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Oxytocin and Vasopressin in Treating

Autism: Results of Comparative Research

by Daniel M. Hitzfield

Abstract

Using animal models to understand the mechanisms underlying human social behavior

reveals otherwise inaccessible neurophysiological processes. There are three purposes to this

paper. First, to review the findings of prominent comparative research on oxytocin and

vasopressin in regards to their effect on adult social bonding. Second, to summarize

advancements made in treating autism, a social disorder. Third, to discuss the limits of

comparing animal models to human research.

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Introduction

Long-term, healthy social affiliations (e.g., relationships) have been clinically correlated

with the peak mental health of human individuals (Lim & Young, 2006). The latter century has

yielded the necessary equipment for scientific studies to pinpoint the areas of the human brain

associated with social behavior, such as the amygdala and medial prefrontal cortex (Fossati,

2012). Unfortunately, the neuroendocrinology of human social behavior remains under research

without a wholly consistent explanation for its effects; it is considered a critical area of

neuroscience to explore because understanding the neurophysiological mechanisms will

hopefully highlight possible treatments for human social disorders. This ongoing work is still

largely in the stages of correlating specific pathways with subsets of behavior (e.g., Zink et al.,

2011). At best, analyzing just the human brain and relevant behavior in case studies only allows

for a superficial understanding of the adult mental and behavioral processes governing social

interaction. Animal models, on the other hand, have been previously shown to shed light on the

mental and behavioral processes of humans without overstepping the bounds of ethics that would

be violated in similar experiments actually involving humans (Modi & Young, 2012). Moreover,

animal correlates to human behavior are practically necessary to uncover the the most effective

size, time period and method of treatment in many cases. Defining the effect of oxytocin (OT)

and vasopressin (VP) treatments on animals' adult social affiliative behavior will be the former

purpose of this paper. The latter will be review and summary of case studies and other

experiments performed on humans regarding OT and VP treatment as a potential cure for autism

spectrum disorder (ASD). ASD covers a range of dysfunctional behaviors from almost

unnoticeable to crippling degrees of social impairment.

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Adult Social Affiliation

Affiliative behavior is defined as any action that fosters social relationships, or bonds.

Regarding humans, this set of behaviors dominates life and relationships with peers of either sex

(Lim & Young, 2006). As peer relationships are the most common, they will be the sole

subsection of affiliate behavior discussed. The most long-lasting of these relationships are often

those of pair-bonds (i.e., sexual partners), as evidenced by the research of Young & Wang (2004).

Pair bonds are typically judged by recording the quantity of particular behaviors in non-human

experiments, such as the work done by Garber & Leigh (1997) on eleven different species of

New World primates. These can include social grooming (i.e., allogrooming), sharing resources

and huddling together (Garbe & Leigh, 1997; Adiseshan et al., 2011). Other experiments on

primates, particularly a study done on macaques by Adiseshan et al. (2011), demonstrated much

longer-term social relationships on a scale beyond pair bonds; these varied by kin (i.e., extended-

family alliances) or simple living-proximity group alliances (Adiseshan et al., 2011).

Furthermore, maintenance of these larger-scale alliances has been observed as conciliatory

behavior soon after aggression occurs by one or both parties involved (Cords and Aureli, 1997).

The importance of this social activity as a whole is confirmed by the majority of time spent in

affiliative behavior by primates in general: anywhere from 50-98% (Sussman et al., 2005). This

behavior (ie making and maintaining friendship) is also observed alongside and blunting

aggressive or competitive behavior in a variety of non-human species (Sussman et al., 2005).

These studies of animals and particularly of primates correlate well with studies of equivalent

human social affiliative behavior (Ebstein et al., 2012), making comparison the most promising

method of determining the most efficacious treatments of ASD.

