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Effects of chronic intranasal oxytocin on behavior and cerebral glucose uptake in juvenile titi monkeys.

ABSTRACT: Intranasal oxytocin (IN OXT) has been proposed as a treatment for autism spectrum disorder (ASD); however, little is known about the effects of long-term exposure. This is the first study in a non-human primate species to examine how developmental exposure to chronic IN OXT affects juvenile's interactions with family members, social preference for parents versus strangers, anxiety-like behavior, and cerebral glucose metabolism. Titi monkeys are socially monogamous and biparental; their family bonds share important characteristics with human family bonds. Fourteen males and 15 females were treated intranasally with saline (n?=?14) or 0.8 IU/kg OXT (n?=?15), daily from 12 to 18 months of age. Compared to SAL-treated animals, OXT-treated animals of both sexes spent significantly more time grooming other family members (F₁?=?8.97, p?=?0.006). Overall, OXT-treated subjects were more social (F₁?=?8.35, p?=?0.005) during preference tests. OXT-treated females displayed an enhanced preference for their parents (t?=?2.265, p?=?0.026). OXT-treated males had a blunted preference for their parents and an increase in the time spent near unfamiliar pairs (F1?=?10.89, p?=?0.001). During anxiety tests, OXT-treated males refused to complete the task more often than SAL-treated males and had longer latencies (p?1,9 = 1.07, p?=?0.042). Our results suggest moderate prosocial effects of chronic IN OXT, that did not depend on anxiolytic properties. We also found important sex differences that should be considered in a translational context.

SUBMITTER: Arias Del Razo R

PROVIDER: S-EPMC7909742 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Effects of chronic intranasal oxytocin on behavior and cerebral glucose uptake in juvenile titi monkeys.

Arias Del Razo Rocío R Berger Trish T Conley Alan J AJ Freeman Sara M SM Goetze Leana R LR Jacob Suma S Lawrence Rebecca H RH Mendoza Sally P SP Rothwell Emily S ES Savidge Logan E LE Solomon Marjorie M Weinstein Tamara A R TAR Witczak Lynea R LR Bales Karen L KL

Psychoneuroendocrinology 20191031

Intranasal oxytocin (IN OXT) has been proposed as a treatment for autism spectrum disorder (ASD); however, little is known about the effects of long-term exposure. This is the first study in a non-human primate species to examine how developmental exposure to chronic IN OXT affects juvenile's interactions with family members, social preference for parents versus strangers, anxiety-like behavior, and cerebral glucose metabolism. Titi monkeys are socially monogamous and biparental; their family bo ...[more]

PMID: 31862614

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Project description:In socially monogamous titi monkeys, involuntary separation from a pair mate can produce behavioral distress and increased cortisol production. The neuropeptide oxytocin (OXT) is thought to play an important role in the separation response of pair-bonded species. Previous studies from our lab have shown that chronic intranasal oxytocin (IN OXT) during development can have long-term effects on adult social behavior. In the current study, we examined the chronic and acute effects of IN OXT or Saline (SAL) on the subjects' response to a brief separation from their pair mates. Subjects with a history of chronic IN OXT or SAL treatment during development received a single dose of OXT or SAL as adults 30 min before being separated from their pair mate. Chronic treatment consisted of a daily dose of IN OXT (0.8 IU/kg) or SAL (control) from 12 to 18 months of age. Subjects (N = 29) were introduced to a pair mate at 30 months of age. After the pairs had cohabitated for 5 months, pairs underwent two "Brief Separation" (OXT and SAL) and two "Non-Separation" (OXT and SAL) test sessions. Vocalizations and locomotion were measured as behavioral indices of agitation or distress during the Brief Separation and Non-Separation periods (30 min each). We collected blood samples after the Brief Separation and Non-Separation periods to measure cortisol levels. Our results showed subjects treated with chronic OXT had a reduction in long call and peep vocalizations compared to subjects treated with chronic SAL. Subjects treated with chronic SAL and acute OXT produced more peeps and long calls compared to animals treated with acute SAL; however, patterns in this response depended on sex. Cortisol and locomotion were significantly higher during the Brief Separation period compared to the Non-Separation period; however, we did not find any treatment or sex effects. We conclude that chronic IN OXT given during development blunts the separation response, while acute OXT in chronic SAL subjects had sexually dimorphic effects, which could reflect increased partner seeking behaviors in males and increased anxiety in females.

