Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates

Abstract

In a variety of species, development of attachment to a caregiver is crucial for infant survival and partly mediated by the endogenous 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 infancy. 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 caregiver.

Fig. 1.

Infant attachment as a function of the OPRM1 C77G genotype. Attachment was measured as factor scores (mean ± SEM) extracted from a range of behaviors scored during a critical developmental phase (18–24 months of age) as described in Table 1. Scores were significantly higher in 77G allele carriers [n = 27 vs. 69; F(1,94) = 5.6, P = 0.017]. The proportion of variance in attachment behavior accounted for by the OPRM1 C77G genotype, measured as partial eta², was 5.7%.

Fig. 2.

Infant distress vocalization as a function of the OPRM1 C77G genotype (C/C, ■, or C/G, ▴). 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 temporal course of the response over successive separations [genotype × time 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.

Fig. 3.

Social preference mother-infant reunion as a function of the OPRM1 C77G genotype (C/C, ■, or C/G, ▴). 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 carriers had a different course of behavior over separation cycles than did 77C 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 5.6% of the variance in this behavior. (B) Social Contact-Other: Among carriers 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].