Autism and Oxytocin: New Developments in Translational Approaches to Therapeutics

Joshua J. Green, Eric Hollander Neurotheraputics  Volume 7, Issue 3, Pages 250-257 (July 2010)

Summary 

Autism is a neurodevelopmental disorder characterized by dysfunction in three core symptom domains: speech and communication deficits, repetitive or compulsive behaviors with restricted interests, and social impairment. The neuropeptide oxytocin, along with the structurally similar peptide arginine vasopressin, may play a role in the etiology of autism, and especially in the social impairment domain. Oxytocin is a nonapeptide (i.e., it has nine amino acids). It is synthesized in magnocellular neurons in the paraventricular nucleus and the supraoptic nucleus of the hypothalamus and is released into the bloodstream by way of axon terminals in the posterior pituitary. Oxytocin is released both peripherally, where it is involved in milk letdown and the facilitation of uterine contractions, and centrally, where it acts as a neuromodulator along with arginine vasopressin. Here, we discuss relevant translational research pertaining to the role of oxytocin in social and repetitive behaviors and consider clinical implications. We also discuss current research limitations, review recent preliminary findings from studies involving oxytocin in autism spectrum disorder patient populations, and point to possible directions for future research.

Key WordsAutism, ASD, oxytocin, translational model, repetitive behavior, social behavior, social cognition, social functioning, therapeutics, arginine vasopressin, epigenetic

Andari, E., J. R. Duhamel, T. Zalla, E. Herbrecht, M. Leboyer and A. Sirigu (2010). "Promoting social behavior with oxytocin in high-functioning autism spectrum disorders." Proc Natl Acad Sci U S A.
Social adaptation requires specific cognitive and emotional competences. Individuals with high-functioning autism or with Asperger syndrome cannot understand or engage in social situations despite preserved intellectual abilities. Recently, it has been suggested that oxytocin, a hormone known to promote mother-infant bonds, may be implicated in the social deficit of autism. We investigated the behavioral effects of oxytocin in 13 subjects with autism. In a simulated ball game where participants interacted with fictitious partners, we found that after oxytocin inhalation, patients exhibited stronger interactions with the most socially cooperative partner and reported enhanced feelings of trust and preference. Also, during free viewing of pictures of faces, oxytocin selectively increased patients' gazing time on the socially informative region of the face, namely the eyes. Thus, under oxytocin, patients respond more strongly to others and exhibit more appropriate social behavior and affect, suggesting a therapeutic potential of oxytocin through its action on a core dimension of autism.

Genomic and epigenetic evidence for oxytocin receptor deficiency in autism.

Duke Center for Human Genetics, DUMC, Durham, NC, USA. simon.gregory@duke.edu
BACKGROUND: Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders. METHODS: We describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR). RESULTS: Our analysis revealed a genomic deletion containing the oxytocin receptor gene, OXTR (MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate OXTR expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that OXTR mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls. CONCLUSION: Together, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of OXTR in the development of the disorder.See the related commentary by Gurrieri and Neri: http://www.biomedcentral.com/1741-7015/7/63.
Oxytocin increases gaze to the eye region of human face
Guastella AJ, Mitchell PB, Dadds MR.
Biol Psychiatry. 2008 Jan 1;63(1):3-5. Epub 2007 Sep 21.

BACKGROUND: In nonhuman mammals, oxytocin has a critical role in peer recognition and social approach behavior. In humans, oxytocin has been found to enhance trust and the ability to interpret the emotions of others. It has been suggested that oxytocin may enhance facial processing by increasing focus on the eye region of human faces. METHODS: In a double-blind, randomized, placebo-controlled, between-subject design, we tracked the eye movements of 52 healthy male volunteers who were presented with 24 neutral human faces after intranasal administration of 24 IU oxytocin or placebo. RESULTS: Participants given oxytocin showed an increased number of fixations and total gaze time toward the eye region compared with placebo participants. CONCLUSIONS: Oxytocin increases gaze specifically toward the eye region of human faces. This may be one mechanism by which oxytocin enhances emotion recognition, interpersonal communication, and social approach behavior in humans. Findings suggest a possible role for oxytocin in the treatment of disorders characterized by eye-gaze avoidance and facial processing deficits.

Intranasal Oxytocin Improves Emotion Recognition for Youth with Autism Spectrum Disorders
Guastella AJ, et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry. 2010 Apr 1; 67(7):692-4.


