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Updated: Sep 16, 2025
A Conflict Model of Reward-seeking Behavior in Male Rats
Published on: February 20, 2019
Fentanyl demand and seeking in female rats: Role of the orexin system and estrous cycle
David De Sa Nogueira1, Chuhyon Corwin1, Yogesh Rakholia1
1Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, NJ, USA.
Abstract:
The orexin system plays a major role in drug reward. Orexin-1 receptor (OxR1) blockade reduces fentanyl demand in males. However, there are a number of sex differences in the orexin system, and it is unclear how OxR1 antagonism would decrease fentanyl demand in females. Furthermore, the relationships between the estrous cycle and fentanyl intake are yet to be delineated. Here, we conducted a behavioral economics (BE) procedure in female rats to assess the effects of the OxR1 antagonist SB-334867 on fentanyl demand before and after short-(ShA), long- (LgA) or intermittent-access (IntA) self-administration of fentanyl; we also tested the effect of SB-334867 on cued reinstatement of fentanyl seeking. Finally, we measured the impact of the estrous cycle on fentanyl demand, intake and seeking. Results showed that in females SB-334867 did not consistently modulate demand for fentanyl before or after chronic access periods. However, SB-334867 at 30mg/kg reduced the number of active lever presses during cued-reinstatement of fentanyl seeking. We also found that fentanyl self-administration disrupted estrous cyclicity, in particular proestrus epochs, an effect that depended on short versus chronic access. Furthermore, extended access to fentanyl shifted the role of progesterone from facilitation of fentanyl demand during short periods, to attenuation of fentanyl demand after long term exposure. These results indicate that an orexin-based therapy in women for treating opioid use disorder must consider prior drug history as well as cycle phase.
Insights
Orexin-1 receptor (OxR1) blockade did not consistently reduce fentanyl demand in female rats. However, it did decrease fentanyl seeking and disrupt the estrous cycle, indicating therapy must consider drug history and cycle phase.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Economics
Background:
- The orexin system is crucial for drug reward, with OxR1 blockade reducing fentanyl demand in males.
- Sex differences in the orexin system suggest varied responses to OxR1 antagonism in females.
- The interplay between the estrous cycle and fentanyl intake remains underexplored.
Purpose of the Study:
- To investigate the effects of the OxR1 antagonist SB-334867 on fentanyl demand in female rats.
- To assess the impact of fentanyl self-administration access (short, long, intermittent) on demand and estrous cyclicity.
- To determine the influence of the estrous cycle on fentanyl intake and seeking behavior.
Main Methods:
- Behavioral economics procedures were used to measure fentanyl demand in female rats.
- Rats underwent varying access periods of fentanyl self-administration (ShA, LgA, IntA).
- The OxR1 antagonist SB-334867 was administered, and its effects on demand, reinstatement, and estrous cyclicity were measured.
Main Results:
- SB-334867 did not consistently alter fentanyl demand in females across different access conditions.
- A dose of 30mg/kg SB-334867 reduced active lever presses during cued reinstatement of fentanyl seeking.
- Fentanyl self-administration disrupted estrous cyclicity, particularly proestrus, with effects varying by access duration.
- Progesterone's role in fentanyl demand shifted from facilitation to attenuation with extended fentanyl exposure.
Conclusions:
- Orexin-based therapies for opioid use disorder in women require consideration of prior drug history and the estrous cycle phase.
- The findings highlight sex-specific and cycle-dependent neurobiological mechanisms in opioid reward.
- Understanding these complexities is vital for developing effective, personalized addiction treatments.