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Mechanisms Influencing Social Affiliation

In the history of neurophysiology in relation to social disorders, research on humans in

the past century has been limited to individuals with social impairments or pre-existing brain

damage (as opposed to lesioning performed on non-humans); in the latter part of this century

brain-imaging techniques possible because of developing technology have become the forefront

methods in human studies (Kennedy & Adolphs, 2012). While such studies provide a chance to

determine ultimate cause-and-effect, regulatory pathways and their intermediates are still not

coherently understood to a satisfactory degree. Moreover, the subject of social relationships and

its set of behaviors is a difficult one, because it relies upon the processing of information on

multiple levels of consciousness. In order to make progress, one level of these processing

pathways in the brain is examined at a time and for a particular system. In this case, that system

is the pathway(s) by which OT and VP regulate social cognition and emotion. Fortunately, non-

human social behaviors recorded in a lab setting correlate well with observation of natural non-

human social behavior (Lim & Young, 2006) and with human brain-imaging results (Zink &

Meyer Lindenberg, 2012).

Regarding the influence of OT and VP on social affiliative behavior, researchers have

particularly focused on the prairie vole (Microtus Ochrogaster) and experimental manipulation

of its naturally strong monogamous traits. Earlier experiments were only performed on a

relatively short-term basis (e.g., Carter et al., 1995; Cho et al., 1999; Young & Wang, 2004),

while experiments in the last year or so have expanded experimental parameters to the entire

lifetime of the prairie vole (e.g., Bales et al., 2013). Another species that has proven useful is the

Wistar rat (Rattus Norvegicus), used to determine specific oxytonergic and vasopressinergic

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pathways and observe multiple social behaviors (e.g., De Vries & Bujis, 1983). Similarly, mice,

whether bred as transgenic comparisons to other species or tested as wild-types, have provided

additional data on social behavior (e.g., Young et al., 1999).

Neuropeptides Implicated in Regulating Social Behavior

According to work done by De Vries & Bujis (1983) on rats, OT is originally

manufactured by the paraventricular nuclei (PVN) or supraoptic nuclei (SON) of the

hypothalamus in order to act on its corresponding oxytocin receptors (OTR) scattered in the

brain; this was proven in the experiment by lesioning the PVN, which almost completely

crippled the oxytocinergic system. In a review of OT and VP, Sofroniew (1983) supported the

conclusions of De Vries & Bujis, adding that both the PVN and SON project toward the posterior

pituitary (i.e., neurohypophysis) and both OT and VP are secreted from that point as peptides

into peripheral circulation; OT in particular was associated with numerous projection sites from

the PVN: the hippocampus, striatum, nucleus accumbens and spinal cord. Like OT, VP is

produced in the PVN and SON; it is additionally produced in the suprachiasmatic nucleus, bed

nucleus of the stria terminalis and medial amygdala (De Vries & Miller, 1998). Either VP or OT

that is released centrally instead of peripherally has been determined for some time to have a

strong influence on social behavior; evidence that has been uniform across numerous rodent and

other mammalian experimental subjects (Lim & Young, 2006). These two have been the

promising candidates for research in later decades because of their additional evidence for

altering neuronal activity.

Adult Affiliative Behavior: Oxytocin

Rats are ordinarily social animals with several distinctive non-sexual affiliative behaviors

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which makes them one of the more tested subjects to determine the role of OT. In a study very

recently performed on them by Calcagnoli et al. (2013), it was determined that acute, short-term,

centrally-injected doses of OT resulted in two distinctive behavior changes: reduced levels of

anti-social intruder aggression, and marked increase of time spent in social contact. Note, “social

contact” simply denotes exploration among and proximity with other individuals, not necessarily

the observation of specific behaviors. In the same experiment, another experimental group was

centrally-injected with an OT antagonist, resulting in a non-significant increase of aggression

among naturally low-aggression rats, and almost no difference in ordinarily high-aggression rats.

In short, observation for one hour after the intracerebroventricular OT injections did not yield

any significant increase in the behaviors correlated with social affiliation, instead merely

lowering aggression. While most other experiments over the last two decades have studied the

immediate affiliative behavioral effects of experiments on males rats such as the above, Witt et

al. (1992) performed continuous observation for six hours after centrally administering OT to

male rats. All the experimental and control males still had their gonads intact and hormonal

secretion uninterrupted, paired equally between estrous and ovariectomized females. The only

significant difference were two times the number of non-sexual, specifically affiliative social

behaviors—such as grooming and anogenital sniffing—in the experimental group compared to

the control group. The conclusion is that constant exposure to OT heavily influences the

tendency to engage in social affiliative interactions given a relatively long time to exert its

influence (e.g., six hours or more).