Project description:Coordination of oxytocin (OT) activity and partner interactions is important for the facilitation and maintenance of monogamous pair bonds. We used coppery titi monkeys (Callicebus cupreus) to identify the effects of male aggressive temperament on OT activity, affiliative partner-directed behaviors, aggressive partner-directed behaviors, anxiety-related behaviors, and hormone-behavior interactions. We used a mirror technique, simulating an intruder in the home territory of pairs to elicit behavioral responses, and quantified behaviors using an established ethogram. Plasma concentrations of OT (pg/ml) were quantified using enzyme immunoassay. We used general linear mixed models to predict 1) percent change in OT as a function of aggression score, and 2) percent change in behaviors as a function of aggression, OT, and OT by aggression interactions. High-aggressive males exhibited a significant drop in OT concentration relative to control when exposed to the front of the mirror (β = -0.22, SE = 0.10, t = -2.20, p = 0.04). High-aggressive males spent significantly less time in contact with their mates (β = -1.35, SE = 0.60, t = -2.26, p = 0.04) and lip-smacked less (β = -1.02, SE = 0.44, t = -2.32, p = 0.03) relative to control. We also saw a trend toward an interaction effect between OT and proximity such that High-aggressive males displaying a drop in OT exhibited a smaller percent increase in social proximity (β = 6.80, SE = 3.48, t = 1.96, p = 0.07). Males exhibiting a decrease in OT also trended toward back-arching and tail-lashing less in response to the mirror (β = 4.53, SE = 2.5, t = 1.82, p = 0.09). To our knowledge, this is the first empirical study to examine interactions between OT and temperament in adult monogamous primates. Future studies should incorporate measures of pair-mate interactions and early-life experience to further understand variation in responses to social stressors and their effects on pair bonding.

Project description:Recent studies support the hypothesis that the adverse effects of early-life adversity and transgenerational stress on neural plasticity and behavior are mediated by inflammation. The objective of the present study was to investigate the immune and behavioral programing effects of intranasal (IN) vasopressin (AVP) and oxytocin (OXT) treatment of chronic social stress (CSS)-exposed F1 dams on F2 juvenile female offspring. It was hypothesized that maternal AVP and OXT treatment would have preventative effects on social stress-induced deficits in offspring anxiety and social behavior and that these effects would be associated with changes in interferon-? (IFN?). Control and CSS-exposed F1 dams were administered IN saline, AVP, or OXT during lactation and the F2 juvenile female offspring were assessed for basal plasma IFN? and perseverative, anxiety, and social behavior. CSS F2 female juvenile offspring had elevated IFN? levels and exhibited increased repetitive/perseverative and anxiety behaviors and deficits in social behavior. These effects were modulated by AVP and OXT in a context- and behavior-dependent manner, with OXT exhibiting preventative effects on repetitive and anxiety behaviors and AVP possessing preventative effects on social behavior deficits and anxiety. Basal IFN? levels were elevated in the F2 offspring of OXT-treated F1 dams, but IFN? was not correlated with the behavioral effects. These results support the hypothesis that maternal AVP and OXT treatment have context- and behavior-specific effects on peripheral IFN? levels and perseverative, anxiety, and social behaviors in the female offspring of early-life social stress-exposed dams. Both maternal AVP and OXT are effective at preventing social stress-induced increases in self-directed measures of anxiety, and AVP is particularly effective at preventing impairments in overall social contact. OXT is specifically effective at preventing repetitive/perseverative behaviors, yet is ineffective at preventing deficits in overall social behavior.

