Variation at the mu-opioid receptor gene (OPRM1)
influences attachment behavior in infant primates
Christina S. Barr*†‡, Melanie L. Schwandt*, Stephen G. Lindell*, J. Dee Higley§, Dario Maestripieri¶, David Goldman†,
Stephen J. Suomi?, and Markus Heilig*
*Laboratory of Clinical and Translational Studies, National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892;
†Laboratory of Neurogenetics, National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, Rockville, MD 20852;§Department of
Psychology, Brigham Young University, Provo, UT 84602;¶Department of Comparative Human Development, University of Chicago, Chicago, IL 60637;
and?Laboratory of Comparative Ethology, National Institutes of Health/National Institute of Child Health and Human Development, Poolesville, MD 20837
Edited by Mortimer Mishkin, National Institutes of Health, Bethesda, MD, and approved February 13, 2008 (received for review October 30, 2007)
In a variety of species, development of attachment to a caregiver
is crucial for infant survival and partly mediated by the endoge-
nous opioids. Functional mu-opioid receptor gene polymorphisms
are present in humans (OPRM1 A118G) and rhesus macaques
(OPRM1 C77G). We hypothesized that rhesus infants carrying a
gain-of-function OPRM1 77G allele would experience increased
reward during maternal contact and would, therefore, display
increased measures of attachment. We collected behavioral data
from rhesus macaques (n ? 97) during early infancy and at 6
months of age, across four cycles of maternal separation (4 days)
and reunion (3 days). Animals were genotyped for the OPRM1
C77G polymorphism, and the effects of this allele on attachment-
related behaviors were analyzed. Infants carrying the G allele
exhibited higher levels of attachment behavior during early in-
fancy. During prolonged periods of maternal separation, although
infant macaques homozygous for the C allele exhibited decreases
in their levels of distress vocalization with repeated separation,
this response persisted in G allele carriers. The OPRM1 77G allele
also affected social preference during reunion. C/G infants spent
increasing amounts of time in social contact with their mothers as
a function of repeated separation and were less likely to interact
with other individuals in the social group, a pattern not observed
among infants with the C/C genotype. These findings suggest a
role for OPRM1 variation in the expression of attachment behavior
in human subjects, especially as a function of separation from the
genetic ? rhesus macaque ? mother-infant bond ? C77G ? A118G
of nourishment, but also for protection from injury and preda-
tion. In a wide variety of animal species, attachment increases
the motivation of an infant to use evolutionarily conserved
behavioral strategies to maintain proximity to its mother and to
gain her attention during periods of separation (1). The sepa-
ration distress response is an important expression of infant
attachment, because cries signal an infant’s location, permitting
the mother to locate and retrieve it when the two are separated
(2). This adaptive response may be especially important during
later stages of infancy, when mothers begin to engage in con-
sortships, leaving their infants behind (3). This is also the
developmental phase during which infants become more mobile
and independent and, therefore, begin to wander from their
mothers to play and explore.
The stress-mitigating and rewarding effects that an infant
experiences while interacting with its mother are thought to be
mediated in part by release of the endogenous opioids (4, 5), and
work in rodents, dogs, and primates suggests that the diminution
in endogenous opioid system activation during mother–infant
separation is important in eliciting a distress vocalization re-
sponse (6–8). In fact, it has been stated that separation distress
may reflect a state of ‘‘endorphin withdrawal’’ (9). Studies
ormation and maintenance of the mother–infant attachment
bond is essential to infant survival, not only for the provision
performed during mother–infant separation show that nonse-
dating doses of morphine reduce separation distress vocalization
and that mu-opioid receptor blockade with naloxone produces
opposite effects (6, 9). During periods of mother–infant reunion,
when mothers attend to their infants, groom them, cradle them,
and keep them in close physical contact, the endogenous opioid
system is said to be reactivated, reinforcing the established
attachment bond. Consistent with this, pharmacologic studies
demonstrate that the degree to which an infant clings to its
mother is decreased with nonsedating doses of morphine and,
conversely, potentiated with mu-opioid receptor blockade (10,
11). Effects of mu-opioid receptor activation and blockade on
these behavioral responses have been demonstrated in a wide
variety of species, including rhesus macaques (6, 8, 11).
