Neural correlates and effect of jealousy on cognitive flexibility in the female titi monkey (Plecturocebus cupreus).

Jealousy is a social emotion that manifests as behavioral reactions from an individual toward a threat to a valuable relationship. Monogamous species exhibit jealousy-type behaviors as an adaptive response to preserve the relationship. Jealousy is also a complex, negatively-valenced emotion which may include fear of loss, anxiety, suspiciousness, and anger. Negative emotion may impair cognitive processes such as cognitive flexibility, an ability important for coping with new situations. However, little is known about how complex social emotions influence cognitive flexibility. To understand the interaction between jealousy and cognitive flexibility, we examined the neural, physiological, and behavioral factors involved in jealousy and cognitive flexibility in female titi monkeys. We presented subjects with a jealousy provoking scenario, followed by a reversal learning task and a PET scan with a glucose-analog radiotracer. We found that female titi monkeys reacted to a jealousy provoking scenario with increased locomotor behavior and higher glucose uptake in the cerebellum; however, hormone measures and were not affected. As only two females demonstrated cognitive flexibility, the effects of jealousy were difficult to interpret. Locomotion behavior was also negatively correlated with glucose uptake in brain areas linked with motivation, sociality, and cognitive flexibility. Surprisingly, glucose uptake in the orbitofrontal cortex (OFC) was significantly decreased during jealousy scenarios, while uptake in the anterior cingulate cortex (ACC) was decreased during reversal tasks. Our findings suggest that the presence of an intruder produces less visible behavioral reactions in female titis than in males, while still reducing activity in the OFC.

Long term effects of chronic intranasal oxytocin on adult pair bonding behavior and brain glucose uptake in titi monkeys (Plecturocebus cupreus).

Intranasal oxytocin (IN OXT) administration has been proposed as a pharmacological treatment for a range of biomedical conditions including neurodevelopmental disorders. However, studies evaluating the potential long-lasting effects of chronic IN OXT during development are still scarce. Here we conducted a follow-up study of a cohort of adult titi monkeys that received intranasal oxytocin 0.8 IU/kg (n = 15) or saline (n = 14) daily for six months during their juvenile period (12 to 18 months of age), with the goal of evaluating the potential long-lasting behavioral and neural effects one year post-treatment. Subjects were paired with an opposite-sex mate at 30 months of age (one year post-treatment). We examined pair affiliative behavior in the home cage during the first four months and tested for behavioral components of pair bonding at one week and four months post-pairing. We assessed long-term changes in brain glucose uptake using 18FDG positron emission tomography (PET) scans. Our results showed that OXT-treated animals were more affiliative across a number of measures, including tail twining, compared to SAL treated subjects (tail twining is considered the "highest" type of affiliation in titi monkeys). Neuroimaging showed no treatment differences in glucose uptake between SAL and OXT-treated animals; however, females showed higher glucose uptake in whole brain at 23 months, and in both the whole brain and the social salience network at 33 months of age compared to males. Our results suggest that chronic IN OXT administration during development can have long-term effects on adult social behavior.

Prenatal Stress as a Risk-and an Opportunity-Factor.

Two separate lines of research indicate (a) that prenatal stress is associated with heightened behavioral and physiological reactivity and (b) that these postnatal phenotypes are associated with increased susceptibility to both positive and negative developmental experiences. Therefore, prenatal stress may increase sensitivity to the rearing environment. We tested this hypothesis by manipulating prenatal stress and rearing-environment quality, using a cross-fostering paradigm, in prairie voles. Results showed that prenatally stressed voles, as adults, displayed the highest behavioral and physiological reactivity when cross-fostered to low-contact (i.e., low-quality) rearing but the lowest behavioral and physiological reactivity when cross-fostered to high-contact (i.e., high-quality) rearing; non-prenatally stressed voles showed no effect of rearing condition. Additionally, while neither prenatal stress nor rearing condition affected oxytocin receptor binding, prenatally stressed voles cross-fostered to high-contact rearing showed the highest vasopressin-1a receptor binding in the amygdala. Results indicate that prenatal stress induces greater environmental sensitivity, making it both a risk and an opportunity factor.

Oxytocin, vasopressin, and primate behavior: Diversity and insight.

