Graduation Semester and Year
Summer 2026
Language
English
Document Type
Thesis
Degree Name
Master of Science in Psychology
Department
Psychology
First Advisor
Dr Linda I Perrotti
Second Advisor
Tracy L. Greer, Ph.D.
Third Advisor
Yuan B. Peng, Ph.D.
Abstract
Strong activation of the brain’s reward circuitry by morphine and morphine-associated cues drives the progression toward morphine abuse. Additionally, orexin neurons in the lateral hypothalamus (LH) are activated in response to cues paired with morphine reward. The orexin system, particularly the orexin-1 receptor (OX1R) regulates reward-seeking behavior through its activation. Despite the well-established role of orexins in reward-related behaviors, the specific contribution of OX1R in morphine-associated reward remains unclear. Furthermore, while sex differences in drug reward and reward-related behaviors are well documented, they remain unexplored in the regulation of morphine-associated reward by orexins. To address this gap, the present study investigated the sex-specific effects of systemic administration of the selective OX1R antagonist SB334867 on morphine-induced conditioned place preference (CPP). Fifty-one Long-Evans rats were assigned to one of three treatment groups: saline control (saline + saline), morphine control (vehicle + morphine), or treatment (SB334867 + morphine). Rats underwent an eight-day CPP paradigm consisting of a pre-test, six conditioning sessions, and a post-test. SB334867 (30 mg/kg, i.p.) or vehicle was administered 30 minutes before morphine (10 mg/kg, s.c.) during conditioning, whereas the saline control group received saline (i.p.) followed 30 v minutes later by saline (s.c.). Following behavioral testing, animals were transcardially perfused with 4% paraformaldehyde. Perfused brains were isolated and coronally sectioned to obtain slices containing lateral hypothalamus (LH). Double-label immunohistochemistry (DL-IHC) was performed to quantify c-Fos expression in orexin-positive neurons within the LH to determine whether systemic OX1R antagonism with SB-334867 alters the activation of LH orexin neurons following morphine-induced CPP in a sex-specific manner. Morphine conditioning produced significant CPP in both male and female rats compared to saline controls. Additionally, morphine significantly increased the percentage of LH orexin-positive neurons expressing c-Fos compared to saline. Pretreatment with SB334867 did not significantly attenuate morphine-induced CPP in either sex. In contrast, SB334867 significantly reduced morphine-induced LH orexin neuron activation to levels comparable with saline controls. Furthermore, male rats exhibited significantly greater morphine-induced LH orexin neuron activation than female rats. These findings suggest that OX1R signaling contributes to the neurobiological response to morphine within the LH in a sex-specific manner. However, lack of sex differences in the behavioral expression of morphine reward suggests involvement of additional neural mechanisms. Collectively, these findings suggest that targeting OX1R alone may not be sufficient to reduce morphine reward, despite altering orexin neuronal activity and highlights the importance of considering sex differences in the neural mechanisms underlying opioid reward.
Keywords
Morphine, Orexin, Orexin-1 receptor (OX1R), Conditioned place preference (CPP), SB-334867, Sex differences, Lateral hypothalamus (LH), c-Fos, Reward, Estradiol
Disciplines
Experimental Analysis of Behavior
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Koly, Farzana Akter, "INVESTIGATING SEX DIFFERENCES IN THE REGULATION OF CONDITIONED MORPHINE REWARD BY OREXIN" (2026). Psychology Theses. 5.
https://mavmatrix.uta.edu/psychology_theses2/5