Four distinguishing characteristics of attachment have been
described for primates: secure base (using the attachment figure
as a secure base from which to explore), safe haven (returning
to the attachment figure for comfort/safety in the face of
to the attachment figure), and separation distress (distress in the
actual or virtual absence of the attachment source) (2). It is
known that both the strength and the quality of the attachment
bond differ among human subjects (9). Like humans, rhesus
and social attachment is partially attributable to heritable factors
(13). This suggests that genetic factors may contribute to indi-
vidual variation in attachment behavior during infancy, but no
specific loci contributing to this variation have yet been identi-
to prevent the emission of separation-induced vocalization in
mice (8). However, to date, there have not been any studies
examining whether spontaneous variation in the OPRM1 gene
influences the quality of attachment in a primate. Such findings
could potentially have implications in terms of both vulnerability
to psychopathology and natural selection.
In both humans and rhesus macaques, polymorphisms in the
OPRM1 gene (OPRM1 A118 G and C77G, respectively) cause
amino acid substitutions in the N-terminal arm of the receptor,
conferring increased affinity for ?-endorphin in vitro (14, 15).
Although the exact mechanism remains unclear (16, 17), in vivo
data support a gain-of-function role for these variants, as shown,
for example, by increased alcohol-induced stimulation, an effect
Author contributions: S.J.S. and M.H. contributed equally to the work; C.S.B., S.G.L., J.D.H.,
D.G., and S.J.S. designed research; M.L.S. and S.G.L. performed research; J.D.H., D.G., and
and C.S.B., D.M., and M.H. wrote the paper;
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
‡To whom correspondence should be addressed. E-mail: email@example.com.
This article contains supporting information online at www.pnas.org/cgi/content/full/
© 2008 by The National Academy of Sciences of the USA
April 1, 2008 ?
vol. 105 ?
no. 13 ?
mediated through release of endogenous opioids (18–20). The
aim of the present study was to examine whether the rhOPRM1
77G allele would influence attachment behavior in rhesus
macaque infants. We predicted that infants carrying this gain-
of-function variant would experience increased reward from
being in contact with their mothers, resulting in increased
measures of attachment and a higher degree of distress during
maternal separation. Because of the role of the endogenous
opioids in the reinforcement of the attachment bond during
reunion, we wanted to test whether this variant influenced
attachment behavior as a function of repeated mother–infant
separations and reunions. As part of the weaning process, infants
were subjected to four cycles of 4-day-long maternal separation,
variant on the frequency of distress vocalization during periods
of maternal separation and on preference for maternal contact
during periods of reunion.
The frequency of the G allele was 15%, and genotype frequen-
cies did not deviate from Hardy–Weinberg equilibrium. Consis-
tent with prior studies, homozygosity for the G allele was
uncommon (15). Because preliminary analyses demonstrated no
difference in outcomes between G/G (n ? 1) and C/G animals
(n ? 26), these were collapsed into a ‘‘G allele carrier’’ group for
the all analyses performed.
Extraction of Varimax rotated orthogonal factors from be-
havioral data collected during infancy identified three factors
with eigenvalues ?1.0, which together explained 58.0% of the
variance. Based on factor loadings shown in Table 1 (positive
loading for social contact-mother and mutual break), one of
these was identified as ‘‘attachment.’’ OPRM1 77G carriers
scored significantly higher on this factor than 77C homozygous
individuals [n ? 27 vs. 69; F(1,94) ? 5.6, P ? 0.017; Fig. 1]. The
proportion of variance in attachment behavior accounted for by
OPRM1 C77G genotype, measured as partial eta2, was 5.7%.
Scores on the other two factors, ‘‘gregariousness’’ and ‘‘asser-
tiveness,’’ were not influenced by genotype (not significant; data
Acute separation distress vocalization [emitted on the first day
of separation and known to be a universal response among both
free-ranging and captive primates (21–23)] did not show a
consistent pattern of differences (not significant; data not
shown). In contrast, during protracted periods of separation,
there was a main effect of genotype on the level of vocalization
[n ? 25 vs. 64; F(1,88) ? 5.2, P ? 0.025] and a differential
temporal course of the response over successive separations
P ? 0.007]. Whereas vocalization among infants homozygous for
the major OPRM1 77C allele declined over separation cycles,
high levels of distress vocalization persisted with repeated sep-
aration among carriers of the 77G allele (Fig. 2). The OPRM1
C77G genotype and its interaction with separation exposure
accounted for 9.4% of the observed variance in vocalization.
