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

In the paper

“OXTR expression across primate species has also been found in two major cholinergic regions of the brain: in all four species, in the nucleus basalis of Meynert (NBM) (Fig. 2) and, in rhesus macaques, in the pedunculopontine tegmental nucleus (PPT).”

In the paper

“In the primary visual path from the retina, OXTR has been detected in the superior colliculus (SC), pulvinar (Pv) and primary visual cortex (interestingly, AVPR1a binding has also been detected in many these regions) (Table 1).”

In the paper

“Similar experiments could also be performed in titi monkeys, which are socially monogamous but, unexpectedly, do not exhibit OXTR binding in the NAcc (Fig. 3b).”

In the paper

“The rhesus macaque brain in general exhibits extremely sparse OXTR expression relative to AVPR1a (27,31), with the most dense OXTR binding seen in the NBM and superficial grey layer of the SC (Fig. 2c,f).”

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
• 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

In the paper

“Instead, titi monkeys have AVPR1a expression in the NAcc (Fig. 3c) and extremely dense OXTR binding in the dentate gyrus (Fig. 3d) of the hippocampus (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

“Although these compounds bind selectively to their respective receptors in rodents, they have now been shown to exhibit relatively high affinities for both OXTR and AVPR1a in primates (27,28).”

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
• 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

“The earliest radioligand available for this purpose was a tritiated version of OT (14), although the cross-reactivity of this ligand with the closely-related AVPR1a, combined with long exposure times needed on film before results can be attained, caused it to be an unfavourable and generally inconvenient tool for autoradiographic analysis of the brain.”

What the sources say

• Not checked yetcites [14] Freund-Mercier MJ Stoeckel ME Palacios JM Pazos A Reichhart JM Porte A Richard P Pharmacological characteristics and anatomical distribution of [3H]oxytocin-binding sites in the Wistar rat brain studied by autoradiography Neuroscience 1987 20 599 614 3647280 source

In the paper

“Specifically, there has been a significant gap in the understanding of the neural systems responsive to OT and AVP in primates, and the use of intranasal OT (IN-OT) in humans, in particular, has advanced rapidly despite a lack of knowledge of the mechanism or neurological targets engaged by this manipulation (11-13).”

What the sources say

• Not checked yetcites [11] Walum H Waldman ID Young LJ Statistical and methodological considerations for the interpretation of intranasal oxytocin studies Biol Psychiatry 2015 79 251 257 26210057 PMC4690817 source
• Not checked yetcites [12] Leng G Ludwig M Intranasal oxytocin: myths and delusions Biol Psychiatry 2015 79 243 250 26049207 source
• Not checked yetcites [13] Insel TR Translating oxytocin neuroscience to the clinic: a National Institute of Mental Health perspective Biol Psychiatry 2016 79 153 154 26723108 source

In the paper

“It has been shown that infants, toddlers and adolescents with autism spectrum disorder (ASD) all show disrupted patterns of eye movements in response to images/videos of human faces or naturalistic social scenes, including avoidance of the eye region of faces, atypical fixation targets to the nonsocial aspects of social scenes and a lack of attentional bias toward faces, as measured by faster sacc”

What the sources say

• Not checked yetcites [61] Rice K Moriuchi JM Jones W Klin A Parsing heterogeneity in autism spectrum disorders: visual scanning of dynamic social scenes in school-aged children J Am Acad Child Adolesc Psychiatry 2012 51 238 248 22365460 PMC3306820 source
• Not checked yetcites [62] Chawarska K Volkmar F Klin A Limited attentional bias for faces in toddlers with autism spectrum disorders Arch Gen Psychiatry 2010 67 178 185 20124117 PMC4871149 source
• 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

“These nuclei are major sources of cholinergic input to the rest of the brain (44-46) and are important regulators of selective attention and motivation (47-52).”

