Comparative Perspectives on Oxytocin and Vasopressin Receptor Research in Rodents and Primates: Translational Implications

In the paper

“Although MC4R agonists show promise for eliciting OT-mediated behaviours, they also interact with other behaviourally relevant neurochemical systems (23) and thus are not useful tools for isolating OT function.”

What the sources say

• Supported

  The Discussion says MC4R interacts with the dopamine system and activates corticotropin-releasing factor and AVP neurons. It explicitly cautions that the study cannot prove melanocortin-receptor effects on behavior are due to the OT system, supporting the claim that these agonists cannot isolate OT function. (LLM, conf=0.92)

  cites [23] Barrett CE Arambula SE Young LJ The oxytocin system promotes resilience to the effects of neonatal isolation on adult social attachment in female prairie voles Transl Psychiatry 2015 5 e606 26196439 PMC5068726 source

In the paper

“We have also independently confirmed the findings reported by Schorscher-Petcu et al. (2009) for OXTR and AVPR1a binding in the forebrain of the common marmoset (Callithrix jacchus) (S. M. Freeman, unpublished observations).”

What the sources say

• Not checked yetcites Schorscher-Petcu et al. (2009)

In the paper

“We have recently reported the design of a pharmacologically optimised method for competitive binding receptor autoradiography that can selectively and reliably reveal the distributions of OXTR and AVPR1a in primate tissue (27).”

What the sources say

• Not checked yetcites [27] Freeman SM Inoue K Smith AL Goodman MM Young LJ The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta) Psychoneuroendocrinology 2014 45 128 141 24845184 PMC4043226 source

In the paper

“For example, all of the primate species investigated to date have OXTR in the NBM”

In the paper

“In this context, it is not surprising that there is considerable overlap in OXTR expression among primate species in areas that are important for visual processing, shifts in gaze direction and the allocation of attention to visual stimuli (Fig. 1c,d and Table 1).”

In the paper

“In areas involved in saccadic eye movements in response to visual stimuli, OXTR is expressed in the superficial grey layer of the SC (Fig. 2), as well as deeper layers, and in the oculomotor nucleus (III) and the nucleus prepositus, which are two brainstem motor nuclei that control the muscles of the eye and participate in the horizontal gaze stabilisation system, respectively (41-43).”

What the sources say

• Not checked yetcites [41] Büttner-Ennever JA Anatomy of the oculomotor system Dev Ophthalmol 2007 40 1 14 17314476 source
• Not checked yetcites [42] McCrea RA Horn AKE Nucleus prepositus Prog Brain Res 2006 151 205 230 16221590 source
• Not checked yetcites [43] Gandhi NJ Katnani HA Motor functions of the superior colliculus Annu Rev Neurosci 2011 34 205 231 21456962 PMC3641825 source

In the paper

“Additionally, we have mapped OXTR and AVPR1a in the brain of the socially monogamous coppery titi monkey (Callicebus cupreus) (35).”

What the sources say

• Not checked yetcites [35] Freeman SM Walum H Inoue K Smith AL Goodman MM Bales KL Young LJ Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus) Neuroscience 2014 273 12 23 24814726 PMC4083847 source

In the paper

“However, the dense OXTR binding seen in the NAcc of the common marmoset (30) makes marmosets a particularly appropriate choice for exploring the role of OT in social reward, which would complement recent discoveries in mice (25).”

What the sources say

• Not checked yetcites [30] Schorscher-Petcu A Dupré A Tribollet E Distribution of vasopressin and oxytocin binding sites in the brain and upper spinal cord of the common marmoset Neurosci Lett 2009 461 217 222 19539696 source

In the paper

“Accordingly, regions expressing OXTR in the rodent brain are most frequently found in areas of the olfactory pathway (Fig. 1a,b).”

In the paper

“In monogamous titi monkeys, there is remarkably dense OXTR binding in the dentate gyrus of the hippocampus (35), although the function of this population of OXTR is unknown.”

What the sources say

• Not checked yetcites [35] Freeman SM Walum H Inoue K Smith AL Goodman MM Bales KL Young LJ Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus) Neuroscience 2014 273 12 23 24814726 PMC4083847 source

In the paper

“With this method, which combines the use of the radioligands mentioned above with selective competitor ligands, we have now successfully mapped OXTR in the brain of the most common NHP model organism used in biomedical research: the rhesus macaque (Macaca mulatta) (27).”

What the sources say

• Not checked yetcites [27] Freeman SM Inoue K Smith AL Goodman MM Young LJ The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta) Psychoneuroendocrinology 2014 45 128 141 24845184 PMC4043226 source

In the paper

“However, after radiolabelling L-368,899 and performing in vivo PET imaging in macaques, we found that there is minimal uptake in the brain, and the compound appears to accumulate in the ventricles and not in neural tissue (100).”