The OPRM1 77G allele also affected social preference during
reunion (Fig. 3). In general, the time that an infant spent with
its mother during reunion was much higher than that observed
before the first mother–infant separation. When data collected
during mother–infant reunion were considered over repeat
separation cycles and as a function of genotype, G allele carriers
exhibited a different course of behavior than did 77C homozy-
gotes [n ? 26 vs. 64; OPRM1 genotype ? time interaction,
F(3,252) ? 3.2, P ? 0.02]. Whereas C/G infants exhibited
progressive increases in the amount of time spent in contact with
their mothers with repeated separation, those with the C/C
genotype did not (Fig. 3A). The interaction of the OPRM1
genotype with time accounted for 5.6% of the variance. Among
G allele carriers, there was also a decrease in the amount of time
spent with other group members over repeated separation–
reunion cycles [Fig. 3B; F(3,243) ? 3, P ? 0.03], demonstrating
that the increased time spent in maternal contact was not
reflective of a nonspecific increase in sociability and, therefore,
was suggestive of increased preference for maternal contact.
A child’s fear of being left alone is among those referred to as
the ‘‘irrational fears of childhood.’’ Bowlby (2) used an etho-
Table 1. Behavioral dimensions generated by factor analysis
1. Gregariousness3.684Explore environment
2. Assertiveness 1.714
Behavioral dimensions generated by using factor analysis. Behaviors col-
lected over the 18th through the 24th weeks of life were averaged, and
factor loadings, one of these was identified as infant attachment.
Attachment was measured as factor scores (mean ? SEM) extracted from a
range of behaviors scored during a critical developmental phase (18–24
allele carriers [n ? 27 vs. 69; F(1,94) ? 5.6, P ? 0.017]. The proportion of
measured as partial eta2, was 5.7%.
Infant attachment as a function of the OPRM1 C77G genotype.
type (C/C, ?, or C/G, Œ). Values are mean frequencies of vocalizations (? SEM)
during the chronic phase of four consecutive (S1–S4) cycles of mother–infant
separation. 77G carriers showed overall higher vocalization [main effect of
genotype: n ? 25 vs. 64; F(1,88) ? 5.2, P ? 0.025], and had a differential
interaction, F(3,246) ? 4.2, P ? 0.007]. The OPRM1 C77G genotype and its
interaction with separation exposure accounted for 9.4% of the observed
variance in vocalization.
Infant distress vocalization as a function of the OPRM1 C77G geno-
www.pnas.org?cgi?doi?10.1073?pnas.0710225105Barr et al.
logical approach to argue that such fears could be highly
adaptive, stating that ‘‘all accounts agree on the intensity of
and the intensity of distress that follows when she cannot be
found. All agree, too, on the intensity of clinging that occurs
after the two are reunited.’’ We have shown that a functional
genetic variant in the mu-opioid receptor gene (OPRM1 C77G)
is associated with increases in such behaviors in infant macaques.
We found that the OPRM1 77G allele was associated with the
attachment behavioral dimension, assessed at a developmental
and, as such, begin to wander, play, and explore. We also
demonstrated that these infants exhibit more of a protest re-
sponse when separated from their mothers. Although most
infants decreased their levels of vocalization during protracted
periods of maternal separation, carriers of the OPRM1 77G
allele were more likely to persist in this response, even after
repeated separation exposures. The fact that rhesus macaque
infants with the C/G genotype persist, despite the absence of
maternal responding, represents a behavior that could be highly
adaptive, especially during periods of stress or when food
to frequently leave infants behind for protracted periods of time
to forage for food or to engage in consortships or aggressive
encounters with conspecifics (3). Proximity maintenance after
mother–infant reunion would also be predicted to confer selec-
tive advantage, because, during times of stress or social conflict,
when mother–infant separation may become more common,
OPRM1 77G allele carriers would be expected to remain in close
proximity to their mothers, making them less vulnerable to
injury, predation, or aggression from conspecifics.
