Distribution of Oxytocin Receptors and Vasopressin 1a Receptors in the Titi Monkey, an Emerging Animal Model for the Study of Social Attachment

Background: Oxytocin (OT) and vasopressin (AVP) are structurally related neuropeptides that act in the brain to modulate the expression of species-specific social behaviors. Research in this field has plowed ahead to investigate the effects of OT in humans, including individuals with autism spectrum disorder (ASD), despite a lack of understanding of the fundamental neurophysiology of these systems in humans and nonhuman primates (NHP) alike. Studying the brains of NHP provides an opportunity to elucidate the neural mechanisms by which OT and AVP modulate social cognition. The coppery titi monkey is a socially monogamous New World primate that has been used to investigate the behavioral neuroendocrinology of social attachment. By establishing the neurochemical basis of pair bonding in this monogamous species, we can better understand how the brain coordinates complex social behaviors more broadly, such as selective attachment, cooperation, and social memory. This research provides valuable insight into the mechanisms underlying social behavior in humans, which can then lead to the development of better treatments for individuals diagnosed with ASD.

Objectives: To identify the distribution of the oxytocin receptor (OXTR) and vasopressin 1a receptor (AVPR1a) in order to provide a neuroanatomical foundation for the study of these neuropeptides in mediating social behavior in primates.

Methods: We used a pharmacologically optimized, competitive-binding receptor autoradiography protocol to identify the distribution of OXTR and AVPR1a in hemispheres of titi monkey brain (n=5). In this procedure, either the AVPR1a radioligand (¹²⁵I-LVA) or the OXTR radioligand (¹²⁵I-OVTA) was incubated on tissue in one of three conditions: 50 pM radioligand alone, or in the presence of either 10 nM of a selective human AVPR1a ligand (SR49059) or 20 nM of a selective human OTR ligand (ALS-II-69).

Results: The AVPR1a distribution is widespread throughout the brain, but the OTR distribution is much more limited, with the most abundant binding in the hippocampus, dentate gyrus, presubiculum, nucleus basalis of Meynert, and several hindbrain regions. AVPR1a binding exists throughout the cortex (especially cingulate and occipital cortex), as well as in the caudate, putamen, hippocampus, globus pallidus, lateral geniculate nucleus, periaqueductal grey, substantia nigra, olivary nucleus, and cerebellum. Furthermore, we show that ALS-II-69 reduces OXTR radioligand binding by 40-50% without affecting AVPR1a binding, and that SR49049 is capable of reducing AVPR1a radioligand binding by 75% or more, without significantly affecting binding to OXTR.

Conclusions: Both receptors are found in brain regions that modulate visual attention and control orienting responses to visual stimuli. This has important implications for 1) the development of therapies to improve social visual attention and 2) our understanding of neural mechanisms underlying social gaze. Furthermore, both ALS-II-69 and SR49049 emerge as candidates for the pharmacological manipulation of OXTR and AVPR1a in future behavioral experiments in titi monkeys and other primates. These results can ultimately facilitate the development of pharmacological strategies to target the OT and AVP systems for the improvement of social function in individuals with ASD.

Funding: MH090776 and MH64692 to LJY; HD053555 and the Good Nature Institute to KLB; P51OD011107 to CNPRC and P51OD11132 to YNPRC.