What the sources say

• Not checked yetcites [100] Smith AL Freeman SM Voll RJ Young LJ Goodman MM Carbon-11 N-methyl alkylation of L-368,899 and in vivo PET imaging investigations for neural oxytocin receptors Bioorg Med Chem Lett 2013 23 902 906 23270988 PMC3756487 source

In the paper

“However, after radiolabelling L-368,899 and performing in vivo PET imaging in macaques, we found that there is minimal uptake in the brain, and the compound appears to accumulate in the ventricles and not in neural tissue (100).”

What the sources say

• Not checked yetcites [100] Smith AL Freeman SM Voll RJ Young LJ Goodman MM Carbon-11 N-methyl alkylation of L-368,899 and in vivo PET imaging investigations for neural oxytocin receptors Bioorg Med Chem Lett 2013 23 902 906 23270988 PMC3756487 source

In the paper

“Unfortunately, these compounds have not been found useful for detecting OXTR binding sites in vivo using PET.”

What the sources say

• Not checked yetcites [91] Smith AL Freeman SM Stehouwer JS Inoue K Voll RJ Young LJ Goodman MM Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors Bioorg Med Chem 2012 20 2721 2738 22425346 PMC3701955 source
• Not checked yetcites [92] Smith AL Freeman SM Voll RJ Young LJ Goodman MM Investigation of an F-18 oxytocin receptor selective ligand via PET imaging Bioorg Med Chem Lett 2013 23 5415 5420 23978650 PMC3955700 source

In the paper

“For example, the highly social and selectively breeding marmoset has dense OXTR in the NAcc (Fig. 3a) similar to that of the prairie vole (30,85).”

What the sources say

• Not checked yetcites [30] Schorscher-Petcu A Dupré A Tribollet E Distribution of vasopressin and oxytocin binding sites in the brain and upper spinal cord of the common marmoset Neurosci Lett 2009 461 217 222 19539696 source
• Not checked yetcites [85] Lim MM Murphy AZ Young LJ Ventral striatopallidal oxytocin and vasopressin V1a receptors in the monogamous prairie vole (Microtus ochrogaster) J Comp Neurol 2004 468 555 570 14689486 source

In the paper

“However, we now know that this region of the macaque brain does not contain detectable levels of OXTR binding (27), although OXTR may be present on NBM terminals in the amygdala.”

What the sources say

• Not checked yetcites [27] Freeman SM Inoue K Smith AL Goodman MM Young LJ The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta) Psychoneuroendocrinology 2014 45 128 141 24845184 PMC4043226 source

In the paper

“Thus, knowing the receptor distributions in the brains of these rodents made it possible to more precisely determine the neural circuits and genetics underlying species-specific social behaviours.”

In the paper

“Research on the neuropeptides oxytocin (OT) and arginine vasopressin (AVP) using various rodent species has provided a wealth of information about the role these peptides play in the expression of species-specific social behaviours.”

In the paper

“Taken together, these studies across several rodent species demonstrate an important modulatory role for OT and AVP in social behaviours, such as maternal responsiveness and defence, social bond formation, and social memory.”

In the paper

“Mice with impaired OT release or signalling display impairments in maternal responsiveness (3,4).”

What the sources say

• Not checked yetcites [3] Jin D Liu H-X Hirai H Torashima T Nagai T Lopatina O Shnayder NA Yamada K Noda M Seike T Fujita K Takasawa S Yokoyama S Koizumi K Shiraishi Y Tanaka S Hashii M Yoshihara T Higashida K Islam MS Yamada N Hayashi K Noguchi N Kato I Okamoto H Matsushima A Salmina A Munesue T Shimizu N Mochida S Asano M Higashida H CD38 is critical for social behaviour by regulating oxytocin secretion Nature 2007 446 41 45 17287729 source
• Not checked yetcites [4] Takayanagi Y Yoshida M Bielsky IF Ross HE Kawamata M Onaka T Yanagisawa T Kimura T Matzuk MM Young LJ Nishimori K Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice Proc Natl Acad Sci USA 2005 102 16096 16101 16249339 PMC1276060 source

In the paper

“Nevertheless, before these pharmacological limitations were fully understood, these radioligands (as well as the older tritiated versions of the endogenous neuropeptides themselves) were used for receptor autoradiography in three primate species: in the common marmoset for OXTR and AVPR1a (29,30), in the rhesus macaque for AVPR1a (31), and in human for OXTR and AVPR1a (32,33).”

