Mu-opioid receptor (OPRM1) variation, oxytocin levels and maternal attachment in free-ranging rhesus macaques Macaca mulatta

“Thirty-three of the study females (average age 15.1 0.9 years) were followed by trained observers between 700 and 1430, with 30 min samples collected at least twice per week per individual for 9 months using continuous (focal animal) sampling (Altmann, 1974).”

“Functionally similar nonsynonymous OPRM1 SNPs have arisen and been maintained in humans (A118G; Bond et al., 1998) and rhesus macaques (C77G; Miller et al., 2004).”

“Moreover, women’s plasma OT concentrations during both early pregnancy and the early postpartum period show significant positive correlations with maternal behavior (Feldman et al., 2007).”

“Increasing OT levels experimentally also increases affiliation in primates in other contexts, such as between pair-bonded marmosets (Smith et al., 2010), and human couples (Ditzen et al., 2009).”

“…it has been suggested that there are two major components of attachment mechanisms in mammals—one mediating senses of social-absence, and the other senses of social engagement, with the neural circuits involved in the two being quite different (Panksepp et al., 1997; Nelson & Panksepp, 1998).”

“OT has long been known to play an important role in the expression of maternal behavior in both sheep and rodents (reviewed by Numan & Insel, 2003), while growing evidence indicates that it plays a similar role in primates.”

“Relationships between the opiate system and OT have been reasonably well established; it is generally thought that opioids, especially at - and k-receptors, inhibit OT release (Vuong et al., 2010).”

“Since OT is also associated with sexual behavior in primates (e.g., humans, Carmichael et al., 1987; Carter, 1992; cotton-top tamarins, Snowdon et al., 2010), the observed higher levels of OT among NPNL females homozygous for the C allele may indicate that such females are more motivated to mate as…”

“Since OT is also associated with sexual behavior in primates (e.g., humans, Carmichael et al., 1987; Carter, 1992; cotton-top tamarins, Snowdon et al., 2010), the observed higher levels of OT among NPNL females homozygous for the C allele may indicate that such females are more motivated to mate as…”

“Samples were assayed in duplicate for OT by enzyme immunoassay using a commercially available kit (Assay Designs Inc., Ann Arbor, MI), which has been validated for use on rhesus macaque CSF samples by the Emory Assay Core (Winslow et al., 2003).”

“In humans, mothers whose plasma OT levels increased from early to mid/late pregnancy report significantly higher levels of attachment to their fetuses than those whose OT levels decreased or remained stable across the same time period (Levine et al., 2007).”

“…in higher mammals, principally because there is good evidence that the underlying mechanisms of maternal attachment have been evolutionarily co-opted to serve as the basis for all conspecific social bonds (Keverne, 1992; Nelson & Panksepp, 1998; Curley & Keverne, 2005; Broad et al., 2006).”

“, 2007) but also itself stimulates the release of OT (e.g., nursing; McNeilly et al., 1983).”

“, 2008) and humans (Way et al., 2009), suggest that OPRM1 variation may be involved in mediating senses of social-absence, since genotype appears to predict behavioral response to separation or rejection.”

“Increasing OT levels experimentally also increases affiliation in primates in other contexts, such as between pair-bonded marmosets (Smith et al., 2010), and human couples (Ditzen et al., 2009).”

“…in higher mammals, principally because there is good evidence that the underlying mechanisms of maternal attachment have been evolutionarily co-opted to serve as the basis for all conspecific social bonds (Keverne, 1992; Nelson & Panksepp, 1998; Curley & Keverne, 2005; Broad et al., 2006).”

“The G allele for this gene causes an amino acid substitution in the N-terminal arm of the receptor, which was originally reported to increase their affinity for -endorphin (Bond et al., 1998), although this effect may be cell-line dependent (Kroslak et al., 2007).”

“…it has been suggested that there are two major components of attachment mechanisms in mammals—one mediating senses of social-absence, and the other senses of social engagement, with the neural circuits involved in the two being quite different (Panksepp et al., 1997; Nelson & Panksepp, 1998).”

“Further, results in both infant rhesus macaques (Barr et al., 2008) and humans (Way et al.”