BACKGROUND: A diagnostic hallmark of autism spectrum disorders is a qualitative impairment in social communication and interaction. Deficits in the ability to recognize the emotions of others are believed to contribute to this. There is currently no effective treatment for these problems. METHODS: In a double-blind, randomized, placebo-controlled, crossover design, we administered oxytocin nasal spray (18 or 24 IU) or a placebo to 16 male youth aged 12 to 19 who were diagnosed with Autistic or Asperger's Disorder. Participants then completed the Reading the Mind in the Eyes Task, a widely used and reliable test of emotion recognition. RESULTS: In comparison with placebo, oxytocin administration improved performance on the Reading the Mind in the Eyes Task. This effect was also shown when analysis was restricted to the younger participants aged 12 to 15 who received the lower dose. CONCLUSIONS: This study provides the first evidence that oxytocin nasal spray improves emotion recognition in young people diagnosed with autism spectrum disorders. Findings suggest the potential of earlier intervention and further evaluation of oxytocin nasal spray as a treatment to improve social communication and interaction in young people with autism spectrum disorders.

Oxytocin enhances processing of positive versus negative emotional information in healthy male volunteers
Di Simplicio M et al.
J Psychopharmacol. 2009 May;23(3):241-8. Epub 2008 Sep 18.

Animal studies have shown the role of oxytocin in affiliation and attachment, and recent evidence suggests that oxytocin is also involved in human models of approach behaviour, possibly by modulating the processing of emotionally valenced stimuli. Although oxytocin administration has been reported to decrease neural responses to facial emotional information, the effects on a wider range of behavioural measures of emotional processing shown to be sensitive to antidepressant manipulation have not been examined. The aim of this study was to investigate whether intranasally administered oxytocin affects the processing of positive and negative affective information in healthy male volunteers across tasks measuring attention, perception and memory. Twenty-nine male healthy volunteers were randomly allocated to receive a single dose of oxytocin nasal spray (24 UI) or placebo. 50 min later, participants completed a battery of psychological tests measuring emotional processing. A single dose of intranasally administered oxytocin slowed reaction time to correctly identify fearful facial expressions and reduced the misclassification of positive emotions as negative ones. These effects occurred in the absence of significant differences in subjective ratings of mood and anxiety. These results suggest that oxytocin modulates emotion processing in healthy male volunteers. This action may contribute to the emerging role of the neuropeptide in promoting affiliative and approach behaviours by reducing the salience of potentially ambiguous and threatening social stimuli.

Intranasal administration of oxytocin increases envy and schadenfreude (gloating)
Shamay-Tsoory SG et al.
Biol Psychiatry. 2009 Nov 1;66(9):864-70. Epub 2009 Jul 29.

BACKGROUND: Humans have a strong social tendency to compare themselves with others. We tend to feel envious when we receive less valuable rewards and may rejoice when our payoffs are more advantageous. Envy and schadenfreude (gloating over the other's misfortune) are social emotions widely agreed to be a symptom of the human social tendency to compare one's payoffs with those of others. Given the important social components of envy and gloating, we speculated that oxytocin may have a modulating effect on the intensity of these emotions. METHODS: Fifty-six participants participated in this double-blind, placebo-controlled, within-subject study. Following the administration of oxytocin or a placebo, participants played a game of chance with another (fake) participant who either won more money (envy manipulation), lost more money (schadenfreude manipulation), or won/lost equal amounts of money. RESULTS: In comparison with the placebo, oxytocin increased the envy ratings during unequal monetary gain conditions involving relative loss (when the participant gained less money than another player). Oxytocin also increased the ratings of gloating during relative gain conditions (when the participant gained more money than the other player). By contrast, oxytocin had no effect on the emotional ratings following equal monetary gains nor did it affect general mood ratings. CONCLUSIONS: These results suggest that the oxytocinergic system is involved in modulating envy and gloating. Thus, contrary to the prevailing belief that this system is involved solely in positive prosocial behaviors, it probably plays a key role in a wider range of social emotion-related behaviors.

Oxytocin enhances the encoding of positive social memories in humans
Guastella AJ, Mitchell PB, Mathews F.
Biol Psychiatry. 2008 Aug 1;64(3):256-8. Epub 2008 Mar 17.