It has become increasingly clear that the nonapeptide hormones oxytocin and vasopressin have more diverse behavioral and physiological effects across species and across individuals than was initially recognized. To reflect this variation, we would like to introduce our Special Issue, entitled Oxytocin and Vasopressin in Primate Behavior, by celebrating the diversity that is found across the articles within it. While every article directly addresses the topic of this Special Issue, they also vary in many characteristics: the species studied, the methods used, and the perspectives taken. By highlighting the interesting ways in which these articles differ from one another, we can gain unique insights into the subject that ties them together: our understanding of oxytocin and vasopressin and the behavior of primates. Nonhuman primates are critical intermediates between rodents and humans and are the best models for human biology and behavior, especially with respect to complex cognitive social constructs, such as visual social attention, face processing, and vocal communication. While rodent studies have laid an important and foundational framework for our understanding of nonapeptides, brains, and behavior, these studies cannot fully recapitulate human phenomena. Therefore, we hope the articles presented here contribute to a greater understanding on the role of oxytocin and vasopressin in primate physiology and behavior and help to further advance the application of this knowledge to human biology.

Effect of reward type on object discrimination learning in socially monogamous coppery titi monkeys (Callicebus cupreus).

Highly valued food items are often used as rewards to reinforce an animal's behavior. For social species, social interaction is rewarding and can drive an individual's behavior as well. In the currently study, we wanted to compare the efficacy of a food reward and a social reward on object discrimination learning in socially monogamous titi monkeys. We hypothesized that titi monkeys would perform more accurately for a social reward (their pair mate) than for a food reward (a highly desired food item). Eleven adult titi monkeys were tested with a two-object visual discrimination task for both types of reward. The colors and shapes of the objects in the two-object discrimination task were counterbalanced across subjects. During each trial, subjects were shown two objects, and the trial ended when the subject touched the reinforced shape (S+) or after 5 min. A correct trial was defined as one when the subject touched S+ first. We found that 45.5% of subjects were able to learn the task with a social reward, and 83.3% were able to learn the task with a food reward. We found that subjects balked more often and had fewer correct trials for the social reward. Finally, subjects took longer to approach the shapes for a social reward, possibly indicating lower motivation to engage in the task when a social reward is used compared to a food reward. Although significantly fewer subjects met criteria of success with the social reward than with the food reward, our results show that titi monkeys can learn a visual discrimination task with either type of reward.

An evaluation of central penetration from a peripherally administered oxytocin receptor selective antagonist in nonhuman primates.

The physiology of the oxytocin receptor has increasingly become a focus of scientific investigation due to its connection with social behavior and psychiatric disorders with impairments in social funciton. Experimental utilization of small molecule and peptide antagonists for the oxytocin receptor has played a role in deciphering these biological and social behavior connections in rodents. Described herein is the evaluation of a potent and selective oxytocin receptor antagonist, ALS-I-41, and details to consider for its use in nonhuman primate behavioral pharmacology experiments utilizing intranasal or intramuscular administration. The central nervous system penetration and rate of metabolism of ALS-I-41 was investigated via mass spectroscopy analysis of cerebrospinal fluid and plasma in the rhesus macaque after intranasal and intramuscular administration. Positron emission tomography was also utilized with [18F] ALS-I-41 in a macaque to verify observed central nervous system (CNS) penetration and to further evaluate the effects of administration rate on CNS penetration of Sprague-Dawley rats in comparison to previous studies.

Initial investigation of three selective and potent small molecule oxytocin receptor PET ligands in New World monkeys.

The neuropeptide oxytocin is part of a neuroendocrine system that has physiological effects ranging from ensuring uterine myometrial contractions at parturition and post-partum mammary gland milk ejection to the modulation of neural control of social relationships. This initial study was performed to investigate the potential use of positron emission tomography (PET) for localizing oxytocin receptors in two New World primates. Three biomarkers for PET (1-3) that are known to have high affinity and selectivity for the human oxytocin receptor were investigated in the common marmoset (Callithrix jacchus) via PET imaging. Brain penetration, and uptake in the salivary gland area were both observed with biomarkers 2 and 3. No brain penetration was observed with 1, but uptake was observed more specifically in several peripheral endocrine glands compared to 2 or 3. Biomarker 2, which displayed the best brain penetration of the three biomarkers in the marmoset, was then investigated in the monogamous coppery titi monkey (Callicebus cupreus) in a brain scan and a limited full body scan. No significant brain penetration of 2 was observed in the titi monkey, but significant uptake was observed in various locations throughout the periphery. Metabolism of 2 was suspected to have been significant based upon HPLC analysis of blood draws, but parent compound was still present near the end of the scan. Follow-up investigations will focus on next generation biomarkers bearing improved binding characteristics and brain penetrability as well as investigating tissue in regions where biomarker uptake was observed.