What the sources say

• Not checked yetcites [44] Mesulam MM Mufson EJ Levey AI Wainer BH Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey J Comp Neurol 1983 214 170 197 6841683 source
• Not checked yetcites [45] Garcia-Rill E The pedunculopontine nucleus Prog Neurobiol 1991 36 363 389 1887068 source
• Not checked yetcites [46] Jones EG Burton H Saper CB Swanson LW Midbrain, diencephalic and cortical relationships of the basal nucleus of Meynert and associated structures in primates J Comp Neurol 1976 167 385 419 818134 source
• Not checked yetcites [47] Demeter E Sarter M Leveraging the cortical cholinergic system to enhance attention Neuropharmacology 2013 64 294 304 22796110 PMC3445745 source
• Not checked yetcites [48] Sarter M Gehring WJ Kozak R More attention must be paid: the neurobiology of attentional effort Brain Res Rev 2006 51 145 160 16530842 source
• Not checked yetcites [49] Balducci C Nurra M Pietropoli A Samanin R Carli M Reversal of visual attention dysfunction after AMPA lesions of the nucleus basalis magnocellularis (NBM) by the cholinesterase inhibitor donepezil and by a 5-HT1A receptor antagonist WAY 100635 Psychopharmacology 2003 167 28 36 12618916 source
• Not checked yetcites [50] Sarter M Givens B Bruno JP The cognitive neuroscience of sustained attention: where top-down meets bottom-up Brain Res Brain Res Rev 2001 35 146 160 11336780 source
• Not checked yetcites [51] Muir JL Page KJ Sirinathsinghji DJ Robbins TW Everitt BJ Excitotoxic lesions of basal forebrain cholinergic neurons: effects on learning, memory and attention Behav Brain Res 1993 57 123 131 7509608 source
• Not checked yetcites [52] Kobayashi Y Inoue Y Yamamoto M Isa T Aizawa H Contribution of pedunculopontine tegmental nucleus neurons to performance of visually guided saccade tasks in monkeys J Neurophysiol 2002 88 715 731 12163524 source

In the paper

“Furthermore, cholinergic input from the PPT strongly innervates the macaque SC (53), and neurones in the PPT have also been shown to be active in monkeys during saccade tasks (54) and to directly stimulate SC neurones and facilitate the initiation of saccadic eye movements (55).”

What the sources say

• Not checked yetcites [53] Ma TP Graybiel AM Wurtz RH Location of saccade-related neurons in the macaque superior colliculus Exp Brain Res 1991 85 21 35 1715825 source
• Not checked yetcites [54] Okada K-I Kobayashi Y Characterization of oculomotor and visual activities in the primate pedunculopontine tegmental nucleus during visually guided saccade tasks Eur J Neurosci 2009 30 2211 2223 20128856 source
• Not checked yetcites [55] Kobayashi Y Saito Y Isa T Facilitation of saccade initiation by brain-stem cholinergic system Brain Dev 2001 23 Suppl 1 S24 S27 11738837 source

In the paper

“The Pv has also been implicated in the salience of visual stimuli (40).”

What the sources say

• Not checked yetcites [40] Robinson DL Petersen SE The pulvinar and visual salience Trends Neurosci 1992 15 127 132 1374970 source

In the paper

“Activity in the right amygdala was increased in these patients in response to presentation of images of faces with direct gaze compared to averted gaze (38,39), and this activity co-varied in a condition-dependent way with activity in the SC and Pv (38).”

What the sources say

• Not checked yetcites [38] Morris JS DeGelder B Weiskrantz L Dolan RJ Differential extrageniculostriate and amygdala responses to presentation of emotional faces in a cortically blind field Brain 2001 124 1241 1252 11353739 source
• Not checked yetcites [39] Burra N Hervais-Adelman A Kerzel D Tamietto M de Gelder B Pegna AJ Amygdala activation for eye contact despite complete cortical blindness J Neurosci 2013 33 10483 10489 23785160 PMC6618602 source

In the paper

“Furthermore, NBM projects to the amygdala and is the primary source of cholinergic input to the basolateral amygdala (44,46,56,57).”

What the sources say

• Not checked yetcites [44] Mesulam MM Mufson EJ Levey AI Wainer BH Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey J Comp Neurol 1983 214 170 197 6841683 source
• Not checked yetcites [46] Jones EG Burton H Saper CB Swanson LW Midbrain, diencephalic and cortical relationships of the basal nucleus of Meynert and associated structures in primates J Comp Neurol 1976 167 385 419 818134 source
• Not checked yetcites [56] Woolf NJ Butcher LL Cholinergic projections to the basolateral amygdala: a combined Evans Blue and acetylcholinesterase analysis Brain Res Bull 1982 8 751 763 6182963 source
• Not checked yetcites [57] Nagai T Kimura H Maeda T McGeer PL Peng F McGeer EG Cholinergic projections from the basal forebrain of rat to the amygdala J Neurosci 1982 2 513 520 7069469 PMC6564247 source

In the paper

“Titi monkeys, similar to prairie voles, form lasting pair bonds and are highly territorial, which renders this species an excellent primate model for similar questions of nonapeptide function in social and spatial memory.”

In the paper

“This cholinergic input is required for memory consolidation (58,59), possibly promoting the encoding of memory during sustained attention to visual stimuli.”

What the sources say

• Not checked yetcites [58] Power AE Vazdarjanova A McGaugh JL Muscarinic cholinergic influences in memory consolidation Neurobiol Learn Mem 2003 80 178 193 14521862 source
• Not checked yetcites [59] Power AE McGaugh JL Phthalic acid amygdalopetal lesion of the nucleus basalis magnocellularis induces reversible memory deficits in rats Neurobiol Learn Mem 2002 77 372 388 11991764 source

In the paper

“These findings provide new insights into the diversity and conservation of OT and AVP function in the primate brain and contrast with findings from rodent studies.”