BACKGROUND: In nonhuman mammals, oxytocin has a critical role in social recognition and the development of long-term bonds. There has been limited research evaluating effects of oxytocin on the encoding and recognition of faces in humans. METHODS: In a double-blind, randomized, placebo-controlled, between-subject design, we administered oxytocin (24 IU) or a placebo to 69 healthy human male volunteers and then presented 36 happy, angry, or neutral human faces. Participants returned the following day to make "remember," "know," or "new" judgments for a mix of 72 new and previously seen faces. RESULTS: Oxytocin-administered participants were more likely to make remember and know judgments for previously seen happy faces compared with angry and neutral human faces. In contrast, oxytocin did not influence judgments for faces that had not been presented previously. CONCLUSIONS: This study shows that the administration of oxytocin to male humans enhances the encoding of positive social information to make it more memorable. Results suggest that oxytocin could enhance social approach, intimacy, and bonding in male humans by strengthening encoding to make the recall of positive social information more likely

Oxytocin and experimental therapeutics in autism spectrum disorders
Bartz JA, Hollander E.
Prog Brain Res. 2008;170:451-62.

Autism is a developmental disorder characterized by three core symptom domains: speech and communication abnormalities, social functioning impairments and repetitive behaviours and restricted interests. Oxytocin (OXT) is a nine-amino-acid peptide that is synthesized in the paraventricular and supraoptic nucleus of the hypothalamus and released into the bloodstream by axon terminals in the posterior pituitary where it plays an important role in facilitating uterine contractions during parturition and in milk let-down. In addition, OXT and the structurally similar peptide arginine vasopressin (AVP) are released within the brain where they play a key role in regulating affiliative behaviours, including sexual behaviour, mother-infant and adult-adult pair-bond formation and social memory/recognition. Finally, OXT has been implicated in repetitive behaviours and stress reactivity. Given that OXT is involved in the regulation of repetitive and affiliative behaviours, and that these are key features of autism, it is believed that OXT may play a role in autism and that OXT may be an effective treatment for these two core symptom domains. In this chapter we review evidence to date supporting a relationship between OXT and autism; we then discuss research looking at the functional role of OXT in autism, as well as a pilot study investigating the therapeutic efficacy of OXT in treating core autism symptom domains. Finally, we conclude with a discussion of directions for future research.

Oxytocin improves "mind-reading" in humans
Domes G et al.
Biol Psychiatry. 2007 Mar 15;61(6):731-3. Epub 2006 Nov 29.

BACKGROUND: The ability to "read the mind" of other individuals, that is, to infer their mental state by interpreting subtle social cues, is indispensable in human social interaction. The neuropeptide oxytocin plays a central role in social approach behavior in nonhuman mammals. METHODS: In a double-blind, placebo-controlled, within-subject design, 30 healthy male volunteers were tested for their ability to infer the affective mental state of others using the Reading the Mind in the Eyes Test (RMET) after intranasal administration of 24 IU oxytocin. RESULTS: Oxytocin improved performance on the RMET compared with placebo. This effect was pronounced for difficult compared with easy items. CONCLUSIONS: Our data suggest that oxytocin improves the ability to infer the mental state of others from social cues of the eye region. Oxytocin might play a role in the pathogenesis of autism spectrum disorder, which is characterized by severe social impairment.

Oxytocin increases retention of social cognition in autism
Hollander E et al.
Biol Psychiatry. 2007 Feb 15;61(4):498-503. Epub 2006 Aug 14.

BACKGROUND: Oxytocin dysfunction might contribute to the development of social deficits in autism, a core symptom domain and potential target for intervention. This study explored the effect of intravenous oxytocin administration on the retention of social information in autism. METHODS: Oxytocin and placebo challenges were administered to 15 adult subjects diagnosed with autism or Asperger's disorder, and comprehension of affective speech (happy, indifferent, angry, and sad) in neutral content sentences was tested. RESULTS: All subjects showed improvements in affective speech comprehension from pre- to post-infusion; however, whereas those who received placebo first tended to revert to baseline after a delay, those who received oxytocin first retained the ability to accurately assign emotional significance to speech intonation on the speech comprehension task. CONCLUSIONS: These results are consistent with studies linking oxytocin to social recognition in rodents as well as studies linking oxytocin to prosocial behavior in humans and suggest that oxytocin might facilitate social information processing in those with autism. These findings also provide preliminary support for the use of oxytocin in the treatment of autism.

The effect of intranasal administration of oxytocin on fear recognition
Fischer-Shofty M et al.
Neuropsychologia. 2010 Jan;48(1):179-84.

