Oxytocin under opioid antagonism leads to supralinear enhancement of social attention

Abstract

To provide new preclinical evidence toward improving the efficacy of oxytocin (OT) in treating social dysfunction, we tested the benefit of administering OT under simultaneously induced opioid antagonism during dyadic gaze interactions in monkeys. OT coadministered with a μ-opioid receptor antagonist, naloxone, invoked a supralinear enhancement of prolonged and selective social attention, producing a stronger effect than the summed effects of each administered separately. These effects were consistently observed when averaging over entire sessions, as well as specifically following events of particular social importance, including mutual eye contact and mutual reward receipt. Furthermore, attention to various facial regions was differentially modulated depending on social context. Using the Allen Institute's transcriptional atlas, we further established the colocalization of μ-opioid and κ-opioid receptor genes and OT genes at the OT-releasing sites in the human brain. These data across monkeys and humans support a regulatory relationship between the OT and opioid systems and suggest that administering OT under opioid antagonism may boost the therapeutic efficacy of OT for enhancing social cognition.T he efficacy of oxytocin (OT) in improving social abilities is under debate, largely due to frequently observed weak effect sizes and problems with replicability (1-3). Clinical trials of OT in autistic patients are ongoing, yet several studies have produced inconclusive results (4-8), demanding improvements to the efficacy and reliability of OT-based therapeutics. One strategy is to take advantage of existing physiological pathways in the brain that regulate OT activity to combinatorially enhance the oxytocinergic effects on social functions. In this regard, a promising candidate is the opioid system.In addition to the evolutionarily conserved OT system (9), the opioid system has been implicated in regulating social behavior. Excessive opioid activity in the brain has been discussed with respect to the development of early childhood autism (10). Abnormalities in central opioid levels have been observed in some individuals with autism, and clinical trials with predominantly μ-opioid blockers, such as naltrexone or naloxone (NAL), have yielded promising results in ameliorating both social and nonsocial deficits (11). Specifically, μ-opioid receptors have been studied in relation to reward, emotion, and behavior in the social domain (12) and are strongly expressed in reward-related regions of the primate brain (13). In rhesus macaques, carrying the G allele of the μ-opioid receptor gene OPRM1, compared with homozygous C alleles, is associated with stronger maternal attachment in infants (14) and more effective prevention of infant separation in mothers (15). Additionally, opioid agonists, such as morphine, decrease physical contact between social partners, whereas NAL administration increases solicitation for social contact, such as grooming and proximity (16)(17)(18)(19).The physiological relationship between the opi...

Empathy modulates the temporal structure of social attention

“…Our findings appear consistent with recent pharmacological work, which indicates that administration of oxytocin (associated with the experience of empathy in humans and mesolimbic dopaminergic activity involved in responding to rewards) predicts maintained periods of eye-contact in macaque monkeys [14]. We speculate the similarity of these findings with our own reflect some common mechanism that promotes prolonged perceptual selection of socially relevant inputs.…”

The role of social cognition in parasite and pathogen avoidance

“…Results of recent studies have also indicated that OT and mu opioids can also influence human social interaction [122]. Changes in mu and kappa opioid activity were similarly associated with the altered responses to female odours of males infected with E. vermiformis as well as the responses of the females to infected males [65].…”

Bridging the gap between rodents and humans: The role of non‐human primates in oxytocin research

“…Recent studies in NHPs have also suggested a regulatory relationship between the opioid and OT systems. When AE OT was paired with a ¼-opioid receptor antagonist, rhesus monkeys increased the number of fixations on a partner monkey, beyond the effect of either OT or the antagonist alone (Dal Monte et al, 2017). The mechanism of this supralinear effect is not yet understood, but this observation strongly suggests that OT may potentiate the effects of neurotransmitter system with broader (and better understood) control over the circuits that govern socio-emotional behavior.…”