What the sources say

• Not checked yetcites [29] Wang Z Toloczko D Young LJ Moody K Newman JD Insel TR Vasopressin in the forebrain of common marmosets (Callithrix jacchus): studies with in situ hybridization, immunocytochemistry and receptor autoradiography Brain Res 1997 768 147 156 9369311 source
• Not checked yetcites [30] Schorscher-Petcu A Dupré A Tribollet E Distribution of vasopressin and oxytocin binding sites in the brain and upper spinal cord of the common marmoset Neurosci Lett 2009 461 217 222 19539696 source
• Not checked yetcites [31] Young LJ Toloczko D Insel TR Localization of vasopressin (V1a) receptor binding and mRNA in the rhesus monkey brain J Neuroendocrinol 1999 11 291 297 10223283 source
• Not checked yetcites [32] Loup F Tribollet E Dubois-Dauphin M Dreifuss JJ Localization of high-affinity binding sites for oxytocin and vasopressin in the human brain. An autoradiographic study Brain Res 1991 555 220 232 1657300 source
• Not checked yetcites [33] Loup F Tribollet E Dubois-Dauphin M Pizzolato G Dreifuss JJ Localization of oxytocin binding sites in the human brainstem and upper spinal cord: an autoradiographic study Brain Res 1989 500 223 230 2557960 source

In the paper

“In prairie voles, site-specific infusion of an OXTR antagonist directly into the nucleus accumbens (NAcc) or the prefrontal cortex, two areas with dense OXTR binding, is sufficient to block the formation of a partner preference (18).”

What the sources say

• Not checked yetcites [18] Young LJ Lim MM Gingrich B Insel TR Cellular mechanisms of social attachment Horm Behav 2001 40 133 138 11534973 source

In the paper

“and resilience to early life stress (23).”

What the sources say

• Not checked yetcites [23] Barrett CE Arambula SE Young LJ The oxytocin system promotes resilience to the effects of neonatal isolation on adult social attachment in female prairie voles Transl Psychiatry 2015 5 e606 26196439 PMC5068726 source

In the paper

“This knowledge gap can be attributed mainly to the loss of binding selectivity when the radioligands 125I-OVTA and 125I-LVA are used in primate tissue.”

In the paper

“Despite the progress in OT and AVP research in rodents, there has been a significant lag in the mapping of neurohypophyseal peptide receptors in the brains of primate species, particularly for OXTR.”

In the paper

“Later, highly selective radiolabelled peptide analogues for OXTR and AVPR1a binding were developed for use in rodent brain tissue (15,16).”

What the sources say

• Not checked yetcites [15] Elands J Barberis C Jard S Tribollet E Dreifuss JJ Bankowski K Manning M Sawyer WH 125I-labelled d(CH2)5[Tyr(Me)2, Thr4, Tyr-NH2(9)] OVT: a selective oxytocin receptor ligand Eur J Pharmacol 1988 147 197 207 2835249 source
• Not checked yetcites [16] Elands J Barberis C Jard S Lammek B Manning M Sawyer WH de Kloet ER 125I-d(CH2)5[Tyr(Me)2, Tyr(NH2)9]AVP: iodination and binding characteristics of a vasopressin receptor ligand FEBS Lett 1988 229 251 255 2964381 source

In the paper

“Interestingly, OXTR binding in the NAcc, which is dense in monogamous prairie voles, is low to absent in the non-monogamous but closely-related meadow and montane voles (19)”

What the sources say

• Not checked yetcites [19] Insel TR Shapiro LE Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles Proc Natl Acad Sci USA 1992 89 5981 5985 1321430 PMC402122 source

In the paper

“Recent research in mice has now shown that OT works in concert with the serotonin system in the NAcc of mice to modulate the rewarding aspects of social interaction (25).”

What the sources say

• Not checked yetcites [25] Dölen G Darvishzadeh A Huang KW Malenka RC Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin Nature 2013 501 179 184 24025838 PMC4091761 source

In the paper

“In monogamous prairie voles (Microtus ochrogaster), OT and AVP interact with the dopamine system to facilitate the formation of pair bonds between mates (2,6).”

What the sources say

• Not checked yetcites [2] Numan M Young LJ Neural mechanisms of mother-infant bonding and pair bonding: similarities, differences, and broader implications Horm Behav 2015 77 98 112 26062432 PMC4671834 source
• Not checked yetcites [6] Johnson ZV Young LJ Neurobiological mechanisms of social attachment and pair bonding Curr Opin Behav Sci 2015 3 38 44 26146650 PMC4486624 source

In the paper

“OXTR and AVP receptor 1a (AVPR1a) knockout mice both have social amnesia and are thus incapable of remembering previously encountered individuals as familiar.”