“Genetic polymorphisms (e.g., in or related to dopamine receptor genes and the serotonin transporter gene; Fairbanks et al., 2006; McCormack et al., 2009) and neuroendocrine variables (e.g., reproductive and stress hormones, endogenous opioids and oxytocin (OT), and monoamine neurotransmitters;…”

“…et al., 2006; McCormack et al., 2009) and neuroendocrine variables (e.g., reproductive and stress hormones, endogenous opioids and oxytocin (OT), and monoamine neurotransmitters; reviewed by Maestripieri, 2010; Saltzman & Maestripieri, 2011) are known to account for part of this variation.”

“…ventricles of two female rhesus monkeys appeared to increase their interest in and affiliative behavior toward infants, whereas peripheral administration of an OT receptor antagonist that accumulated in the brain appeared to have the opposite effect in a single female (Boccia et al., 2007).”

“Since OT is also associated with sexual behavior in primates (e.g., humans, Carmichael et al., 1987; Carter, 1992; cotton-top tamarins, Snowdon et al., 2010), the observed higher levels of OT among NPNL females homozygous for the C allele may indicate that such females are more motivated to mate as…”

“Our study adds to the growing literature showing that variation in the mu-opioid receptor gene OPRM1 is associated with social attachment and rejection (e.g., Barr et al., 2008; Way et al., 2009; Troisi et al., 2011).”

“Rhesus macaques are seasonal breeders, and in the Cayo Santiago population there is currently a six-month mating season beginning in March, followed by a sixmonth birth season beginning in September (Hoffman et al., 2008).”

“Functionally similar nonsynonymous OPRM1 SNPs have arisen and been maintained in humans (A118G; Bond et al., 1998) and rhesus macaques (C77G; Miller et al., 2004).”

“Following precedent (e.g., Barr et al., 2007; 2008), analyses were undertaken using just two genotypes (C77/C77 vs. G77/C77 and G77/G77 combined) due to the rarity of homozygous G77 individuals.”

“Most females usually give birth every year while in their reproductive prime (ages 4–18), though years are occasionally skipped, with the probability of skipping a year increasing with female age (Hoffman et al., 2010).”

“Rhesus macaque females form long-lasting attachments to their infants that are behaviorally well characterized (e.g., Maestripieri, 2003a; Maestripieri, 2011).”

“As reported elsewhere (Parker et al., 2010), OT assays were conducted on CSF samples collected from a subset of 32 adult females (average age 15.6 1.0 years), of which 20 were lactating, and 12 were classified as Non-Pregnant Non Lactating (NPNL) as they were not pregnant, lactating, or (as rhesus…”

“Holman and Goy (1995) found that infusion of OT into the cerebral ventricles of two female rhesus monkeys appeared to increase their interest in and affiliative behavior toward infants, whereas peripheral administration of an OT receptor antagonist that accumulated in the brain appeared to have the…”

“…in higher mammals, principally because there is good evidence that the underlying mechanisms of maternal attachment have been evolutionarily co-opted to serve as the basis for all conspecific social bonds (Keverne, 1992; Nelson & Panksepp, 1998; Curley & Keverne, 2005; Broad et al., 2006).”

“…et al., 2006; McCormack et al., 2009) and neuroendocrine variables (e.g., reproductive and stress hormones, endogenous opioids and oxytocin (OT), and monoamine neurotransmitters; reviewed by Maestripieri, 2010; Saltzman & Maestripieri, 2011) are known to account for part of this variation.”

“For example, morphine causes a reduction in plasma OT in virgin, but not in lactating, rats (Evans & Olley, 1998).”

“…2006, Sia et al. 2008), show increased distress upon separation from their mothers (Barr et al. 2008), and mothers who carry the G allele are more likely to prevent their infants from separating from them (Higham et al. 2011) (possibly because of the increased distress associated with separation).”

“The mu-opioid receptor and the evolution of mother-infant attachment: theoretical comment on Higham et al. (2011).”

“…OPRM1 77G in non-human primates are associated both with increased negative reactions to social separation and increased positive responses to social affiliation, i.e., enhanced social reward and rejection reactivity (Barr et al., 2008; Way et al., 2009; Higham et al., 2011; Troisi et al., 2011).”