Later research on adult male house mice (Mus Musculus) by Murakami et al. (2011)

supported the associations made in rats; social behavior was linked by simple correlations with

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mRNA and neuropeptide receptor expression. The medial amygdala and PVN were the primary

sites of activity for mRNA expression of OT and VP receptors and their corresponding

neuropeptides, respectively. Interestingly, the levels of OT and VP mRNA were associated with

estrogen receptors as well as increased social interaction, suggesting that estrogen receptor

activity has a strong regulatory influence on both hormones' expression.

Interestingly, the results from Carter et al. (1995) in an experiment on monogamous

prairie voles (Microtus Ochrogaster) yielded somewhat different results than the aforementioned

research with male rats. Pair-bonding took place to different degrees, measured by observation of

affiliated behaviors under the influence of various test variables, such as the injection of VP,

injection of OT, and being allowed to mate. Unlike in male rats, centralized injection of OT into

male voles did not produce a significantly stronger effect on pair-bonding, while it did in females

even in the absence of mating (Carter et al., 1995). In a similar experiment years later which

involved hour-long OT and/or VP doses alongside mating, similar results were obtained with an

increased rate of pair-bonding only with the presence of mating alongside injections (Cho et al.,

1999). Unfortunately, OT injections that last from childhood to adulthood appear to have a far

less positive effect than much more short-term injections. According to the latest research

performed by Bales et al. (2013) on prairie voles, long-term developmental treatment causes a

lack of discernment in social interactions. The frequency of expected behaviors increased, but

not in accordance with normal partner-preference. That is, affiliative behaviors will increase to

the point that the subject will not bond with any other; the subject will effectively act

polygamous in a typically monogamous species.

Attempting to apply both rat and vole models to humans at face value is problematic.

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However, the key for interpreting these results is the baseline behavior. In the case of rats, there

is no long-lived or lifelong pair-bonding. As a result, it was expected that an OT injection would

increase nonspecific social behavior. It did. In the case of prairie voles, the baseline behavior is

vastly different: lifelong monogamy. It was unknown whether an OT injection would strengthen

or erode a pair-bond in its effect. The results, as discussed, were intriguing. Acute injections

temporarily increased partner preference only when mating also occurred. Chronic injections

crippled partner preference, increasing social behavior to the point of almost complete non-

specificity. This is the common link between the two models, and the application to humans. OT

injections can be said to increase non-specific social affiliative behavior, the results differing by

time period of injections and the baseline of behavior. If the baseline is pure monogamy, chronic

injections can cripple that baseline. In the case of humans, our baseline is far from clear; we can

be monogamous, polygamous, promiscuous, etc. There is no direct correlation we can make in

applying the rat and vole models to humans by dosage and time period of OT treatment.

Humanity cannot be neatly lined up against a monogamous or promiscuous animal species; it is

somewhere in between. Hence, the value of both animal models.

This “somewhere in between” postulation can be seen played out in primates. In a study

on macaques done by Rosenblum et al. (2002), OT levels significantly fluctuated between

species; in the relatively social Bonnet macaques (Macaca Radiate), centralized OT

concentrations located in the cerebrospinal fluid was far higher than in comparatively asocial

Pigtail macaques (Macaca Nemestrina). This research implies that there is a range of effect for

OT, dependent on genetically-determined receptor density and external variables, such as mating.

Or in other words, the baseline social behavior tied to OT can vary even within a species!

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Adult Affiliative Behavior: Vasopressin

The effect of centralized VP infusions in voles recorded by Young et al. (1999) had

intriguing results, differing in whether the species of vole tested was ordinarily monogamous or

promiscuous; the monogamous prairie voles, normally social to begin with, had their affiliative

behavior significantly increased while promiscuous montane voles had little to no change in the

same subset of behavior (Young et al., 1999). The researchers involved postulated that this

difference in effect was a result of the natural and far lower density of vasopressin receptors

(VPR) in montane voles. To test this, transgenic house mice (Mus Musculus) were bred by the

same researchers with a genetic alteration in VPR expression to mimic the densities of prairie

voles; in testing with OT infusions the same results were obtained as with the voles—higher

social afffiliative behavior (Young et al., 1999). From this, the researchers were confirmed in

their hypothesis: VP, like OT, has a range of effect dependent on receptor density.

