UC Davis

Social bonds are fundamental to health and well-being, and their disruption is associated with significant physiological and psychological consequences. The kappa opioid receptor (KOR) system has been proposed as a key modulator of oxytocin (OT) release during partner separation, but this model has not been tested directly in a pair-bonding primate. This dissertation examined KOR-OT interactions during long-term partner separation in titi monkeys (Plecturocebus cupreus) through complementary observational and pharmacological approaches.The first study used positron emission tomography (PET) with the KOR-selective radiotracer [11C]GR103545 to measure KOR availability in 16 pair-bonded titi monkeys across a within-subject two-week separation paradigm. Separation significantly elevated plasma cortisol in both sexes, confirming the physiological impact of the manipulation. KOR availability was significantly reduced in the nucleus accumbens during separation, with a non-significant trend in the anterior cingulate cortex. A significant Condition × Sex interaction for plasma OT reflected a crossover pattern in which males decreased during separation while females showed a non-significant increase.The second study tested this system pharmacologically. Using a within-subjects counterbalanced crossover design, subjects received daily oral administration of the KOR antagonist CERC-501 (3.0 mg/kg) or vehicle throughout a two-week separation. CERC-501 was associated with significantly elevated cerebrospinal fluid OT relative to vehicle, consistent with KOR antagonism disinhibiting central OT release. No significant effects were observed on plasma OT, plasma cortisol, or stress-related behavior, and central and peripheral OT were uncorrelated.Together, these studies provide the first in vivo neuroimaging evidence of KOR system engagement during partner separation in a pair-bonded primate, and pharmacological confirmation that KOR antagonism engages the central OT system during pair-bond disruption. They also reveal a striking dissociation between central and peripheral OT, with implications for how OT signaling is measured and interpreted. This work advances understanding of the neurobiology of social loss and highlights the value of non-human primate models for translational research on KOR-targeted therapeutics.