In the paper

“and individuals with high NAcc OXTR show enhanced social attachment (22)”

What the sources say

• Not checked yetcites [22] King LB Walum H Inoue K Eyrich NW Young LJ Variation in the oxytocin receptor gene predicts brain region specific expression and social attachment Biol Psychiatry 2015 doi:10.1016/j.biopsych.2015.12.008 PMC4909578 26893121 source

In the paper

“Furthermore, individual differences in the density of OXTR in the NAcc in prairie voles have now been shown to be mediated by a single nucleotide polymorphism (SNP) in a regulatory region of the OXTR gene (22)”

What the sources say

• Not checked yetcites [22] King LB Walum H Inoue K Eyrich NW Young LJ Variation in the oxytocin receptor gene predicts brain region specific expression and social attachment Biol Psychiatry 2015 doi:10.1016/j.biopsych.2015.12.008 PMC4909578 26893121 source

In the paper

“However, this rapid expansion of research into the behavioural consequences of OT manipulations in humans and NHP has outpaced our fundamental understanding of primate OT neurobiology.”

In the paper

“Furthermore, an elegant study using a multidisciplinary approach demonstrated that OXTR signalling tunes the auditory cortex to maximally respond to pup vocalisations, which facilitates maternal responsiveness (26).”

What the sources say

• Not checked yetcites [26] Marlin BJ Mitre M D’amour JA Chao MV Froemke RC Oxytocin enables maternal behaviour by balancing cortical inhibition Nature 2015 520 499 504 25874674 PMC4409554 source

In the paper

“and infusions of an OXTR antagonist into the MeA of wild-type mice recapitulates those deficits in social memory (24).”

What the sources say

• Not checked yetcites [24] Ferguson JN Aldag JM Insel TR Young LJ Oxytocin in the medial amygdala is essential for social recognition in the mouse J Neurosci 2001 21 8278 8285 11588199 PMC6763861 source

In the paper

“which suggests that species-specific differences in neural distributions of OXTR can reflect the social organisation of the species (20,21).”

What the sources say

• Not checked yetcites [20] Young LJ Wang Z The neurobiology of pair bonding Nat Neurosci 2004 7 1048 1054 15452576 source
• Not checked yetcites [21] Donaldson ZR Young LJ Oxytocin, vasopressin, and the neurogenetics of sociality Science 2008 322 900 904 18988842 source

In the paper

“The iodinated OXTR radioligand, 125I-ornithine vasotocin analogue (125I-OVTA), and AVPR1a radioligand, 125I-linear vasopressin-1a antagonist (125I-LVA), allowed researchers to quickly and reliably map the central distributions of both OXTR and AVPR1a.”

In the paper

“whereas i.c.v. infusion of oxytocin receptor (OXTR) antagonists delays the onset of maternal responsiveness in parturient dams”

In the paper

“To our knowledge, rodent species with known OXTR and AVPR1a distributions include laboratory mice and rats, hamsters, guinea pigs, the socially monogamous California mouse and the promiscuous deer mouse, a social and a solitary species of tuco-tuco, two species of Central American singing mice, the eusocial naked mole-rat and the solitary Cape mole-rat, and the socially monogamous prairie and pine”

What the sources say

• Not checked yetcites [17] Beery AK Lacey EA Francis DD Oxytocin and vasopressin receptor distributions in a solitary and a social species of tuco-tuco (Ctenomys haigi and Ctenomys sociabilis) J Comp Neurol 2008 507 1847 1859 18271022 source

In the paper

“Work in rats has demonstrated that central OT signalling is crucial for the onset of maternal nurturing behaviour (1,2).”

What the sources say

• Not checked yetcites [1] Rilling JK Young LJ The biology of mammalian parenting and its effect on offspring social development Science 2014 345 771 776 25124431 PMC4306567 source
• Not checked yetcites [2] Numan M Young LJ Neural mechanisms of mother-infant bonding and pair bonding: similarities, differences, and broader implications Horm Behav 2015 77 98 112 26062432 PMC4671834 source

In the paper

“Intracerebroventricular (i.c.v.) infusion of OT facilitates the onset of maternal nurturing in virgin female rats”

In the paper

“The OT and AVP systems are also involved in more subtle aspects of social cognition, including recognising individuals as familiar (8,9).”