Project description:Interactions between social experiences at different stages of development (e.g., with parents as juveniles and peers as subadults) can profoundly shape the expression of social behavior. Rarely are the influences of more than one stage of developmental sensitivity to social environment investigated simultaneously. Furthermore, oxytocin (OT) has an extraordinary effect on a breadth of social behaviors, activationally or organizationally. The use of intranasal OT (IN-OT) has become increasingly common therapeutically in humans and scientifically in non-human experiments, however very little attention has been paid to the potential developmental consequences on social behavior that might result. We investigated the effects of early-life social environments and the impact of chronic IN-OT on social behavior at different stages of development in male prairie voles (Microtus ochrogaster). We raised animals under two conditions: "socially enriched" (in which they were biparentally reared and then weaned into group housing as subadults), or "socially limited" (in which they were reared by a single-mother, and that were then weaned into social isolation). Males raised under each condition were either administered daily doses of IN-OT or a saline control for 21 days from postnatal day (PND) 21-42. During this time, we assessed the prosocial behavior subjects demonstrated by evaluating juvenile affiliation (as subadults), alloparental care (as adults no longer being exposed to IN-OT), and partner preference tests to assess tendencies to form adult monogamous pairbonds. We found that "socially limited" males, exhibited increased social contact in juvenile affiliation tests at PND 35 and 42. These males were also more likely to form a partner preference than "socially enriched" males and formed stronger partner preferences overall. IN-OT did not alter these behavioral effects. We also found that "socially limited" males exhibited a distinct response to chronic IN-OT treatment. When compared to all other treatment groups, "socially limited" males that received IN-OT exhibited a greater amount of huddling behavior in the alloparental care test. This effect was, in part, explained by an absence of attack behavior, found only in these males. This study contributes to understanding the complex interactions between the developmental social environment, oxytocin, and social behavior.

Project description:Chronic cocaine use is associated with neurobiological and cognitive deficits that persist into abstinence, hindering success of behavioral treatment strategies and perhaps increasing likelihood of relapse. The effects of current cocaine use and abstinence on neurobiology and cognition are not well characterized.Adult male rhesus monkeys with an extensive cocaine self-administration history (? 5 years) and age-matched control animals (n = 4/group) performed cognitive tasks in morning sessions and self-administered cocaine or food in afternoon sessions. Positron emission tomography and [(18)F]-fluorodeoxyglucose were employed to assess cerebral metabolic rates of glucose utilization during cognitive testing.Cocaine-experienced monkeys required significantly more trials and committed more errors on reversal learning and multidimensional discriminations, compared with control animals. Cocaine-naive, but not cocaine-experienced, monkeys showed greater metabolic rates of glucose utilization during a multidimensional discrimination task in the caudate nucleus, hippocampus, anterior and posterior cingulate, and regions associated with attention, error detection, memory, and reward. Using a delayed match-to-sample task, there were no differences in baseline working memory performance between groups. High-dose cocaine self-administration disrupted delayed match-to-sample performance but tolerance developed. Acute abstinence from cocaine did not affect performance, but by day 30 of abstinence, accuracy increased significantly, while performance of cocaine-naive monkeys was unchanged.These data document direct effects of cocaine self-administration on cognition and neurobiological sequelae underlying cognitive deficits. Improvements in working memory can occur in abstinence, albeit across an extended period critical for treatment seekers, suggesting pharmacotherapies designed to enhance cognition may improve success of current behavioral modification strategies.

Project description:Pair-bonded primates have uniquely enduring relationships and partners engage in a suite of behaviors to maintain these close bonds. In titi monkeys, pair bond formation has been extensively studied, but changes across relationship tenure remain unstudied. We evaluated differences in behavioral indicators of pair bonding in newly formed (~6 months paired, n = 9) compared to well-established pairs (average 3 years paired, n = 8) of titi monkeys (Callicebus cupreus) as well as sex differences within the pairs. We hypothesized that overall males would contribute more to maintenance than females, but that the pattern of maintenance behaviors would differ between newly formed and well-established pairs. Each titi monkey (N = 34) participated in a partner preference test (PPT), where the subject was placed in a middle test cage with grated windows separating the subject from the partner on one side and an opposite-sex stranger on the other side. During this 150-min behavioral test, we quantified four key behaviors: time in proximity to the partner or stranger as well as aggressive displays toward the partner or stranger. Overall, we found different behavioral profiles representing newly formed and well-established pair-bond relationships in titi monkeys and male-biased relationship maintenance. Males spent ∼40% of their time in the PPT maintaining proximity to the female partner, regardless of relationship tenure. Males from well-established bonds spent less time (14%) near the female stranger compared to males from newly formed bonds (21%) at the trend level. In contrast, females from well-established bonds spent less (23%) time near the male partner in the PPT compared to females from newly formed bonds (47%). Aggressive displays were more frequent in newly formed bonds compared to well-established bonds, especially for females. Scan sampling for homecage affiliation showed that newly formed pairs were more likely to be found tail twining than well-established pairs.

Dataset Information

Effects of chronic intranasal oxytocin on behavior and cerebral glucose uptake in juvenile titi monkeys.

Publications

Effects of chronic intranasal oxytocin on behavior and cerebral glucose uptake in juvenile titi monkeys.

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