Development of a partner preference test that differentiates between established pair bonds and other relationships in socially monogamous titi monkeys (Callicebus cupreus).

Partner preference, or the selective social preference for a pair mate, is a key behavioral indicator of social monogamy. Standardized partner preference testing has been used extensively in rodents but a single test has not been standardized for primates. The goal of this study was to develop a partner preference test with socially monogamous titi monkeys (Callicebus cupreus) adapted from the widely used rodent test. In Experiment 1, we evaluated the test with pairs of titi monkeys (N = 12) in a three-chambered apparatus for 3 hr. The subject was placed in the middle chamber, with grated windows separating it from its partner on one side and an opposite sex stranger on the other side. Subjects spent a greater proportion of time in proximity to their partners' windows than the strangers', indicating a consistent preference for the partner over the stranger. Touching either window did not differ between partners and strangers, suggesting it was not a reliable measure of partner preference. Subjects chose their partner more than the stranger during catch and release sessions at the end of the test. In Experiment 2, we compared responses of females with current partners (N = 12) in the preference test with other relationship types representing former attachment bonds (N = 13) and no attachment bond (N = 8). Only females from established pair bonds spent significantly more time near their partner's window compared to the stranger's indicating that this measure of preference was unique to current partners. Other measures of preference did not differentiate behavior toward a current partner and other relationship types. This test reproduces behavioral patterns found in previous studies in titi monkeys highlighting the accuracy of this new partner preference test. This test can be used as a standardized measure of partner preference in titi monkeys to quantitatively study pair bonding and evaluate factors influencing partner preference.

Effects of Dietary Fiber on Short Chain Fatty Acid Receptor mRNA in Microglia and Serotonergic Neurons in the Mouse Brain.

Short-chain fatty acids (SCFAs) are bioactive lipids that are released into the colon as a metabolite of bacterial fermentation of dietary fibers. Beyond their function in the gastrointestinal tract, SCFAs can also have effects inthe brain, as a part of the gut-brain axis. Recent investigations into potential therapeutic interventions via the manipulation of the gut microbiome-and thus their SCFA metabolites-has been emerging as a new branch of personalized medicine,especially for mental health conditions. The current study sought to measure and localize SCFA receptors in the mouse brain. Two cell types have been implicated in the gut-brain axis: microglia and serotonergic neurons. We used fluorescentin situhybridization in brain sections from mice fed diets with different compositions of fat and fiber to quantify the mRNA levels of known gene markers of these two cell types and colocalize each with mRNA for free fatty acid receptors that bind SCFAs. We focused onmicroglia in the hippocampus and the serotonergic neurons of the dorsal raphe. We found high colocalization of SCFA receptors in both microglia and serotonergic neurons and discovered that SCFA receptor expression in the dorsal raphe is driven by fiber solubility, while SCFA receptor expression in the hippocampus is driven by fiber amount. Higher dietary fiber was associated with decreased tyrosine hydroxylase expression. Thus, our results indicate that the amount and solubility of dietary fiber can change gene expression in the brain's microglia and serotonin neurons, potentially via sensitivity to circulating levels of SCFAs produced in the gut.

Expression of bond-related behaviors affects titi monkey responsiveness to oxytocin and vasopressin treatments.

Social bonds influence physiology and behavior, which can shape how individuals respond to physical and affective challenges. Coppery titi monkey (Plecturocebus cupreus) offspring form selective bonds with their fathers, making them ideal for investigating how father-daughter bonds influence juveniles' responses to oxytocin (OT) and arginine-vasopressin (AVP) manipulations. We quantified the expression of father-daughter bond-related behaviors in females (n = 10) and gave acute intranasal treatments of saline, low/medium/high OT, low/high AVP, or an OT receptor antagonist (OTA) to subjects prior to a parent preference test. While females spent more time in proximity to their parents than strangers, we found a large degree of individual variation. Females with greater expression of bonding behaviors responded to OT treatments in a dose-dependent manner. Subjects also spent less time in proximity to strangers when treated with High OT (p = 0.003) and Low OT (p = 0.007), but more time when treated with High AVP (p = 0.007), Low AVP (p = 0.009), and OTA (p = 0.001). Findings from the present study suggest that variation in the expression of bond-related behaviors may alter responsiveness to OT and AVP, increasing engagement with unfamiliar social others. This enhanced sociality with strangers may promote the formation of pair bonds with partners.