What the sources say

• Not checked yetcites [8] Ferguson JN Young LJ Hearn EF Matzuk MM Insel TR Winslow JT Social amnesia in mice lacking the oxytocin gene Nat Genet 2000 25 284 288 10888874 source
• Not checked yetcites [9] Bielsky IF Hu S-B Szegda KL Westphal H Young LJ Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice Neuropsychopharmacology 2004 29 483 493 14647484 source

In the paper

“AVP also facilitates the expression of selective aggression, or mate guarding behaviour, in male prairie voles (7).”

What the sources say

• Not checked yetcites [7] Winslow JT Hastings N Carter CS Harbaugh CR Insel TR A role for central vasopressin in pair bonding in monogamous prairie voles Nature 1993 365 545 548 8413608 source

In the paper

“Infusions of OT directly into the medial amygdala (MeA) of OT knockout mice rescues the social amnesia described above”

What the sources say

• Not checked yetcites [24] Ferguson JN Aldag JM Insel TR Young LJ Oxytocin in the medial amygdala is essential for social recognition in the mouse J Neurosci 2001 21 8278 8285 11588199 PMC6763861 source

In the paper

“Central OT and AVP signalling also modulate the expression of maternal aggression in defence of pups (5).”

What the sources say

• Not checked yetcites [5] Bosch OJ Maternal aggression in rodents: brain oxytocin and vasopressin mediate pup defence Philos Trans R Soc Lond B Biol Sci 2013 368 20130085 24167315 PMC3826214 source

In the paper

“Thus, it is possible that these OT-sensitive cholinergic areas could be mediating some aspects of the changes in eye movements and shifts in visual attention in response to changing social cues in the environment.”

In the paper

“Taken together, it is clear that areas that are involved in the processing of olfactory input and areas that are sensitive to OT are highly co-localised in the rodent brain, providing an ecologically relevant neural circuit for the processing of social information in rodents.”

In the paper

“In primates, the eyes, along with the other components of the face, have developed important functions in social communication (37).”

What the sources say

• Not checked yetcites [37] Emery NJ The eyes have it: the neuroethology, function and evolution of social gaze Neurosci Biobehav Rev 2000 24 581 604 10940436 source

In the paper

“More severe disruptions in eye movements and social visual attention in ASD patients correlate with the intensity of social dysfunction (63,64).”

What the sources say

• Not checked yetcites [63] Jones W Carr K Klin A Absence of preferential looking to the eyes of approaching adults predicts level of social disability in 2-year-old toddlers with autism spectrum disorder Arch Gen Psychiatry 2008 65 946 954 18678799 source
• Not checked yetcites [64] Klin A Jones W Schultz R Volkmar F Cohen D Visual fixation patterns during viewing of naturalistic social situations as predictors of social competence in individuals with autism Arch Gen Psychiatry 2002 59 809 816 12215080 source

In the paper

“In rodents, social interactions are driven mainly by chemical communication and olfactory investigations, such as scent marking and anogenital sniffing.”

In the paper

“For example, in the studies in mice that demonstrated the requirement of OT in the MeA for social memory of a familiar conspecific, social memory was measured by the habituation of time spent in olfactory exploration of the stimulus animal after repeated presentations (8,24).”

What the sources say

• Not checked yetcites [8] Ferguson JN Young LJ Hearn EF Matzuk MM Insel TR Winslow JT Social amnesia in mice lacking the oxytocin gene Nat Genet 2000 25 284 288 10888874 source
• Not checked yetcites [24] Ferguson JN Aldag JM Insel TR Young LJ Oxytocin in the medial amygdala is essential for social recognition in the mouse J Neurosci 2001 21 8278 8285 11588199 PMC6763861 source

In the paper

“OXTR expression across rodent species is observed in the olfactory bulb and accessory olfactory nucleus, as well as downstream regions that receive projections from this primary sensory area and are involved in olfactory processing, including the MeA, central amygdala, bed nucleus of stria terminalis and the piriform cortex.”

In the paper

“Identification of individuals as either kin, a familiar conspecific or an unrelated potential mate of the opposite sex is based on olfactory processing of major urinary proteins (36).”

What the sources say

• Not checked yetcites [36] Brennan PA The nose knows who’s who: chemosensory individuality and mate recognition in mice Horm Behav 2004 46 231 240 15325224 source

In the paper

“Although these efforts give us a preliminary view of the localisation of OXTR and AVPR1a across a few primate species, the results needed to be re-evaluated, confirmed and expanded, given the new knowledge of the lack of selectivity exhibited by the radioligands that were used.”

In the paper

“OXTR is often also expressed in areas that are not involved in olfactory processing but may be involved in the processing of social information, including the lateral septum, hippocampus, NAcc and prefrontal cortex.”