The oxytocinergic system has recently been placed amongst the most promising targets for various psychiatric treatments due to its role in prosocial behavior and anxiety reduction. Although recent studies have demonstrated a general effect of administration of oxytocin on emotion recognition, no study to date has examine the effect of oxytocin on each emotion separately. In the present study, a double-blind placebo-controlled crossover design was used in a dynamic facial expression task, in order to assess the effects of administration of oxytocin on emotion recognition. A single dose of oxytocin or a placebo was administered intranasally to 27 healthy male subjects 45 min prior to task performance. The results showed that a single intranasal administration of oxytocin, as opposed to the placebo, improved the subjects' ability to recognize fear, but not other emotions. These results suggest a specific role for oxytocin in fear recognition, which could be relevant for clinical disorders that manifest deficits in processing emotional facial expressions, particularly fear.


A randomized controlled trial of intranasal oxytocin as an adjunct to exposure therapy for social anxiety disorder
Guastella AJ et al.
Psychoneuroendocrinology. 2009 Jul;34(6):917-23. Epub 2009 Feb 25.

In humans, oxytocin nasal administration reduces social-threat perception and improves processes involved in communication and the encoding of positive social cues. The aim of this study was to determine whether oxytocin given as an adjunct to exposure therapy improves treatment for social anxiety disorder (SAD) as indicated by a comprehensive set of symptom outcome measures. In a randomized, double-blind, placebo-controlled trial, we administered 24 IU of oxytocin or a placebo in combination with exposure therapy to twenty-five participants who met primary diagnosis for SAD. Participants administered with oxytocin showed improved positive evaluations of appearance and speech performance as exposure treatment sessions progressed. These effects did not generalize to improve overall treatment outcome from exposure therapy. Participants who received oxytocin or placebo reported similar levels of symptom reduction following treatment across symptom severity, dysfunctional cognition, and life-impairment measures. This study shows that the administration of oxytocin improves mental representations of self, following exposure therapy. These effects may be either short term or situation specific. Future research is now needed to determine whether oxytocin can enhance treatment outcomes for SAD when used with greater frequency, with a wider variety of social learning experiences, and in conjunction with interventions that more specifically target change in broader dysfunctional cognitions.

Does oxytocin influence the early detection of angry and happy faces?
Guastella AJ et al.
Psychoneuroendocrinology. 2009 Feb;34(2):220-5. Epub 2008 Oct 9.

Oxytocin has a crucial role in social behaviour, although its effects on social cognition are not fully understood. Past research shows that oxytocin enhances encoding and conceptual recognition of positive social stimuli over social-threat stimuli. In this study, we evaluated whether oxytocin modified responses to positive and threatening social stimuli at an earlier perceptual stage of processing using the visual search task. In a double-blind, randomized, placebo-controlled, between-subject design, oxytocin (24 IU) or a placebo was administered to 104 healthy volunteers. Participants returned to complete the visual search paradigm 45min later. Results showed that angry faces were detected more efficiently than happy faces. Participants also gazed longer and more frequently toward angry faces. Oxytocin did not, however, influence response time, accuracy, or gaze toward angry or happy faces, even when participants were separated into high- and low-social anxiety. The results of this study suggest that oxytocin may not influence the detection of positive and threatening social stimuli at early perceptual levels of processing. Oxytocin may have greater influence in altering the cognitive processing of social valence at more conceptual and elaborate levels of processing.

Oxytocin, vasopressin and pair bonding: implications for autism
Hammock EA, Young LJ.
Philos Trans R Soc Lond B Biol Sci. 2006 Dec 29;361(1476):2187-98.
http://rstb.royalsocietypublishing.org/content/361/1476/2187.long

