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Comparative and Developmental Perspectives on Oxytocin and Vasopressin

Karen L. Bales

University of California, Davis

The neurobiology of social bonding is orchestrated by the neuropeptide hormones

oxytocin and vasopressin. These neuropeptide hormones, while well studied in rodents, are less

understood in non-human primates and humans. In addition, they play a crucial role in the

development of social behaviors including maternal and paternal behavior, pair-bonding,

aggression, and sexual behavior. We are just beginning to understand the long-term effects of

early stressors and exposures on the oxytocin and vasopressin systems, as well as the

consequences of human health-related practices on these systems and their behavioral sequelae.

For instance, humans have long exposed perinatal infants to oxytocin in the form of pitocin

during labor induction. In addition, chronic intranasal oxytocin is now being proposed as a

treatment for developmental disorders including autism and schizophrenia. In this talk, I will

review what is known regarding the role of oxytocin and vasopressin across species and

development, from brain to social group.

Oxytocin and Vasopressin

The role of social connections in human lives has long been a central focus of many

disciplines, including psychology, anthropology, sociology, and religion. More recently, we

have begun to focus on the biology underlying these connections, particularly close social

relationships such as mother-infant and adult romantic relationships. Because the process of

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childbirth involves a unique endocrine environment for the mother, the neurohormone oxytocin

(OT) was identified as a candidate for the formation of mother-infant bonds and the initiation of

maternal behavior (Pedersen & Prange Jr., 1979; Pedersen, Ascher, Monroe, & Prange Jr., 1982).

Because of similarities in chemical structure and sex differences in production, it was

hypothesized that the closely related hormone arginine vasopressin (AVP) served a similar

function in male social bonding (Winslow & Insel, 1991; Winslow, Hastings, Carter, Harbaugh,

& Insel, 1993).

OT and AVP are both nine-amino acid peptides produced in the paraventricular and

supraoptic nuclei of the hypothalamus, and differing only by two amino acids (du Vigneaud,

Ressler, Swan, Roberts, & Katsoyannis, 1954; Zingg, 2002; Verney, 1946; Wang, Young, De

Vries, & Insel, 1998). They are capable of binding to each other's receptors (Gimpl &

Fahrenholz, 2001; Barberis & Tribollet, 1996), with many pharmacological agents having

actions at both OT and AVP receptors (Bankowski, Manning, Seto, Haldar, & Sawyer, 1980;

Manning et al., 1995; Manning, Stoev, Cheng, Wo, & Chan, 2001). AVP is also produced in

several other brain areas, including some of which are sexually dimorphic. Males of many

species have AVP-producing cell bodies in the medial amygdala and bed nucleus of the stria

terminalis, with fibers extending to the lateral septum (De Vries & Villalba, 1997), however

females do not. AVP production in these areas is androgen-dependent (De Vries & Villalba,

1997). OT has one currently known receptor type, while AVP has three (V1a, V1b, and

V2)(Gimpl & Fahrenholz, 2001; Barberis & Tribollet, 1996). In addition, it is important to

remember that OT is also produced peripherally by organs such as the ovaries (Churchland &

Winkielman, 2011), and that it is possible that peripheral OT can act on the brain.

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OT and AVP in Comparative Perspective

While mother-infant bonding is widespread among mammals, the existence of

attachments between adults is less common. The role of OT and AVP in regulation of adult

social bonding was confirmed by studying voles, a taxonomic group of rodents which includes

many closely related species that vary in patterns of social bonding. For instance, pine and

prairie voles (Microtus pinetorum and Microtus ochrogaster) are monogamous, while meadow

and montane voles (Microtus pennsylvanicus and Microtus montanus) demonstrate polygynous

social structures (Getz & Hofmann, 1986; Winslow, Shapiro, Carter, & Insel, 1993). OT and

AVP receptor distribution in the brain varies between monogamous and polygynous vole species

(Shapiro & Insel, 1992; Insel, Wang, & Ferris, 1994; Witt, Carter, & Insel, 1991). In particular,

monogamous voles have higher OT receptor binding in the nucleus accumbens and higher AVP

V1a binding in the ventral pallidum, areas in which there are also high numbers of dopamine D2

receptors. The current model is that the coordinated activation of OT/AVP receptors and D2

receptors in these areas leads to the formation of adult pair-bonds in monogamous vole species

(Lim, Hammock, & Young, 2004; Pitkow et al., 2001; Lim & Young, 2004; Ross et al., 2009a;

Ross et al., 2009b).