In the paper

“These selective antagonists, given centrally or peripherally, can be used in combination with IN-OT to parse apart the contribution of OXTR and AVPR1a in the brain or in the periphery to the behavioural effects observed after IN-OT treatment.”

In the paper

“This ability of IN-OT to modulate the social attention of macaques is congruent with the OXTR distribution in areas of the brain that are important for gaze direction, eye movements and attention, such as the NBM or the SC.”

In the paper

“Although MC4R agonists show promise for eliciting OT-mediated behaviours, they also interact with other behaviourally relevant neurochemical systems (23) and thus are not useful tools for isolating OT function.”

What the sources say

• Not checked yetcites [23] Barrett CE Arambula SE Young LJ The oxytocin system promotes resilience to the effects of neonatal isolation on adult social attachment in female prairie voles Transl Psychiatry 2015 5 e606 26196439 PMC5068726 source

In the paper

“Thus, with the growing number of IN-OT studies in humans, rhesus and other primates, we need to consider the idea that the effects of intranasal OT may be mediated in part by activation of AVPR1a.”

In the paper

“Indeed, IN-OT has been shown to acutely increase gaze to the eye region of human faces in autistic populations (65,66), although the benefit of chronic or developmental OT exposure is only beginning to be explored (67,68).”

What the sources say

• Not checked yetcites [65] Andari E Duhamel J-R Zalla T Herbrecht E Leboyer M Sirigu A Promoting social behavior with oxytocin in high-functioning autism spectrum disorders Proc Natl Acad Sci USA 2010 107 4389 4394 20160081 PMC2840168 source
• Not checked yetcites [66] Auyeung B Lombardo MV Heinrichs M Chakrabarti B Sule A Deakin JB Bethlehem RAI Dickens L Mooney N Sipple JAN Thiemann P Baron-Cohen S Oxytocin increases eye contact during a real-time, naturalistic social interaction in males with and without autism Transl Psychiatry 2015 5 e507 25668435 PMC4445747 source

In the paper

“The Merck compound L-368,899 is another small molecule OXTR antagonist that has been used in NHP studies (93), has excellent bioavailability after oral administration (94) and has been also reported to accumulate in limbic structures of the brains of rhesus macaques after peripheral injection (95).”

What the sources say

• Not checked yetcites [94] Thompson KL Vincent SH Miller RR Colletti AE Alvaro RF Wallace MA Feeney WP Chiu SH Pharmacokinetics and disposition of the oxytocin receptor antagonist L-368,899 in rats and dogs Drug Metab Dispos 1997 25 1113 1118 9321512

In the paper

“Peripheral MT-II administration also facilitates OT-dependent social bonding in prairie voles and eliminates the social behaviour deficits associated with neonatal social isolation in prairie voles (23,103,104).”

What the sources say

• Not checked yetcites [23] Barrett CE Arambula SE Young LJ The oxytocin system promotes resilience to the effects of neonatal isolation on adult social attachment in female prairie voles Transl Psychiatry 2015 5 e606 26196439 PMC5068726 source
• Not checked yetcites [103] Modi ME Inoue K Barrett CE Kittelberger KA Smith DG Landgraf R Young LJ Melanocortin receptor agonists facilitate oxytocin-dependent partner preference formation in the prairie vole Neuropsychopharmacology 2015 40 1856 1865 25652247 PMC4839509 source
• Not checked yetcites [104] Barrett CE Modi ME Zhang BC Walum H Inoue K Young LJ Neonatal melanocortin receptor agonist treatment reduces play fighting and promotes adult attachment in prairie voles in a sex-dependent manner Neuropharmacology 2014 85 357 366 24923239 PMC4158739 source

In the paper

“In rhesus macaques, three studies have found that treatment with IN-OT impacts social visual attention and looking behaviours in a variety of tasks (77-79).”

What the sources say

• Not checked yetcites [77] Chang SWC Barter JW Ebitz RB Watson KK Platt ML Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta) Proc Natl Acad Sci USA 2012 109 959 964 22215593 PMC3271866 source
• Not checked yetcites [78] Parr LA Modi M Siebert E Young LJ Intranasal oxytocin selectively attenuates rhesus monkeys’ attention to negative facial expressions Psychoneuroendocrinology 2013 38 1748 1756 23490074 PMC3743934 source
• Not checked yetcites [79] Ebitz RB Watson KK Platt ML Oxytocin blunts social vigilance in the rhesus macaque Proc Natl Acad Sci USA 2013 110 11630 11635 23798448 PMC3710816 source

In the paper

“The expression of OXTR in two of the main cholinergic areas of the brain indicates a potential involvement of acetylcholine in the regulation of social behaviour in primates.”