Understanding the neurobiological substrates regulating normal social behaviours may provide valuable insights in human behaviour, including developmental disorders such as autism that are characterized by pervasive deficits in social behaviour. Here, we review the literature which suggests that the neuropeptides oxytocin and vasopressin play critical roles in modulating social behaviours, with a focus on their role in the regulation of social bonding in monogamous rodents. Oxytocin and vasopressin contribute to a wide variety of social behaviours, including social recognition, communication, parental care, territorial aggression and social bonding. The effects of these two neuropeptides are species-specific and depend on species-specific receptor distributions in the brain. Comparative studies in voles with divergent social structures have revealed some of the neural and genetic mechanisms of social-bonding behaviour. Prairie voles are socially monogamous; males and females form long-term pair bonds, establish a nest site and rear their offspring together. In contrast, montane and meadow voles do not form a bond with a mate and only the females take part in rearing the young. Species differences in the density of receptors for oxytocin and vasopressin in ventral forebrain reward circuitry differentially reinforce social-bonding behaviour in the two species. High levels of oxytocin receptor (OTR) in the nucleus accumbens and high levels of vasopressin 1a receptor (V1aR) in the ventral pallidum contribute to monogamous social structure in the prairie vole. While little is known about the genetic factors contributing to species-differences in OTR distribution, the species-specific distribution pattern of the V1aR is determined in part by a species-specific repetitive element, or 'microsatellite', in the 5' regulatory region of the gene encoding V1aR (avpr1a). This microsatellite is highly expanded in the prairie vole (as well as the monogamous pine vole) compared to a very short version in the promiscuous montane and meadow voles. These species differences in microsatellite sequence are sufficient to change gene expression in cell culture. Within the prairie vole species, intraspecific variation in the microsatellite also modulates gene expression in vitro as well as receptor distribution patterns in vivo and influences the probability of social approach and bonding behaviour. Similar genetic variation in the human AVPR1A may contribute to variations in human social behaviour, including extremes outside the normal range of behaviour and those found in autism spectrum disorders. In sum, comparative studies in pair-bonding rodents have revealed neural and genetic mechanisms contributing to social-bonding behaviour. These studies have generated testable hypotheses regarding the motivational systems and underlying molecular neurobiology involved in social engagement and social bond formation that may have important implications for the core social deficits characterizing autism spectrum disorders.


Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger's disorders
Hollander E et al.
Neuropsychopharmacology. 2003 Jan;28(1):193-8.
http://www.nature.com/npp/journal/v28/n1/abs/1300021a.html

Autism is a neurodevelopmental disorder characterized by dysfunction in three core behavioral domains: repetitive behaviors, social deficits, and language abnormalities. There is evidence that abnormalities exist in peptide systems, particularly the oxytocin system, in autism spectrum patients. Furthermore, oxytocin and the closely related peptide vasopressin are known to play a role in social and repetitive behaviors. This study examined the impact of oxytocin on repetitive behaviors in 15 adults with autism or Asperger's disorder via randomized double-blind oxytocin and placebo challenges. The primary outcome measure was an instrument rating six repetitive behaviors: need to know, repeating, ordering, need to tell/ask, self-injury, and touching. Patients with autism spectrum disorders showed a significant reduction in repetitive behaviors following oxytocin infusion in comparison to placebo infusion. Repetitive behavior in autism spectrum disorders may be related to abnormalities in the oxytocin system, and may be partially ameliorated by synthetic oxytocin infusion.


Bartz, J. A. and E. Hollander (2008). "Oxytocin and experimental therapeutics in autism spectrum disorders." Prog Brain Res 170: 451-62.
Autism is a developmental disorder characterized by three core symptom domains: speech and communication abnormalities, social functioning impairments and repetitive behaviours and restricted interests. Oxytocin (OXT) is a nine-amino-acid peptide that is synthesized in the paraventricular and supraoptic nucleus of the hypothalamus and released into the bloodstream by axon terminals in the posterior pituitary where it plays an important role in facilitating uterine contractions during parturition and in milk let-down. In addition, OXT and the structurally similar peptide arginine vasopressin (AVP) are released within the brain where they play a key role in regulating affiliative behaviours, including sexual behaviour, mother-infant and adult-adult pair-bond formation and social memory/recognition. Finally, OXT has been implicated in repetitive behaviours and stress reactivity. Given that OXT is involved in the regulation of repetitive and affiliative behaviours, and that these are key features of autism, it is believed that OXT may play a role in autism and that OXT may be an effective treatment for these two core symptom domains. In this chapter we review evidence to date supporting a relationship between OXT and autism; we then discuss research looking at the functional role of OXT in autism, as well as a pilot study investigating the therapeutic efficacy of OXT in treating core autism symptom domains. Finally, we conclude with a discussion of directions for future research.

Bartz, J. A. and L. A. McInnes (2007). "CD38 regulates oxytocin secretion and complex social behavior." Bioessays 29(9): 837-41.
The peptide hormone oxytocin plays a critical role in regulating affiliative behaviors including mating, pair-bond formation, maternal/parenting behavior, social recognition, separation distress and other aspects of attachment. Jin and colleagues recently reported intriguing findings that CD38, a transmembrane receptor with ADP-ribosyl cyclase activity, plays a critical role in maternal nurturing behavior and social recognition by regulating oxytocin secretion. This research may have implications for understanding disorders marked by deficits in social cognition and social functioning, including autism, social anxiety disorder, borderline personality disorder and schizophrenia.