The structure and distribution of OT and AVP peptide themselves are highly conserved

across mammals (Acher, Chauvet, & Chauvet, 1995), including most primates (Ragen & Bales,

2012). However, recently it was discovered that some (but not all) New World primates have

genetic variations in the OT gene that result in a different form of OT, which may have

functional consequences (Lee et al., 2011). A study which investigated the role of intranasal OT

(normal sequence) in pair-bonding in a species of marmoset which produces the altered OT

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sequence, found only minimal effects of the conserved peptide on the demonstration of a partner

preference in that species (Smith, Agmo, Birnie, & French, 2010).

OT and AVP are also involved in social bonds in non-monogamous species, although

their role may depend on whether bonds are actually attachments, as defined by Bowlby

(Bowlby, 1969). That is, some types of relationships are characterized by a preference for the

other individual, distress upon separation, and the ability of the attachment figure to serve as a

buffer against stress (Mason & Mendoza, 1998). In species such as mice, rats, or rhesus

monkeys, adults are unlikely to form attachment bonds to other adults. Experimentally

administered extra OT or AVP (or the addition of receptors in areas such as the nucleus

accumbens and ventral pallidum), usually increase general affiliative behavior, without making

these species "monogamous". For instance, increased AVP V1a expression in the ventral

pallidum of mice increased affiliation but did not induce a preference for a familiar partner

(Young, Nilsen, Waymire, MacGregor, & Insel, 1999). The story is more complicated for

closely-related polygynous vole species, which may form partner preferences given certain

conditions (Parker, Phillips, & Lee, 2001). While increasing OT receptors in the nucleus

accumbens of female meadow voles did not induce a partner preference (Ross et al., 2009b),

increasing AVP V1a receptor expression in the ventral pallidum of male meadow voles did

induce a partner preference (Lim et al., 2004).

The structure of the OT and AVP V1a receptor genes may be important in determining

receptor distributions and thus creating different social structures, although it is likely that the

details of these genetic variations differ between species (Hammock & Young, 2005; Babb,

Fernandez-Duque, & Schurr, 2010; Rosso, Keller, Kaessmann, & Hammond, 2008; Walum et

al., 2008). The prairie vole V1a receptor gene has a number of tandem repeats not present in the

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meadow vole gene, and introducing the prairie vole gene into the meadow vole ventral pallidum

increased partner preference (Lim et al., 2004). Within prairie voles, males selectively bred for

increased number of repeats in the V1a promoter region form pair-bonds more quickly

(Hammock & Young, 2005). However, when considering a larger number of rodent species,

longer promoter regions were not associated with social monogamy (Fink, Excoffier, & Heckel,

2006). Humans exhibit a different polymorphism in the V1a receptor gene, the 'RS3'

polymorphism, which has been associated with marital satisfaction in men (Walum et al., 2008),

but is not present in a socially monogamous New World monkey, the owl monkey (Aotus azarai)

(Babb et al., 2010). One SNP for the OT receptor was recently associated with pair-bonding in

human females (Walum et al., 2012), but this requires further investigation.

More unusual rodent species, studied recently, support the viewpoint that while OT and

AVP are probably widely involved in mammalian sociality, it is likely that the mechanisms are

different for each species (see review in Beery, Lacey, & Francis, 2008). For instance, a social

species of tuco-tuco (Ctenomys sociabilis, a South American rodent) had quite different patterns

of OT and AVP V1a receptor binding than a solitary species (Ctenomys haigi) (Beery et al.,

2008). Likewise, two species of singing mice (Scotinomys teguina and Scotinomys

xerampelinus) differed in level of vocality as well as some aspects of social behavior. S.

xerampelinus, the species with higher maternal investment (smaller litter size, larger pups, etc.)

had higher V1a receptor binding in many areas including the medial amygdala and many

thalamic areas, as well as higher OT receptor binding in the nucleus accumbens and central

amygdala; while the more vocal species (S. teguina) had higher V1a receptor binding in the

anterior hypothalamus and periaqueductal gray of the midbrain (an area associated with

vocalizations) (Campbell, Ophir, & Phelps, 2009). The eusocial mole-rat (Fukomys anselli)

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which lives in monogamous, multi-generational families, also shows the presence of OT cell

bodies in the supramammillary nucleus, a finding not found in other rodents (Valesky, Burda,

Kaufmann, & Oeslschlager, 2012). The naked mole-rat (Heterocephalus glaber), also eusocial,

shows higher OTR binding in the nucleus accumbens than solitary Cape mole-rats (Georychus

capensis) (Kalamatianos et al., 2010), which is a similar pattern to that found in monogamous vs.

polygynous vole species.