In the paper

“It has also recently been shown that treatment with IN-OT in macaques can alter neural responses to emotional faces (80).”

What the sources say

• Not checked yetcites [80] Liu N Hadj-Bouziane F Jones KB Turchi JN Averbeck BB Ungerleider LG Oxytocin modulates fMRI responses to facial expression in macaques Proc Natl Acad Sci USA 2015 112 E3123 E3130 26015576 PMC4475931 source

In the paper

“There is also growing evidence from genetic studies that specific SNPs in the human OXTR gene are associated with an ASD diagnosis (71).”

What the sources say

• Not checked yetcites [71] LoParo D Waldman ID The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis Mol Psychiatry 2015 20 640 646 25092245 source

In the paper

“Previous studies have highlighted the importance of using selective ligands when probing the OXTR and AVPR1a systems in primates as a result of the high levels of homology between OT and AVP themselves, as well as their receptors.”

In the paper

“Peripheral MT-II administration also facilitates OT-dependent social bonding in prairie voles and eliminates the social behaviour deficits associated with neonatal social isolation in prairie voles (23,103,104).”

What the sources say

• Not checked yetcites [23] Barrett CE Arambula SE Young LJ The oxytocin system promotes resilience to the effects of neonatal isolation on adult social attachment in female prairie voles Transl Psychiatry 2015 5 e606 26196439 PMC5068726 source
• Not checked yetcites [103] Modi ME Inoue K Barrett CE Kittelberger KA Smith DG Landgraf R Young LJ Melanocortin receptor agonists facilitate oxytocin-dependent partner preference formation in the prairie vole Neuropsychopharmacology 2015 40 1856 1865 25652247 PMC4839509 source
• Not checked yetcites [104] Barrett CE Modi ME Zhang BC Walum H Inoue K Young LJ Neonatal melanocortin receptor agonist treatment reduces play fighting and promotes adult attachment in prairie voles in a sex-dependent manner Neuropharmacology 2014 85 357 366 24923239 PMC4158739 source

In the paper

“Although the central OXTR distribution in NHP may or may not be predictive of that of humans, given the remarkable species differences in receptor distribution, evidence is building from behavioural studies in both humans (76) and NHP that IN-OT is capable of altering social visual attention.”

What the sources say

• Not checked yetcites [76] Tollenaar MS Chatzimanoli M van der Wee NJA Putman P Enhanced orienting of attention in response to emotional gaze cues after oxytocin administration in healthy young men Psychoneuroendocrinology 2013 38 1797 1802 23562249 source

In the paper

“There is one report of decreased OXTR mRNA in cortical tissue in a very small sample of ASD subjects (75).”

What the sources say

• Not checked yetcites [75] Gregory SG Connelly JJ Towers AJ Genomic and epigenetic evidence for oxytocin receptor deficiency in autism BMC Med 2009 7 62 19845972 PMC2774338 source

In the paper

“For example, melanocortin receptor 4 (MC4R) signalling has been shown to evoke OT release in hypothalamic slices in the rat (102).”

What the sources say

• Not checked yetcites [102] Sabatier N Caquineau C Dayanithi G Bull P Douglas AJ Guan XMM Jiang M Van der Ploeg L Leng G Alpha-melanocyte-stimulating hormone stimulates oxytocin release from the dendrites of hypothalamic neurons while inhibiting oxytocin release from their terminals in the neurohypophysis J Neurosci 2003 23 10351 10358 14614094 PMC6741015 source

In the paper

“ALS-II-69 was evaluated in previous studies and shown to effectively block OXTR radioligand binding to primate brain tissue (27).”

What the sources say

• Not checked yetcites [27] Freeman SM Inoue K Smith AL Goodman MM Young LJ The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta) Psychoneuroendocrinology 2014 45 128 141 24845184 PMC4043226 source

In the paper

“Species differences in receptor binding characteristics vary widely, especially in light of recent discoveries in New World monkeys, which show genetic variations in both the OT and AVP peptide and receptor genes across species (105-110).”

