Peripherally administered non-peptide oxytocin antagonist, L368,899®, accumulates in limbic brain areas: A new pharmacological tool for the study of social motivation in non-human primates

Abstract

Central administration of oxytocin (OT) antagonists inhibits maternal and sexual behavior in non-primates, providing the strongest experimental evidence that endogenous OT facilitates these behaviors. While there have been a few reports that ICV administration of OT increases social behaviors in monkeys, no studies to date have assessed the effects of OT antagonists. Therefore, we studied in rhesus monkeys whether L368,899, a non-peptide antagonist produced by Merck that selectively blocks the human uterine OT receptor, penetrates the CNS after peripheral administration and alters female maternal and sexual behavior. In two studies in four male monkeys, L368,899 was injected iv (1 mg/kg) after which (1) CSF samples were collected at intervals over 4 h and (2) brains were collected at 60 min. Assay of samples confirmed that iv-administered L368,899 entered CSF and accumulated in the hypothalamus, septum, orbitofrontal cortex, amygdala and hippocampus, but not other areas. An adult female monkey was tested for interest in either an infant or sexual behavior, receiving a different iv treatment prior to each test (1 or 3 mg/kg of L368,899 or saline). OT antagonist treatment reduced or eliminated interest in the infant and sexual behavior. These results, although preliminary, are the first to directly implicate endogenous OT in activation of primate maternal interest and sexual behavior. While it remains to be empirically demonstrated that peripherally administered L368,899 blocks central OT receptors, our behavioral findings suggest that this non-peptide antagonist may facilitate testing OT involvement in a variety of social and other behaviors in primates.

Systemic oxytocin induces a prolactin secretory rhythm via the pelvic nerve in ovariectomized rats

“…This peptide OT antagonist, unlike nonpeptide OT antagonists, has limited penetration through the blood-brain barrier (8). Infusion of the OT antagonist alone in OVX rats did not modify PRL levels over the next 1-3 days (data not shown).…”

Oxytocin and Myometrial Contractility in Labor

“…In a study, the non-peptide OT antagonist L-368,899 was accumulated when injected intravenously in four male monkeys in limbic brain areas. This antagonist when injected iv in one adult female monkey altered maternal and sexual behavior (Boccia et al, 2007).…”

The marmoset as a model for the study of primate parental behavior

“…In two studies involving manipulation of oxytocin levels in rhesus macaques, an oxytocin agonist promoted affiliative behavior toward infants by nulliparous females (although the sample sizes were small) (Holman and Goy, 1995), and an oxytocin antagonist reduced interest in infants among nulliparous females (Boccia et al, 2007). In common marmosets, the intracerebral administration of oxytocin to fathers was associated with a reduced rate of rejection of offspring begging for food (Saito and Nakamura, 2011a).…”