While the neurobiology of social bonding has been a subject of broad interest, the only

animal model studied in any depth has been the prairie vole. In our laboratory, we have been

developing the titi monkey (Callicebus cupreus) as a non-human primate model for the

neurobiology of social bonding. Titi monkeys are socially monogamous, arboreal New World

monkeys which live in small family groups consisting of a pair-bonded male and female and

their offspring (Mason, 1966; Mason, 1975). They display a strong emotional bond, which

includes all the characteristics of a human attachment (Mason, 1974; Mason & Mendoza, 1998;

Mendoza & Mason, 1997; Mendoza & Mason, 1986), and thus they make an ideal non-human

primate model for human sociality.

When titi monkey males are given intranasal AVP, they increase their contact with a

partner vs. a stranger female (Jarcho, Mendoza, Mason, Yang, & Bales, 2011). They also

experience a decrease in gene expression of pro-inflammatory cytokines. It is possible that the

interaction with their mate provided social support following a stressful experience, thus

inhibiting the inflammatory response. In any case, the direction of the AVP effects on behavior

were consistent with the rodent literature.

Titi monkey males have regional and global changes in brain activity with the formation

of pair-bonds, including many regions that contain OT and AVP receptors, or produce OT and

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AVP. In a cross-sectional study, males in long-term pair-bonds had higher whole-brain glucose

metabolism, and lower adjusted regional glucose uptake in the nucleus accumbens, ventral

pallidum, medial amygdala, medial preoptic area, supraoptic nucleus, and lateral septum (Bales,

Mason, Catana, Cherry, & Mendoza, 2007). Within 24 hours of pairing, males already

experienced changes in glucose metabolism in the direction of the long-term paired males in the

nucleus accumbens and ventral pallidum. In a more recent longitudinal study with age-matched

control males, we found that the paraventricular and supraoptic nuclei still had significantly

elevated glucose uptake a week following pairing (Maninger et al., 2011). In summary, the OT

and AVP systems are clearly involved in pair-bonding in non-human primates as well as in

prairie voles, although the details may differ. For instance, the nucleus accumbens, as well as

cortical areas, may play a more prominent role in primates than in rodents.

Recent human studies have focused on intranasally-delivered OT as an experimental

methodology for manipulating central OT. It is important to remember that the study often cited

to support central nervous system penetrance of intranasal OT (Born et al., 2002) did not actually

examine OT, but AVP and several other peptides. It is quite possible that OT is acting on the

brain via peripheral input (Churchland & Winkielman, 2011), but the distinction should be

remembered. Intranasal OT has been shown to affect reactions to facial expression (Domes et

al., 2010; Domes et al., 2007; Goldman, Gomes, Carter, & Lee, 2011; Marsh, Yu, Pine, & Blair,

2010), as well as facial recognition memory (Savaskan, Ehrhardt, Schulz, Walter, &

Schachinger, 2008), trust (Kosfeld, Heinrichs, Zak, Fischbacher, & Fehr, 2005; Baumgartner,

Heinrichs, Vonlanthen, Fischbacher, & Fehr, 2008), and perceptions of trustworthiness

(Theodoridou, Rowe, Penton-Voak, & Rogers, 2009). All of these processes would be important

in the formation of close relationships in adult humans. On the other hand, in subsets of the

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population, intranasal OT can have the opposite effects (Bartz et al., 2010a; Bartz et al., 2010b).

It will be important to carefully integrate the pharmacological data with measurements of the

endogenous OT system itself (Zak, Kurzban, & Matzner, 2005; Schneiderman, Zagoory-Sharon,

Leckman, & Feldman, 2012). That is, do humans with naturally high baseline levels of OT react

differently to intranasal OT than humans with low baseline levels?

OT and AVP in Developmental Perspective

The OT and AVP systems are present and functional very early in the developing rodent

(Tribollet, Charpak, Schmit, Dubois-Dauphin, & Dreifuss, 1989; Tribollet, Goumaz,

Raggenbass, Dubois-Dauphin, & Dreifuss, 1991; Barberis & Tribollet, 1996), although there are

some age-related changes in the distribution of receptors. There are a large number of early

experiences, pharmacological and more natural, that have been shown to have long-term effects

on the OT and AVP systems and on social bonding behaviors, recently reviewed in Bales and

Perkeybile (2012). One well-known example in rats is the division of mothers into high licking

and grooming (High LG) and low licking and grooming (Low LG) mothers (Meaney, 2001).

High LG mothers produce offspring that are less responsive to stress (Liu et al., 1997), better

mothers (Francis, Diorio, Liu, & Meaney, 1999), and which have higher levels of OT receptors

in the medial preoptic area (Francis, Young, Meaney, & Insel, 2002; Champagne, Diorio,

Sharma, & Meaney, 2001). However, prairie voles make particularly good models for the study

of developmental effects on social behaviors, because in addition to studying female-offspring

behavior, it is possible to study long-term developmental effects on adult male-female bonding

and father-offspring care as well. In our laboratory, we have manipulated both early OT as well

as other early experiences, to examine the long-term effects on social behavior and the OT/AVP

systems.