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 [93] Smith AS Ågmo A Birnie AK French JA Manipulation of the oxytocin system alters social behavior and attraction in pair-bonding primates, Callithrix penicillata Horm Behav 2010 57 255 262 20025881 PMC2824532 source

In the paper

“Current studies in progress in rhesus macaques have found that OT delivered directly to the NBM changed social looking behaviour, as well as neural activity, in the basolateral amygdala (84), which is an area that lacks OXTR mRNA but receives strong cholinergic input from the NBM.”

What the sources say

• Not checked yetcites [84] Putnam P Zimmerman P Gothard K Oxytocin injected into the nucleus basalis of Meynert of monkeys enhanced basic social behaviors and modulated neural activity in the basolateral nuclei of the amygdala Gordon Research Conference. New Frontiers in Amygdala Research: From Rodent to Man Easton, MA 2015

In the paper

“First, the mixed selectivity issue within the study of OT and AVP in primates suggests that many of the effects of OT could be mediated by AVPR1a, and vice versa.”

In the paper

“This concept is not new; several previous studies suggested that the effects of OT and AVP are a result of the activation of the ‘opposite’ receptor (4,80,86-89).”

What the sources say

• 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
• 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
• Not checked yetcites [86] Ragnauth AK Goodwillie A Brewer C Muglia LJ Pfaff DW Kow L-M Vasopressin stimulates ventromedial hypothalamic neurons via oxytocin receptors in oxytocin gene knockout male and female mice Neuroendocrinology 2004 80 92 99 15528951 source
• Not checked yetcites [87] Gupta J Russell R Wayman C Hurley D Jackson V Oxytocin-induced contractions within rat and rabbit ejaculatory tissues are mediated by vasopressin V1A receptors and not oxytocin receptors Br J Pharmacol 2008 155 118 126 18552879 PMC2527840 source
• Not checked yetcites [88] Schorscher-Petcu A Sotocinal S Ciura S Dupré A Ritchie J Sorge RE Crawley JN Hu S-B Nishimori K Young LJ Tribollet E Quirion R Mogil JS Oxytocin-induced analgesia and scratching are mediated by the vasopressin-1A receptor in the mouse J Neurosci 2010 30 8274 8284 20554879 PMC2902996 source
• Not checked yetcites [89] Song EZ McCann KE McNeill JKIV Huhman KL Albers HE Oxytocin Induces Social Communication in Male Syrian Hamsters by Activating V1a and not OT Receptors Society for Neurosceince Annual Meeting San Diego, CA 2013

In the paper

“Melanotan-II, an MC4R agonist, given peripherally, activates OT neurones and potentiates central OT release following a physiological stimulus (103).”

What the sources say

• 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

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 [95] Boccia ML Goursaud A-PS Bachevalier J Anderson KD Pedersen CA 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 Horm Behav 2007 52 344 351 17583705 PMC2712625 source

In the paper

“New studies are now revealing receptor distributions and developing selective agents.”

In the paper

“IN-OT studies even in humans are often underpowered given the modest effect sizes, making the interpretation of studies with few subjects unreliable (11).”

What the sources say

• Not checked yetcites [11] Walum H Waldman ID Young LJ Statistical and methodological considerations for the interpretation of intranasal oxytocin studies Biol Psychiatry 2015 79 251 257 26210057 PMC4690817 source

In the paper

“Second, NHP can be used to more precisely understand OT function in the brain than is currently possible using IN-OT in humans, which is useful for understanding the mechanisms by which IN-OT influences behaviour.”

In the paper

“These advancements have remarkable implications not only for basic behavioural neurobiology and social neuroscience in NHP, but also for honing pharmacological therapies that may improve social cognition in psychiatric disorders, such as ASD and schizophrenia.”

In the paper

“Neurohypophyseal receptor distributions in NHP display species differences, as well as a conserved core distribution related to the importance of visual processing of social stimuli.”

In the paper

“Although intranasal delivery of OT in NHP more accurately models current human IN-OT studies, this approach does not provide information on whether the effects are mediated by central or peripheral receptors, or whether they are mediated by OXTR or AVPR1a (12).”

What the sources say

• Not checked yetcites [12] Leng G Ludwig M Intranasal oxytocin: myths and delusions Biol Psychiatry 2015 79 243 250 26049207 source

In the paper

“Research on the role of OT and AVP in regulating social behaviour and cognition in NHP is in its infancy, far behind the level of precision found in rodent research.”