What the sources say

• Not checked yetcites [105] Ren D Lu G Moriyama H Mustoe AC Harrison EB French JA Genetic diversity in oxytocin ligands and receptors in New World monkeys PLoS ONE 2015 10 e0125775 25938568 PMC4418824 source
• Not checked yetcites [106] Ren D Chin KR French JA Molecular variation in AVP and AVPR1a in New World monkeys (Primates, Platyrrhini): evolution and implications for social monogamy PLoS ONE 2014 9 e111638 25360668 PMC4216101 source
• Not checked yetcites [107] Vargas-Pinilla P Paixão-Côrtes VR Paré P Tovo-Rodrigues L Vieira CM Xavier A Comas D Pissinatti A Sinigaglia M Rigo MM Vieira GF Lucion AB Salzano FM Bortolini MC Evolutionary pattern in the OXT-OXTR system in primates: coevolution and positive selection footprints Proc Natl Acad Sci USA 2015 112 88 93 25535371 PMC4291646 source
• Not checked yetcites [108] Lee AG Cool DR Grunwald WC Neal DE Buckmaster CL Cheng MY Hyde SA Lyons DM Parker KJ A novel form of oxytocin in New World monkeys Biol Lett 2011 7 584 587 21411453 PMC3130245 source
• Not checked yetcites [109] Babb PL Fernandez-Duque E Schurr TG Oxytocin receptor gene sequences in owl monkeys and other primates show remarkable inter-specific regulatory and protein coding variation Mol Phylogenet Evol 2015 91 160 177 26025428 source
• Not checked yetcites [110] Wallis M Molecular evolution of the neurohypophysial hormone precursors in mammals: comparative genomics reveals novel mammalian oxytocin and vasopressin analogues Gen Comp Endocrinol 2012 179 313 318 22995712 source

In the paper

“OT and AVP research in NHP has been faced with challenges related to a lack of knowledge of receptor distributions and of selective pharmacological agents.”

In the paper

“Site-specific OT manipulations in receptor containing areas with selective agonists or antagonists can provide even greater precision for clarifying brain mechanisms.”

In the paper

“Finally, combining site-specific manipulations with electrophysiological recording and behavioural analysis has the potential to provide a level of understanding of OT function that is currently only available in rodents.”

In the paper

“Those core conserved receptor populations may be most informative for translational studies that inform human OT neurobiology.”

In the paper

“This information, combined with standard NHP techniques such as electrophysiology, have poised NHP to provide novel, mechanistic insights into how the OT and AVP systems modulate social sensory systems.”

In the paper

“Simply comparing the binding characteristics of the most common ligands for the human and rat OT and AVP receptors reveals considerable variation in pharmacological properties across species (28).”

What the sources say

• Not checked yetcites [28] Manning M Misicka A Olma A Bankowski K Stoev S Chini B Durroux T Mouillac B Corbani M Guillon G Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics J Neuroendocrinol 2012 24 609 628 22375852 PMC3490377 source

In the paper

“NHP provide the opportunity to go far beyond what is possible in humans, with direct central neuropeptide administration or with IN-OT in combination with central selective antagonist administration to identify the central mechanisms of action.”

In the paper

“Species differences in receptor binding characteristics vary widely, especially in light of recent discoveries in New World monkeys, which show genetic variations in both the OT and AVP peptide and receptor genes across species (105-110).”

What the sources say

• Not checked yetcites [105] Ren D Lu G Moriyama H Mustoe AC Harrison EB French JA Genetic diversity in oxytocin ligands and receptors in New World monkeys PLoS ONE 2015 10 e0125775 25938568 PMC4418824 source
• Not checked yetcites [106] Ren D Chin KR French JA Molecular variation in AVP and AVPR1a in New World monkeys (Primates, Platyrrhini): evolution and implications for social monogamy PLoS ONE 2014 9 e111638 25360668 PMC4216101 source
• Not checked yetcites [107] Vargas-Pinilla P Paixão-Côrtes VR Paré P Tovo-Rodrigues L Vieira CM Xavier A Comas D Pissinatti A Sinigaglia M Rigo MM Vieira GF Lucion AB Salzano FM Bortolini MC Evolutionary pattern in the OXT-OXTR system in primates: coevolution and positive selection footprints Proc Natl Acad Sci USA 2015 112 88 93 25535371 PMC4291646 source
• Not checked yetcites [108] Lee AG Cool DR Grunwald WC Neal DE Buckmaster CL Cheng MY Hyde SA Lyons DM Parker KJ A novel form of oxytocin in New World monkeys Biol Lett 2011 7 584 587 21411453 PMC3130245 source
• Not checked yetcites [109] Babb PL Fernandez-Duque E Schurr TG Oxytocin receptor gene sequences in owl monkeys and other primates show remarkable inter-specific regulatory and protein coding variation Mol Phylogenet Evol 2015 91 160 177 26025428 source
• Not checked yetcites [110] Wallis M Molecular evolution of the neurohypophysial hormone precursors in mammals: comparative genomics reveals novel mammalian oxytocin and vasopressin analogues Gen Comp Endocrinol 2012 179 313 318 22995712 source