We report a consistent behavioral pattern indicative of in-
creased attachment in rhesus macaques carrying a variant in the
OPRM1 gene that appears to confer increased affinity for
?-endorphin. The effect size contributed by this variant is in the
range expected for complex, polygenic behavioral traits, and the
combined use of spontaneous genetic variation and an experi-
mental challenge seems to be advantageous for detecting this
type of effect. The OPRM1 variation accounted for ?5–10% of
the variance in the different attachment behaviors observed.
Notably, frequency-based association studies have a limited
power to detect effect sizes at this level, and therefore require
considerably larger sample sizes (24). Our study adds to a line of
that illustrate the gain in power that comes from measuring
quantitative traits under experimental conditions and applying
general linear models to test an a priori hypothesis.
Several studies have demonstrated that cases exist in which
genetic variants that are functionally similar to those that exist
in humans are present in macaques (15, 18, 27, 29). This affords
us the opportunity to examine how genetic variation may influ-
ence complex behavioral traits in subjects living in a controlled
environment (30). Similar to the rhOPRM1 C77G, a polymor-
phism encoding an amino acid substitution in the N-terminal
arm of OPRM1 has independently arisen in humans (OPRM1
A118G) (14). Although its consequences at the molecular level
remain to be fully elucidated (14, 16, 17, 31, 32), recent in vivo
data support the notion that the OPRM1 118G is indeed a
gain-of-function variant, because it is associated with increased
pain threshold, increased sensitivity to euphorogenic effects of
addictive drugs, increased cortisol response after challenge with
the opioid antagonist naltrexone, and higher rates of therapeutic
response to the opioid antagonist naltrexone in alcoholism (19,
20, 33–35). Findings in rhesus macaques suggest that rhOPRM1
77G has a gain-of-function role as well (15, 18), indicating the
human and rhesus OPRM1 variants are functionally similar.
Based on the present data, we cannot exclude the possibility that
another variant in LD with OPRM1 77G contributes to the
functional effects observed here. However, given the functional
parallels between the human and the rhesus variants, the most
parsimonious explanation for their similar functional role in a
range of behavioral and endocrine phenotypes is a direct func-
tional effect of these markers. Because these two variants confer
similar functional effects and, further, both are observed at
relatively high frequencies, it might be hypothesized that they
have evolved as result of similar selective pressures in the two
species. Data to directly address this hypothesis are not presently
Infants carrying the OPRM1 77G allele exhibited stronger
attachment to their mothers in baseline conditions. Unlike other
infants, who spent time playing, exploring, or interacting with
other members of the social group, these infants remained in
close contact with their mothers. The more intense distress
responses to separation and greater contact time with their
mothers during reunion, which emerged among G allele carriers
after repeated mother–infant separation, shares some charac-
teristics with what has been proposed as an anxious/ambivalent
form of insecure attachment in human children (9). Because of
the involvement of the reward systems in the development of
considered an addictive disorder (36), and ‘‘insecure early
attachment’’ is believed to be a risk factor for substance abuse
and addiction (37, 38). Of interest, we have shown there to be
increased levels of alcohol preference in rhesus monkeys carry-
ing the OPRM1 77G allele (15, 18), and OPRM1 variation has
been linked to various addictive disorders in human populations
(25). Our findings may, therefore, lend support to ethological
arguments in favor of attachment theory and its association with
psychopathology, not necessarily in terms of causality, but by
pointing to common underlying genetic or neurobiological sub-
strates. They also highlight how traits that could have theoret-
C77G genotype (C/C, ?, or C/G, Œ). Values are given as the average duration of
time that an infant spent in social contact with its mother or with other
members of the social group (sec ? SEM) in a 300-sec scoring session during
each of four reunion cycles (R1–R4). (A) Social Contact-Mother: 77G allele
homozygotes [n ? 26 vs. 64; OPRM1 genotype x time interaction, F(3,252) ?
3.2, P ? 0.02]. The interaction of OPRM1 genotype with time accounted for
of the G allele, there was a decrease in the amount of time spent with other
group members over repeated separation–reunion cycles [F(3,243) ? 3,
P ? 0.03].
