Oxytocin (OT) has an ancient role in modulating sensing and responding to social stimuli, from nematodes to man. OT regulates not only mammalian labor and nursing, but also maternal behavior. There is increasing evidence that OT influences human parenting and mediates the impact of parenting on infant socio-emotional development (Rilling and Young, 2014). Preclinical studies suggest that OT increases the salience and rewarding value of social stimuli. OT acts in the rodent amygdala to enhance the salience of social olfactory cues. thereby facilitating social recognition, in the striatum to mediate social reward and in the hippocampus to enhance signal to noise neurotransmission. These fundamental processes likely contribute to more complex OT-mediated behaviors, including social bonding.
The effects of OT on social information processing in rodents make it an enticing pharmacological target for enhancing social cognition. However, two issues introduce skepticism for translating the compelling preclinical observations into effective pharmacotherapies to improve social functioning in psychiatric disorders, including autism and schizophrenia: (1) rodents use olfaction as the primary social perception modality, while primates rely more on visual and auditory social perception; (2) little is known regarding the pharmacokinetics of current OT administration methods or the impact of chronic OT treatment. Recent studies from our laboratory address these issues.
A common polymorphism in the human OT receptor (OXTR) gene predicts face recognition skills in families with a child with autism. This effect was present in all family members in two independent populations, yet there was no evidence of an association with autism diagnosis (Skuse et al, 2014). This study supports a role for the OT system in human visual social information processing analogous to its role in olfactory processing in rodents.
Nonhuman primates are useful for exploring the mechanisms of intranasal OT (IN-OT) administration. We showed that OT administered nasally by a pediatric nebulizer modestly elevates OT in the cerebrospinal fluid of anesthetized macaques (Modi et al, 2014). Importantly, intranasal OT also robustly elevated plasma OT for an extended period of time. Thus IN-OT may increase brain OT signaling, but peripheral mechanisms should be considered.
Comparative studies of brain OXTR distribution in primates reveal the potential mechanisms by which OT modulates social information processing (Freeman et al, 2014a, 2014b). In all primate species examined, OXTRs are concentrated in cholinergic regions involved in visual and auditory processing, including the nucleus basalis of Meynert, which coordinates neural activity in the amygdala and cortex, thereby modulating attention to visual cues.
IN-OT may enhance some aspects of social cognition through the mechanisms described above, but the efficacy may be limited by brain penetration. Stimulating endogenous central OT release pharmacologically is a viable alternative for increasing OT neural signaling. Melanocortin receptor agonists stimulate OT release from hypothalamic slices, potentiate OT release in the ventral striatum, and enhance OT-dependent behavior in prairie voles (unpublished data). Neonatal melanocortin receptor activation acutely activates OT neurons, and daily treatment for the first week of life enhances adult social bonding in prairie voles (Barrett et al, 2014). Thus, the OT system remains an attractive target for clinically enhancing social cognition, and alternative pharmacological strategies for enhancing OT neurotransmission should be explored.
FUNDING AND DISCLOSURE
LJY has applied for a patent (US20120108510—Methods of improving behavioral therapies) for combining melanocortin agonists with behavioral therapies to enhance social cognition in psychiatric disorders.
Acknowledgments
Iwould like to acknowledge NIH grants R01MH096983 and 1P50MH100023 and an Autism Speaks grant #7745. Additional funding was provided by NIH OD P51OD11132 to YNPRC.
References
- Barrett CE, Modi ME, Zhang BC, Walum H, Inoue K, Young LJ (2014). Neonatal melanocortin receptor agonist treatment reduces play fighting and promotes adult attachment in prairie voles in a sex-dependent manner. Neuropharmacology 85C: 357–366. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Freeman SM, Inoue K, Smith AL, Goodman MM, Young LJ (2014a). The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta). Psychoneuroendocrinology 45: 128–141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Freeman SM, Walum H, Inoue K, Smith AL, Goodman MM, Bales KL et al. (2014b). Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus). Neuroscience 273: 12–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Modi ME, Connor-Stroud F, Landgraf R, Young LJ, Parr LA (2014). Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques. Psychoneuroendocrinology 45: 49–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rilling JK, Young LJ (2014). The biology of mammalian parenting and its impact on offspring development. Science 345: 771–776. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Skuse DH, Lori A, Cubells JF, Lee I, Conneely KN, Puura K et al. (2014). Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills. Proceedings of the national academy of sciences of the U 111: 1987–1992. [DOI] [PMC free article] [PubMed] [Google Scholar]