In some of the most recent research on rats done by Veneema et al. (2013), juvenile rats

were tested in which social affiliative play behavior was recorded while under the effect of

centralized (eg intracerebroventricular) injections of VP a1 receptor antagonist. Compared to

frequency of social play exhibited by control juveniles, male experimental subjects had their

frequency drastically reduced, while female subjects actually increased their frequency. When

the VP antagonist specifically targeted the lateral septum, the opposite results occurred: males

demonstrated a higher frequency of social play while females displayed less (Veneema et al.,

2013). This showcases how VP's effect on social affiliative behavior is dependent on both sex

and brain region.

Adult Affiliative Behavior: Vasopressin and Oxytocin Interactions

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In the case of Microtus Ochrogaster tested by Cho et al. (1999), it was determined that

OT or VP injection alone (without any external stimulus, e.g., mating) only results in the

occurrence of more pro-social behavior unrelated to forming individual social bonds. On the

other hand, the presence of both OT and VP with functioning receptors was enough to produce a

mild increase in partner-preference even without the added stimulus of mating, suggesting that

OT and VP must act in concert to positively influence pair-bonding. Likewise, OT and VP

injections had no effect when either OTR or VPR antagonists were present. This was confirmed

also by the work of Veneema et al. (2013) in their testing of OT receptor antagonist apart from

the VP antagonist, which had no appreciable effect alone.

Human Social Brain and Abnormalities

As a result of advancing technology (i.e., neuroimaging, fMRI, etc) studies have been

able to pinpoint areas of the brain in relation to social cognition. These have largely validated the

physiological discoveries in model animals, as shall be discussed.

For instance, in both rats and mice the medial amygdala is the primary site of expression

for OTR and VPR; this was also confirmed in humans by Kirsch et al. (2005) using fMRI

techniques. In their clinical study of fifteen adult males, OT was intranasally administered and

then each man was tested with negatively emotional stimuli (e.g., fear). The experimental group

displayed drastic reduction of amygdala activity, muting the negative social effect of fear (Kirsch

et al., 2005). A similar study using intranasally-administered OT in conjunction with fMRI done

by Baumgartner et al. (2008) associated a reduction of activity in the amygdala, midbrain, and

dorsal striatum with a suppression of fear and corresponding increase in trust. These results also

confirm the activity of the striatum seen in rats as a result of secretions from the PVN and SON.

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From these, it can be said that OT reduces negative social emotions (e..g, fear) by directly or

indirectly suppressing activity in the amygdala. The same ultimate results were determined for

VP in one of the first studies done for it by Zink et al. (2010), in which adult men were given

intranasal VP and tested for emotional processing of faces. The fMRI results showed greater

activity in the amygdala and reduced activity in the medial prefrontal cortex (mPFC) for the

experimental group, correlated with reduced fear. The interpretation of these results holds true

with the other experiments described—the connections between the amygdala, the fear center,

and the mPFC are more frequently activated in the presence of negative stimuli (e.g., angry

faces), but the presence of VP mutes the resulting activity in the mPFC.

These studies discussed not only confirmed general areas of OT and VP activity also

found in animal models, but pinpointed an additional area in humans linked to complex social

cognition: the prefrontal cortex. Research is still ongoing on this portion of the human brain, and

conclusions about functional connections are very incomplete, mostly relying on derivation from

primate models such as the macaque (Petrides & Pandya, 1999). Unfortunately, these models are

limited in that most primates have a far less developed PFC than humans. In the last decade,

direct neuro-imaging of the human brain has revealed far more of the mPFC's functions which

OT and VP affect. To summarize over a decade's worth of such direct research and not delve into

topics beyond the scope of this paper, the mPFC has been divided into three major portions, each

activated by a particular type of social cognition, outlined in Figure 1.1. While these discoveries

are undoubtedly of use in many areas of therapy, there have not been enough at this point to base

any direct injections of hormones into the mPFC for treatment of ASD.