Social preference mother-infant reunion as a function of the OPRM1
Barr et al.
April 1, 2008 ?
vol. 105 ?
no. 13 ?
ically conferred selective advantage at some point in the evolu-
tionary history of humans can increase risk for addictive
disorders in modern society.
Bowlby (2) proposed that ‘‘a child’s safety lay in proximity to
its mother and that the behaviors of both child and mother must
have adapted to maintain it.’’ He also stated that, despite the fact
that such behaviors have no obvious role in improving infant
survivability in contemporary society, they persist. The results
reported here are in agreement with what would be predicted by
the established role for opioid transmission in mediation of
suggestion of rhOPRM1 77G as a gain-of-function variant (15,
18). It may be that the OPRM1 A118G variant influences the
development of attachment in human subjects and raises
the question of whether, by influencing attachment behavior, the
OPRM1 C77G and A118G polymorphisms could have conferred
selective advantage at some point in the evolutionary histories of
Materials and Methods
Early Rearing and Mother–Infant Separation. All procedures were approved by
the National Institutes of Health Animal Care and Use Committee. Infant
analyses is given together with each result) were reared in indoor–outdoor
males and six to eight adult females with their infant offspring (National
Institutes of Health Animal Center, Poolesville MD). The sample included
with 3 days of reunion between each of four repetitions of the separation
a novel environment or social isolation, infants remained in the home cage
with the social group (consisting of adult females, males, and infants) for the
duration of study, and their mothers were removed from the enclosure. No
maternal siblings or older juveniles were present in any infant’s social group.
first day (Monday) of each separation week was designated as the ‘‘acute’’
phase of mother–infant separation. The second through the fourth days
(Tuesday through Thursday) were designated as the ‘‘chronic’’ phase of
mother–infant separation (see below). After each separation week, infants
were reunited with their mothers for 3 days (Friday through Sunday).
Behavioral Observations. Focal behavioral scoring was performed in 5-min
sessions. Infants were scored two times a week in the social group for the first
24 weeks of life and then once daily for the 2 weeks preceding the first
mother–infant separation (baseline). Three observations were made on the
first day of mother–infant separation: two observations were made immedi-
ately after separation, and another during the second hour of separation
second, third, and fourth days of mother–infant separation (averaged as
chronic separation). Infants were then scored during mother–infant reunion,
twice on the first day of reunion (Friday, averaged as reunion).
Definitions for behaviors that were recorded are listed in supporting
information (SI) Table S1 (environmental exploration, locomotion, mutual
ventral, mutual break, passive, self-direct, social contact-mother, social con-
tact-other, play, vocalization, and aggression). All behaviors were scored in
Behavioral observations were made by multiple observers, who achieved
interobserver reliabilities of at least 85%. In rare instances, behaviors during
not reliably visualize the infant to score it among the other members of the
Genotyping. By using standard extraction methods, DNA was isolated from
whole blood, collected from the femoral vein under ketamine anesthesia (15
mg/kg, i.m.). Genotyping was performed by using the procedure modified
from Miller et al. (15). A portion of OPRM1 exon 1 was amplified from 25 ng
CCA TGG ACA GCA GCG CTG TCC CCA CGA A-3?) and museekr1 (5?-GTC GGA
CAG GTT GCC ATC TAA GTG-3?) in 15 ?l reactions by using AmpliTaq Gold and
2.5 mM MgCl2 according to the manufacturer’s instructions (Invitrogen).
Amplifications were performed on a PerkinElmer thermocycler (9700) with
one cycle at 96°C followed by 30 cycles at 94°C/15 sec, 56°C/15 sec, 72°C/30 sec,
Biolabs) was then performed with 0.5 ?l of PCR product in a total volume of
20 ?l for 2 h at 37°C. Samples were separated by electrophoresis on 10%
polyacrylamide gels, and the C and G alleles were identified by direct visual-
ization after ethidium bromide staining.
analyses, we performed factor analysis to reduce the dimensionality of the
data. By using this approach, we generated behavioral dimensions from
behaviors averaged over the 18th through the 24th weeks of life, a develop-
mental stage at which both captive and free-ranging infants are being
weaned by their mothers and begin to spend much of their time interacting
with other members of the social group, playing, and exploring. We used a
ioral dimensions from the data, followed by standard Varimax normalized
rotation aimed at minimizing loading of individual items on multiple factors.
