanyl intake compared to those in a non-estrus phase.
Estrus females demonstrated greater cue-induced fentanyl seeking and enhanced drug-induced reinstatement of seeking behaviors.
Acute treatment with liraglutide (0.3 mg/kg s.c.) reduced cue-induced fentanyl seeking and blocked drug-induced reinstatement, especially in estrus females.
These findings suggest a potential benefit of GLP-1 receptor agonists as non-opioid treatments for opioid use disorder.

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Opioid use disorder (OUD) is a crisis in the USA. Despite advances with medications for OUD, overdose deaths have continued to rise and are largely driven by fentanyl. We have previously found that male rats readily self-administer fentanyl, with evident individual differences in fentanyl taking, seeking, and reinstatement behaviors. We also have shown that acute treatment with the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, can reduce fentanyl seeking behavior in male rats. However, given that females are significantly more vulnerable to drug-related cues, drug cravings, and to the development of OUD compared to males, it is imperative that we investigate the biological risk factors on fentanyl use disorder. Further, preclinical models report that females in estrus have increased fentanyl intake, more rapid development of OUD, and enhanced relapse vulnerability compared to those in a non-estrus phase. Thus, we aimed here to understand the effect of estrus phase on our model of OUD and on the effectiveness of acute liraglutide treatment. Herein, we show that female rats readily self-administer fentanyl (1.85 μg/infusion) intravenously, with marked individual differences in fentanyl taking behavior. Additionally, rats in the estrus phase exhibited greater fentanyl intake compared with those in a non-estrus phase, greater cue-induced fentanyl seeking, and greater drug-induced reinstatement of fentanyl seeking. Finally, acute liraglutide treatment (0.3 mg/kg s.c.) reduced cue-induced fentanyl seeking and blocked drug-induced reinstatement of fentanyl seeking, particularly when tested in estrus. Overall, these data support the broad effectiveness of acute GLP-1R agonists as a promising non-opioid treatment for OUD.

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Effect of acute treatment with the glucagon-like peptide-1 receptor agonist, liraglutide, and estrus phase on cue- and drug-induced fentanyl seeking in female rats

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