Binding Affinity, Selectivity, and Pharmacokinetics of the Oxytocin Receptor Antagonist L-368,899 in the Coyote (Canis latrans).

L-368,899 is a selective small-molecule oxytocin receptor (OXTR) antagonist originally developed in the 1990s to prevent preterm labor. Although its utility for that purpose was limited, L-368,899 is now one of the most commonly used drugs in animal research for the selective blockade of neural OXTR after peripheral delivery. A growing number of rodent and primate studies have used L-368,899 to evaluate whether certain behaviors are oxytocin dependent. These studies have improved our understanding of oxytocin's function in the brains of rodents and monkeys, but very little work has been done in other mammals, and only a single paper in macaques has provided any evidence that L-368,899 can be detected in the CNS after peripheral delivery. The current study sought to extend those findings in a novel species: coyotes ( Canis latrans ). Coyotes are ubiquitous North American canids that form long-term monogamous pair-bonds. Although monogamy is rare in rodents and primates, all wild canid species studied to date exhibit social monogamy. Coyotes are therefore an excellent model organism for the study of oxytocin and social bonds. Our goal was to determine whether L-368,899 is a viable candidate for future use in behavioral studies in coyotes. We used captive coyotes at the USDA National Wildlife Research Center's Predator Research Facility to evaluate the pharmacokinetics of L-368,899 in blood and CSF during a 90-min time course after intramuscular injection. We then characterized the binding affinity and selectivity of L-368,899 to coyote OXTR and the structurally similar vasopressin 1a receptor. We found that L-368,899 peaked in CSF at 15 to 30 min after intramuscular injection and slowly accumulated in blood. L-368,899 was 40 times more selective for OXTR than vasopressin 1a receptors and bound to the coyote OXTR with an affinity of 12 nM. These features of L-368,899 support its utility in future studies to probe the oxytocin system of coyotes.

Carbon-11 N-methyl alkylation of L-368,899 and in vivo PET imaging investigations for neural oxytocin receptors.

Compound L-368,899 was successfully alkylated with [(11)C]iodomethane to generate the oxytocin receptor selective (2R)-2-amino-N-((2S)-7,7-dimethyl-1-(((4-(o-tolyl)piperazin-1-yl)sulfonyl)methyl)bicyclo[2.2.1]heptan-2-yl)-N-[(11)C]methyl-3-(methylsulfonyl)propanamide ([(11)C]1) with very high radiochemical purity and high specific activity. PET imaging studies were performed with [(11)C]1 to investigate brain penetration and oxytocin receptor uptake using rat and cynomolgus monkey models. For rat baseline scans, brain penetration was observed with [(11)C]1, but no specific uptake could be distinguished in the brain region. By administering a peptide oxytocin receptor selective antagonist for peripheral blocking of oxytocin receptors, the uptake of [(11)C]1 was amplified in the rat brain temporarily to enable some visual uptake within the rat brain. A baseline scan of [(11)C]1 in a cynomolgus monkey model resulted in no detectable specific uptake in anticipated regions, but activity did accumulate in the choroid plexus.

Investigation of an F-18 oxytocin receptor selective ligand via PET imaging.

The compound 1-(1-(2-(2-(2-fluoroethoxy)-4-(piperidin-4-yloxy)phenyl)acetyl)piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (1) was synthesized and positively evaluated in vitro for high potency and selectivity with human oxytocin receptors. The positron emitting analogue, [F-18]1, was synthesized and investigated in vivo via PET imaging using rat and cynomolgus monkey models. PET imaging studies in female Sprague-Dawley rats suggested [F-18]1 reached the brain and accumulated in various regions of the brain, but washed out too rapidly for adequate quantification and localization. In vivo PET imaging studies in a male cynomolgus monkey suggested [F-18]1 had limited brain penetration while specific uptake of radioactivity significantly accumulated within the vasculature of the cerebral ventricles in areas representative of the choroid plexus.

Can a traditional partner preference test quantify monogamous behavior in captive coyotes?

Social monogamy is a unique social system exhibited by only 3-5% of mammalian taxa; however, all wild canid species exhibit this social system. Despite the high prevalence of social monogamy among canids, little is known about how they form selective social attachment relationships among non-kin. Thus, we aimed to quantify monogamous behavior in a highly ubiquitous canid, the coyote (Canis latrans). We adapted the three-chambered partner preference test, which was originally developed for prairie voles (Microtus ochrogaster), to assess social preference in mated pairs of captive coyotes at the USDA Predator Research Facility. We quantified monogamy-related behaviors, such as time spent in spatial proximity to a pair-mate versus a stranger. Our behavioral ethogram also included visual seeking, olfactory investigations, ears down, scent marking, and affiliative behavior. Test subjects showed significantly greater affiliative behavior toward their partner than toward a stranger. However, there was extremely high variability both within and between coyote pairs across behavioral measures. These data suggest the need for larger sample sizes when working with species with high individual variability, as well as the need for species- and facility-specific modifications to this testing paradigm and/or ethogram to better adapt it from its laboratory and rodent-based origins.