Behavioral factor scores were then used as dependent variables in ANOVA to
test the hypothesis that infants with different genotypes would exhibit dif-
ferences in one or more behavioral dimensions related to social interactions.
We also wanted to determine whether there were associations of the
OPRM1 77G allele with various behavioral responses to repeat cycles of
maternal separation and reunion. Four objective behavioral measures (vocal-
ization, clinging, variation in social preference, and proximity seeking for the
attachment source) have been established for distinguishing quality and
strength of attachment in rhesus monkey infants (41). Because vocalization
during separation is an opioid-dependent response known to signify attach-
ment across species, we selected this measure a priori as the dependent
variable for our analysis of separation response. We used repeated measures
ANOVA to examine the effect of OPRM1 C77G genotype on distress vocaliza-
repeated maternal separation cycles. First, we performed factor analysis to
determine the underlying data structure. The objective was to examine
whether acute (i.e., emitted on day 1 of each separation), and chronic (i.e.,
emitted during days 2–4 of each separation cycle) vocalizations reflect a
common, or separate behavioral dimensions. By using all measures of vocal-
ization available, a principal component extraction, followed by Varimax
rotation, identified two factors with eigenvalues ?1.0. Together, these ex-
plained 60.0% of the variance. All acute vocalizations loaded ?0.7 onto the
first factor, which accounted for 36.6% of the variance. Chronic vocalizations
loaded 0.4–0.8 on the second factor, which accounted for 23.0% of the
variance. Because of this, acute and chronic vocalizations were analyzed
For behaviors collected during mother–infant reunion, we wanted to
examine the effects of genotype on behaviors relating to proximity seeking
and social preference. We used repeated measures ANOVA to determine
whether the 77G allele contributed to the time infants spent in social contact
with their mothers. Because we were specifically interested in associations of
this variant with the strength of the mother–infant bond (i.e., preference for
the mother), we also tested whether the amount of time infants spent
interacting socially with other members of the social group varied as a
function of the G allele.
The frequency of the G allele was 15%, and genotype frequencies did not
deviate from Hardy–Weinberg equilibrium. Because preliminary analyses
(n ? 26), these were collapsed into a ‘‘G allele carrier’’ group for all of the
analyses performed. Sex and preseparation baseline behaviors were evalu-
ated as covariates and kept in the model if they reduced residual variance. In
instances in which there was nonhomogeneity of variance, analyses were
repeated on rank-transformed data, but yielded very similar results on both
approaches. A priori power calculation determined that with the available
sample size, the repeated measures analyses would have a power of ?0.70 to
by using Statistica Statistical software (Statsoft).
based on the known pedigrees within the colony, has previously been deter-
mined to be ?1.45%. This indicates that two randomly selected macaques
would share only 1.45% of their genes by descent (approximately equivalent
to a degree of relationship that is observed between second cousins once
removed and third cousins). This demonstrates that most pairs of individuals
have a low degree of relationship, approximating that observed in some
human populations of study (27). To corroborate this for the present study,
www.pnas.org?cgi?doi?10.1073?pnas.0710225105Barr et al.
functionally unrelated markers, six of which had a comparable number of
animals genotyped. None of these markers displayed a pattern that bore any
resemblance to that shown by OPRM1 77G, i.e., a consistent difference in the
various categories of attachment-related behaviors. This remained true after
controlling for sex differences in this response. For these markers, among all
uncorrected P values generated for individual behaviors and time points, all
result from random variation. Because the IBD was sufficiently low, standard
statistical procedures were applied for testing the association of OPRM1C77G
with attachment behavior.
ACKNOWLEDGMENTS. We thank Karen Smith for assistance in the prepara-
tion of this manuscript and the research and animal care staff at the National
Institutes of Health Animal Center for their assistance in data collection. This
work was supported by the National Institute of Child Health and Human
Development and National Institute on Alcohol Abuse and Alcoholism Intra-
mural Research Programs.
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