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Figure 1.1 | Functional Divisions of the Medial Prefrontal Cortex. (Reproduced from Amodio

& Frith, 2006). Within the medial frontal cortex (MFC), there are divisions between emotional

and cognitive processes. Cognition is associated with the posterior region of the rostral MFC

(prMFC); emotional tasks are associated with the anterior region of the rostral MFC (arMFC).

Punishment and reward tasks have been associated with the orbital MFC (oMFC). Line a divides

the prMFC from the caudal MFC, b the prMFC from the arMFC, and c the arMFC from the

oMFC.

Application to Human Behavior: Autism

As a result of all aforementioned research up to this point, the general consensus is that

OT and VP are strongly involved with the processes of social motivation and approach—the first

steps of social affiliation (Miller et al., 2013). Specifically, they have been implicated in social

recognition via experimentation on the general social behavior in rats, pairs bonds in voles, and

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development of widespread social alliances in primates. Considering how strong this implication

is across lower mammals, they are likewise strong candidates for explaining modulation of

human social affiliative behavior and therefore similar or even identical treatment may improve

disorders such as autism.

Given that humans are naturally social animals and form pair-bonds in addition to wider

social structures, it is assumed that any abnormal amount of asocial behavior is linked with a

deficit in the oxytocinergic and vasopressinergic systems (Green et al., 2001; Modi & Young,

2012). That is to say, genetic defects hindering or crippling such systems creates a tendency for

the same behavior seen in an animal species such as Pigtail macaques, which has a lower

expression of the relevant hormone receptors to begin with. This assumption has been solidly

confirmed in multiple forms. According to the research of Green et al. (2001), the defect was an

unusually high concentration of amidated and C-terminal extended OT prohormones to OT in

blood plasma. This suggests an enzymatic malfunction without any error in the genes that code

for OT's precursors, but that does not mean autism cannot also be linked to other genetic

malfunctions.

Some of the most recent research of the human OTR gene and genetic variation in it has

been implicated to be a contributor to ASD in a case-control study (MA et al., 2013). Moreover, a

specific genetic difference was identified to correlate with ASD in these cases: rs35062132.

Expressed OTRs with this variation exhibited increased rate of endocytosis of bound OT and

decreased levels of free Calcium ions; increased cycling by this particular OTR variant may

decrease overall levels of circulating OT and therefore diminish the positive influence on social

behavior. This step forward implies that autism may not only be eventually aided by OT or OTR

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treatment, but also by genetic manipulation.

Before any non-genetic treatments are discussed below, the value of combining intranasal

OT or VP administration with fMRI techniques must be discussed. It is hypothesized that

administering peptides intranasally lets them move through cerebral spinal fluid to the brain from

nasal epithelium clefts; this ultimate result has been supported by the recorded effects of such

treatment, which will be later discussed. fMRIs have been critical in confirming increased

activity in the brain after administration, clinching ultimate cause and effect. However, the exact

mechanism by which OT and VP affect receptors in the brain—directly or indirectly—is not

clear.

A two-month treatment of transcutaneous electrical acupoint stimulation (TEAS) was

recently explored as a possible therapeutic solution for ASD by Zhang et al. (2012) because it

increases release of both OT and VP in the human brain. The basis for this experiment was past

experimentation on rats by Yang et al. (2007) which increased measured levels of VP and OT in

the brain via acupuncture stimulation, and later studies on the improvement of social behavior in

children with ASD via similar electro-acupuncture (Wong & Chen, 2010). While the exact

mechanisms of action by which acupuncture increases activity of OT and VP systems in the brain

is unknown, the previous results mentioned were encouraging enough to warrant further testing,

and peripheral hormone levels could be implied to correlate with central levels given a

significant deviation from normal concentrations at the time of sampling (e.g., while asleep and

compared to a control group). Sampling of plasma by enzyme immunoassay by Zhang et al.

(2012) yielded higher concentrations of both OT and VP in the experimental group, correlated

with significant reduction of asocially-linked emotions—such as fear and anxiety—along with

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firmer control over them when they did occur. Interestingly, the treatment was only effective for

those that were withdrawn and/or passive, not those already aggressive but still asocial (Zhang et

al., 2012).