“Similarly, the C77G polymorphism in macaques, equivalent to the human A118G polymorphism, results in higher affiliative behaviour in mothers and infants (Barr et al., 2008; Higham et al., 2011).”

“…and the oxytocin level of adult females with data on mother–offspring affiliation fromCS, it emerged that lactating females with a G allele had higher oxytocin levels, but also prevented separation from their infants more frequently than females homozygous for the C allele [Higham et al., 2011].”

“The G allele is associated with enhanced social attachment in animal models (Barr et al., 2008; Curley, 2011; Higham et al., 2011; Moles, Kieffer, & D’Amato, 2004) and possibly enhanced reactivity to the social environment in humans (Bertoletti, Zanoni, Giorda, & Battaglia, 2012; Troisi et al.,…”

“In rhesus macaques, carrying the G allele of the μ-opioid receptor gene OPRM1, compared with homozygous C alleles, is associated with stronger maternal attachment in infants (14) and more effective prevention of infant separation in mothers (15).”

“Other studies have systematically tested each potential field issue to assess its potential effects (e.g., for urinary C-peptide, Higham et al. 2011).”

“mothering style, where mothers restrain infants limiting their exploration and mother-infant separation (Higham et al., 2011; Mandalaywala et al., 2014).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript and dynorphin (Pdyn) (Panksepp et al., 1994; Parada et al., 2008; Higham et al., 2011; Mileva-Seitz et al., 2012; de Moura et al., 2015); shown in red circles in Fig.”

“As rat [17-19], monkey [20, 21], and human studies [2225] indicate, endogenous opioids are essential for social bonding and mediate sensitivity to social reward.”

“iation in maternal behavior [91] that might be similarly expected to affect behavioral development.”

“…to be conserved in humans, where an analogous polymorphism in the MOR gene has been correlated with increased social affection, increased responses to social rejection and social rewards, and altered social attachment (Barr et al., 2008, Way et al., 2009, Higham et al., 2011, Troisi et al., 2011).”

“This result is in harmony with findings in rhesus macaques (Barr et al., 2008; Higham et al., 2011), which suggest that individuals with certain OPRM1 allelic variants differ in behavior relating to social affiliation.”

“keeping the infants from separating from them (Higham et al., 2011).”

“…behaviors that could theoretically be under selection, including aggressive behavior (Miller et al. 2004), and G allele carriers form stronger attachment bonds with their mothers during infancy (Barr et al. 2008; Higham et al. 2011), especially as a function of repeated maternal separation.”

“For example, m-opioid receptor knockout mice pups have reduced distress during mother–infant separation (Moles, Kieffer, & D’Amato, 2004) and the functional m-opioid receptor gene polymorphism in rhesus macaques (OPRM C77G) was associated with higher levels of infant and maternal attachment behaviors (Barr et al., 200…”

“Alternatively, opioid receptor blockade could enable greater contribution to the baby schema effect by the oxytocin/vasopressin system, which has also been strongly implicated in social cognition (Domes, Heinrichs, Michel, Berger, & Herpertz, 2007; Heinrichs, von Dawans, & Domes, 2009; Higham et al., 2011; Kelley, 200…”

“Others studying the same genotypic variation conclude that the μ-opioid system is less sensitive to resting mother-infant behaviors than it is to an infant's separation from its mother, with infant distress vocalizations playing a proximal role in regaining maternal contact.(63) While reward-seeking may have F IGURE 6…”

“Furthermore, paralleling genetic research on attachment in non-human primates (Barr et al., 2008; Curley, 2011; Higham et al., 2011), research in humans has shown that variation in the gene encoding the μ-opioid receptor (OPRM1) is linked to variation in rejection sensitivity and neural reactivity…”

“On the contrary, G-carriers seem genetically predisposed to better cope with the negative emotions that arise in adverse conditions (Bus-sone et al., 2020; Higham et al., 2011; Troisi et al., 2011).”

“156 The role of μ -opioid receptors in humans can be investigated using receptor-specific radioligands in combination with positron emission tomography (PET).”