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Neonatal treatment with OT itself results in long-term changes in many social behaviors.

Pitocin, artificial OT, is used to induce labor in many delivery rooms (Zhang et al., 2011). Given

that stress results in increased permeability of barriers such as the placental barrier and the infant

blood-brain barrier (Laudanski & Pierzynski, 2003), we are most likely exposing the infant's

brain to some level of exogenous OT. In a series of experiments, we found that neonatal

administration of OT to prairie vole pups resulted in a dose-dependent facilitation or disruption

of partner preference in both males and females (Bales et al., 2007b; Carter, Boone, & Bales,

2008). Aggression was increased in OT-treated females that had been exposed to males (Bales

& Carter, 2003), while treatment with either OT or the OT-antagonist (OTA) resulted in changes

in male sexual behavior and lower success getting sperm into the female tract (Bales, Abdelnabi,

Cushing, Ottinger, & Carter, 2004). OTA treatment in males also resulted in lower alloparental

behavior (nurturing behavior towards a strange pup) and higher number of attacks on the pup

(Bales, Pfeifer, & Carter, 2004). The behavioral changes were mediated through changes in

AVP V1a receptors in multiple brain areas (Bales et al., 2007a), with OT up-regulating V1a in

the cingulate cortex in males and OTA down-regulating V1a in the medial preoptic area, bed

nucleus of the stria terminalis, and lateral septum. This suggests that large doses of OT and OTA

given to the developing brain flooded the OT receptors and bound to the V1a receptors.

Other early treatments also affect social behavior and the OT/AVP systems. Handling of

rodent pups is a treatment which has long-term effects on stress reactivity (Levine & Lewis,

1959; Levine, 2002; Denenberg & Whimbey, 1963), possibly through modification of the

mother's behavior upon return of the pups (Smotherman & Bell, 1980; Denenberg, 1999) and/or

pup exposure to novelty (Tang, Akers, Reeb, Romeo, & McEwen, 2006). In prairie voles,

variations in handling of both parents result in long-term changes in male alloparenting and

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female pair-bonding (Bales, Lewis-Reese, Pfeifer, Kramer, & Carter, 2007). In particular,

animals whose parents experienced reduced handling (MAN0) compared to normal colony

animals (MAN1) displayed social deficits later in life. Males were less alloparental, while

females did not form pair-bonds even when given six times the amount of time that control

females would normally take. These changes in behavior were accompanied by up-regulation of

OT receptors in several brain areas (and particularly in females), and lower production of OT in

the supraoptic nucleus (Bales, Boone, Epperson, Hoffman, & Carter, 2011). One key point

demonstrated by this study, as well as by studies of human grief (Taylor et al., 2006) and rodent

social isolation (Grippo et al., 2007) is that high OT or OT receptors may not equal ideal social

circumstances. In fact, the OT system may up-regulate in response to poor early environments

or challenges to attachments.

Other forms of early experience affect later behavior, and possibly the OT and AVP

systems as well. For instance, the experience of alloparenting leads to more "effective"

parenting - spending less time with pups yet the pups gaining significantly more weight (Stone,

Mathieu, Griffin, & Bales, 2010). Just as in rats, offspring of high contact prairie vole parents

display higher levels of social behavior, and lower anxiety; in addition, they also display altered

behavior in an experimental set-up designed to measure dispersal tendencies (Bales, Perkeybile,

and Arias del Razo, unpublished data).

Humans are also engaging in manipulation of developmental OT in clinical contexts

other than pitocin administration. There are a number of clinical trials already in progress to

evaluate the use of chronic intranasal OT for treatment of autism and other psychological

disorders (www.clinicaltrials.gov). In addition to use of OT itself given exogenously, drugs that

cause the brain to endogenously release OT are also being tested. All of these treatments, given

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developmentally, could result in the formation of physiological tolerance via down-regulation

and internalization of the receptor (Gimpl & Fahrenholz, 2001; Ancellin et al., 1999);

potentially, this could result in the opposite behavioral results than those desired. The need for

testing of long-term developmental treatments in animal models before translation to humans, is

therefore paramount.

Conclusions

The OT and AVP systems are closely involved in the neurobiological regulation of social

behavior. This has been shown in a wide variety of mammals, although specific details of

mechanism differ between species. While many of these traits are species-wide, their expression

is often also developmentally plastic. Early experiences of many kinds, including human health

practices, affect the OT and AVP systems and their behavioral output.

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