In a shorter-term experiment performed by Guastalla et al. (2008), a twenty-four hour

intranasal administration of OT to fifty-two human males preceded a thorough test of an

subconscious behavior—eye gaze—tied to social cognition. The experimental group displayed

both increased frequency of locking eyes onto the recorder and overall time of doing so

(Guastalla et al., 2008). Likewise, another double-blind study done by Mikolajczak et al. (2010)

determined that the measure of trust displayed under the effect of OT with either of two different

values at stake—currency and confidential information—was higher, confirming previous

studies' results of the same point and eliminating a confounding factor of that same experiment.

On the other side of the scale, intranasally-administered OT to eighteen human males in a

double-blinded experiment was found to significantly decrease the frequency of aversion

displayed to an angry facial expression (Evans et al., 2010). Moreover, this reduction of negative

social behavior (aversion) was determined to be independent of other financial input, inferring

that OT specifically affects social behavior without direct interaction of others.

Brunnlieb et al. (2013) performed a very similar experiment with intranal administration

of VP on adult men; activation of the right amygdala shown via fMRI was correlated with greater

emotional empathy while the subjects viewed a socially negative scene. Compared to the control

group, the experimental group showed increased activity alongside increased connectivity with

the medial prefrontal cortex (mPFC). Not only was VP confirmed to modulate social emotions,

but also the means of doing so: by reducing suppression of mPFC activity, which in turn

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stimulated the right amygdala. This experiment was unfortunately unable to confirm whether VP

had a direct impact as well.

The effects of OT and VP are more complicated than a simple abnormal concentration

across all humans, unfortunately. In one of the most recent clinical studies on the OT and VP

levels in blood plasma of children by Miller et al. (2013), significant differences were found by

sex and behaviors associated with severe ASD. Females had higher abnormal concentrations of

OT associated with greater anxious behavior and lower VP than males associated with repeated,

rigid mannerisms. Males on the other hand had no significant amount of behaviors that set them

apart from females, despite their higher relative concentrations of VP. These results would

suggest that future treatment of ASD may need to be altered according to sex and desired

behavioral patterns.

Because of the effectiveness of treatments to date, short-term treatments would be

limited to hormonal injections and/or stimulation, and a long-term treatment that hopefully lasts

for life would be genetic recombination.

Limitations on Research and Application

The insights provided by comparative research between humans and animals is relatively

undisputed in reference to multiple generalities (Modi & Young, 2012). Most research has been

focused on the more promising model species: voles, rats, primates, and cats, to name a few.

Unfortunately, with the development of techniques such as functional magnetic resonance

imaging (fMRI), significant variations are being found between even human and primate brains,

which are often the prime correlate utilized in experiments (Sinha, 2005). In recent research by

Zink et al. (2011), fMRI located the left temporoparietal junction in humans to be a critical

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binding site for VP. As research such as this opens new possibilities of treatment, it begins to

make comparative research obsolete. Moreover, any assumption of the same neurophysiological

mechanisms driving behavior between correlate species is suspect, unless it falls under those

well-documented generalities mentioned previously in the paper (e.g., the amygdala and mPFC).

For instance, there is increasing evidence that Bonnet macaques have a wide range of social

tendencies even within tight-knit social groups as a result of a myriad of factors, including

cultural learning (Sinha, 2005). In order to make comparative research more applicable, a wider

range of species tested is necessary to uncover further generalities. Once discovered, these can

provide material from which to extrapolate the function of various structures, as utilized in the

review by Modi & Young (2012).

Conclusion

The majority of the research to date in social neurophysiology for application to disorders

like ASD has been comparative. While this work has laid the foundation for general aims in

future studies and given a number of fruitful insights, caution is necessary; there is simply too

much inter-species and inter-individual variation in the details of structure and function. Recent

advancements in technology and methods also provide direct evidence from which to derive

treatments, subduing the practical use of comparison to model animals (Zink et al., 2011; Zhang

et al., 2012; Zink & Meyer-Lindenberg, 2012). As the primary goal of this field is to treat

disorders, the frequency of experiments will undoubtedly veer toward direct methods in the

future. Treatments for ASD, such as TEAS, have already been proven to have limited value

(Zhang et al., 2012). The value of comparative research remains, though; it is a guide and source

of information from which to aim direct research on humans instead of inevitably inaccurate

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correlations.

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