Neural and behavioral reactions to partners and strangers in monogamous female titi monkeys (Plecturocebus cupreus).

Pair bonding in humans and other socially monogamous species can have positive effects on health and well-being. These attachments also come with the potential for challenges such as separation, jealousy, or grief. Much of the work on the neurobiology of pair bonding in non-human primates has been carried out in coppery titi monkeys (Plecturocebus cupreus), a monogamous South American monkey, although these studies have been primarily in males. In the current study, we utilized female titi monkeys to experimentally examine responses to their monogamous male partner vs. a male stranger or being alone. Positron emission tomography (PET) scans were performed on eight adult female titi monkeys from well-established pairs. We used a within-subjects design in which each female underwent three different conditions after the fluorodeoxyglucose F18 (FDG) injection: a) the subject was reunited with her partner, b) encountered a stranger, or c) was alone in the experimental cage. Behavioural observations were recorded, and plasma assayed for cortisol. Females housed alone showed higher cortisol compared with either the partner or stranger conditions. FDG uptake was higher in the amygdala and hippocampus when interacting with the stranger than the partner. Proximity modulated the relationship between social condition and FDG uptake in several areas. Females entered into mutual proximity more frequently with the partner than with the stranger. Female titi monkeys have different physiological, neural, and behavioural reactions to being with their partner, a stranger male, or being alone.

Parental experience is linked with lower vasopressin receptor 1a binding and decreased postpartum androgens in titi monkeys.

Parenting induces many neurological and behavioral changes that enable parents to rear offspring. Vasopressin plays an important role in this process via its effects on cognition, affect, and neuroplasticity, and in some cases, via interactions with decreased parental androgens. Thus far, the role of these hormones has been primarily studied in rodents. To address this gap, we explored vasopressin receptors and androgens in titi monkeys, a pair-bonding and biparental primate species. In Studies 1 and 2, we used receptor autoradiography to correlate arginine vasopressin receptor 1a (AVPR1a) binding in the hippocampus (Study 1, n = 10) and the rest of the forebrain (Study 2, n = 23) with parental status, parental experience, parity, infant carrying, and pair affiliation. We found that parents exhibited lower AVPR1a binding than non-parents throughout most brain regions assessed, with especially strong effects in the hippocampus (ß = -.61), superior colliculus (ß = -.88), lateral septum (ß = -.35), and medial preoptic area (ß = -.29). The other measures of parental experience also tended to be negatively associated with AVPR1a binding across different brain regions. In Study 3 (n = 44), we compared pre- and postpartum urinary androgen levels in parents and non-parents and found that mothers exhibited a sustained androgen decrease across 3-4 months postpartum (relative to 3 months prepartum; ß ranged from -.72 to -.62 for different comparisons). For males, we found that multiparous fathers exhibited decreased androgen levels at 1-2 weeks postpartum (ß = -.25) and at 3-4 months postpartum (ß = -.40) compared to the prepartum, indicating both immediate and long-term reductions with subsequent paternal experience. Together, the results of this study suggest that decreases in AVPR1a binding and circulating androgens are associated with parental behavior and physiology in titi monkeys.

Intranasal oxytocin does not change partner preference in female titi monkeys (Plecturocebus cupreus), but intranasal vasopressin decreases it.

Strong social bonds are critical to human health; however, the mechanisms by which social bonds are formed and maintained are still being elucidated. The neurohormones oxytocin (OT) and vasopressin (AVP) are considered likely candidates. Primate females, both human and nonhuman, remain understudied populations. Here, we conducted a pharmacological study coupled with a behavioral partner preference test (PPT) to better understand the mechanistic basis of attachment in adult female titi monkeys (Plecturocebus cupreus). This pair-bonding species shares a conserved form of oxytocin with humans and is an excellent model organism to study the neural basis of social bonding. We performed intranasal administration of three doses of oxytocin (IN-OT), two doses of vasopressin (IN-AVP), one dose of an oxytocin antagonist (IN-OTA) and one dose of a saline treatment. We found that compared to the saline control, the IN-AVP treatment (lower dose, 40 IU/kg) decreased the time spent in proximity to the partner and increased lip-smacking toward the stranger. We found no effects of IN-OT or IN-OTA manipulation on partner preference. In contrast, low-dose IN-AVP weakened the partner preference in female titi monkeys.

Titi monkey father-daughter bond-related behaviors explain stress response variability.

Social interactions regulate our behavior and physiology, and strong social bonds can buffer us from stress. Coppery titi monkeys (Plecturocebus cupreus) are socially monogamous South American monkeys that display strong social bonds. Infants form selective bonds with their fathers, making them ideal for studying father-daughter bonds. We established a method for quantifying variability in expression of bond-related behaviors in females (n = 12), and the present study is the second to use this method for explaining titi monkey responses to behavioral tests. We also investigated how manipulations of oxytocin (OT) and vasopressin (AVP) influenced juvenile behavior and physiology. Subjects received acute intranasal treatments of saline, low/medium/high OT, low/high AVP, or OT receptor antagonist (OTA) prior to an acute social separation. General linear mixed-effects model results revealed fathers were significant behavioral and physiological stress buffers for their daughters, as evidenced by fewer distress vocalizations (p < 0.001), less locomotion (p < 0.001), and lower plasma cortisol (p < 0.001) in a social separation paradigm. Females vocalized less if they exhibited greater expression of bond-related behaviors with their fathers as infants (p = 0.01), and this stress-buffering effect remained even when the daughter was separated from the father (p = 0.001). While treatments did not alter behaviors, OTA treatment caused the largest rise in plasma cortisol (p < 0.001), suggesting blockade of OT receptors can inhibit fathers' stress-buffering effects. Remarkably, females with greater expression of father-daughter bond-related behaviors exhibited an overall reduced physiological separation distress response (p = 0.04). Findings from the present study advance current knowledge of the neurobiological mechanisms foundational to female bonds and help inform how social disruptions may differently impact individuals based on expression of bond-related behaviors.

Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors.

Compounds 1-4 were synthesized and investigated for selectivity and potency for the oxytocin receptor (OTR) to determine their viability as radioactive ligands. Binding assays determined 1-4 to have high binding affinity for both the human and rodent OTR and also have high selectivity for the human OTR over human vasopressin V1a receptors (V1aR). Inadequate selectivity for OTR over V1aR was found for rodent receptors in all four compounds. The radioactive (C-11, F-18, and I-125) derivatives of 1-4 were synthesized and investigated for use as autoradiography and positron emission tomography (PET) ligands. Receptor autoradiography performed with [(125)I]1 and [(125)I]2 on rodent brain slices provided the first small molecule radioligand images of the OTR and V1aR. Biodistribution studies determined [(125)I]1 and [(125)I]2 were adequate for in vivo peripheral investigations, but not for central investigations due to low uptake within the brain. A biodistribution study with [(18)F]3 suggested brain uptake occurred slowly over time. PET imaging studies with [(18)F]3 and [(11)C]4 using a rat model provided insufficient uptake in the brain over a 90 and 45 min scan times respectively to merit further investigations in non-human primates.

Using Receptor Autoradiography to Visualize and Quantify Oxytocin and Vasopressin 1a Receptors in the Human and Nonhuman Primate Brain.

Despite its development almost 40 years ago, receptor autoradiography remains a regular and reliable practice for the localization of oxytocin and vasopressin receptors in brain tissue sections. It is used across many laboratories, institutions, and animal species to characterize and quantify the distribution and density of these receptors at baseline and/or in response to experimental manipulations or lived experience. This powerful tool and the neuroanatomical receptor maps that it generates have allowed researchers to more accurately investigate and understand the neural substrates upon which oxytocin and vasopressin act to affect behavior. Researchers have used these maps to design site-specific pharmacological manipulations and electrophysiological recordings in animal studies to directly probe the underlying neural mechanisms in this system. This methods chapter describes the specific procedures by which a pharmacologically optimized, competitive binding modification to receptor autoradiography can be used to reliably localize oxytocin and vasopressin receptors in the human brain and in the brains of nonhuman primates. The ability to reliably perform receptor autoradiography for these targets in human brain tissue can finally inform our interpretation of past intranasal oxytocin neuroimaging studies and allows us to move past the reliance on transcriptomic studies using brain tissue homogenates so that we can directly investigate the involvement of oxytocin and vasopressin receptors in human behavior, physiology, and neuropsychiatric disease.