Elsevier

Psychoneuroendocrinology

Volume 38, Issue 11, November 2013, Pages 2448-2461
Psychoneuroendocrinology

Presence of a pair-mate regulates the behavioral and physiological effects of opioid manipulation in the monogamous titi monkey (Callicebus cupreus)

https://doi.org/10.1016/j.psyneuen.2013.05.009Get rights and content

Summary

The role of opioid receptors in infant–mother attachment has been well established. Morphine, a preferential μ opioid receptor (MOR) agonist, attenuates separation distress vocalizations and decreases physical contact between infant and mother. However, there is little research on how opioid receptors are involved in adult attachment. The present study used the monogamous titi monkey (Callicebus cupreus) to explore the role of opioid receptors in the behavioral and physiological components of pair-bonding. In Experiment 1, paired male titi monkeys (N = 8) received morphine (0.1, 0.5, or 1.0 mg/kg), the opioid antagonist naloxone (1.0 mg/kg), vehicle, or a disturbance control and were filmed with their pair-mate for 1 h. In Experiment 2, the same eight males received morphine (0.25 mg/kg), naloxone (1.0 mg/kg), vehicle, or a disturbance control and were filmed for an hour without their pair-mates. All video sessions were scored for social and non-social behaviors. Blood was sampled immediately prior to drug administration and at the end of the hour session. Plasma was assayed for cortisol, oxytocin, and vasopressin. In Experiment 1, opioid manipulation had no effect on affiliative behaviors; however, morphine dose-dependently decreased locomotor behavior and increased scratching. In Experiment 2 in which males were separated from their pair-mates, naloxone increased locomotion. Morphine dose-dependently attenuated the rise in cortisol, while naloxone potentiated the increase of cortisol. The cortisol increase following naloxone administration was greater when a male was alone compared to when the male was with his pair-mate. Naloxone increased vasopressin but only when the male was tested without his pair-mate. The present study found that the absence of a pair-mate magnified naloxone's effects on stress-related hormones and behaviors, suggesting that the presence of a pair-mate can act as a social buffer against the stress-inducing effects of naloxone.

Introduction

The role of the opioid system in infant–mother bonds is well established (Herman and Panksepp, 1978, Panksepp et al., 1980, Kalin et al., 1988, Kalin et al., 1995, Nelson and Panksepp, 1998). Infants separated from their mother or primary attachment figure emit stereotyped separation vocalizations (Panksepp et al., 1980, Hoffman et al., 1995, Mason and Mendoza, 1998). Preferential MOR agonists (such as morphine and oxymorphone) attenuate these distress vocalizations in young that develop selective attachments to their mothers, such as guinea pigs (Herman and Panksepp, 1978), dogs (Panksepp et al., 1978a), monkeys (Kalin et al., 1988), and chickens (Panksepp et al., 1978b, Panksepp et al., 1980). In contrast, non-specific opioid antagonists such as naltrexone or naloxone, either have no effect or intensify these vocalizations (Herman and Panksepp, 1978, Panksepp et al., 1980, Kalin et al., 1988, Nelson and Panksepp, 1998). Polymorphisms of the OPRM1 gene coding for the MOR in monkeys have also been found to affect separation vocalizations (Barr et al., 2008).

Nelson and Panksepp (1998) have argued that individuals seek to obtain an optimal opioidergic tone, which can be modulated by an attachment figure. Disruptions to opioidergic activity through separation from an attachment figure result in behavioral and physiological changes such as separation vocalizations and activation of the hypothalamic–pituitary–adrenal (HPA) axis. In addition to its effects on separation vocalizations, exogenous opioid manipulation has also been shown to affect the HPA axis (Wand et al., 1998). Acute administration of MOR agonists decreases cortisol concentrations in humans (Zis et al., 1984), macaque monkeys (Broadbear et al., 2004), and sheep (Parrott and Thornton, 1989), while naloxone and naltrexone increase cortisol concentrations in humans (Wand et al., 1998), nonhuman primates (Fabre-Nys et al., 1982), and sheep (Parrott and Thornton, 1989). It is hypothesized that distress vocalizations emitted during separation act to attract the mother, thereby reinstating an infant's ideal opioidergic tone and HPA homeostasis (Panksepp et al., 1980, Nelson and Panksepp, 1998).

In addition to opioids regulating infant–mother attachments, opioids also appear to have a role in affiliative behavior in adult, nonhuman, Old World primates living in large social groups. In talapoin monkeys and macaques, morphine administration decreases the number of grooming solicitations and the amount of grooming received, while naloxone administration increases grooming solicitations and the receipt of grooming (Fabre-Nys et al., 1982, Keverne et al., 1989, Martel et al., 1995). Receipt of grooming results in a release of β-endorphins (Keverne et al., 1989), which primarily bind to MORs (Goodman et al., 1983). It has been proposed that morphine administration results in overactivation of MORs, which ends in an adjustment in an animal's behavior to maintain a homeostatic level of MOR activation by decreasing the amount of grooming received (Nelson and Panksepp, 1998). In contrast, administration of naloxone or naltrexone is predicted to increase the amount of grooming received, which would compensate for the decrease in MOR activation.

The role of opioids in affiliative behavior among adult animals has also been explored in the formation and maintenance of monogamy. The filial-like attachment bond formed between adults in monogamous species enables the possibility of exploring the potential contribution of opioids in this unique social system (Mason and Mendoza, 1998). The neurobiology of adult attachment has focused primarily on neuropeptides such as oxytocin (OT) (Williams et al., 1994, Carter et al., 1995, Smith et al., 2010, Young et al., 2011a, Schneiderman et al., 2012) and vasopressin (AVP) (Winslow et al., 1993, Jarcho et al., 2011, Young et al., 2011a, Gouin et al., 2012) as well as the neurotransmitter dopamine (Aragona et al., 2003, Curtis et al., 2006, Young et al., 2011a). In the monogamous prairie vole, systemic administration of the opioid antagonist naltrexone, or local administration of the specific MOR antagonist CTAP into the dorsal striatum, prevents pair-bond formation (Burkett et al., 2011). Shapiro et al. (1989) found that morphine can reduce side-by-side contact in prairie voles at high doses that also affect locomotor behavior. However, opioid blockade with naloxone or naltrexone has repeatedly failed to increase physical contact in prairie voles whereas it does in nonmonogamous primates (Shapiro et al., 1989, Burkett et al., 2011, Resendez et al., 2012). One of the questions we are concerned with is whether the differences between voles and macaques are due to their social structure or phylogenetic status. The manner in which opioid receptors influence affiliative behaviors may vary depending on the neurophysiological differences found in monogamous versus nonmonogamous species or those found in rodent versus primate species. The present study attempts to answer this question through the use of a monogamous primate species.

The titi monkey (Callicebus cupreus) is a socially monogamous nonhuman primate that forms strong, heterosexual pair-bonds (Mason, 1966), and therefore acts as an excellent nonhuman primate model to examine whether the opioid system is involved in adult attachment. Titi monkeys spend a significant amount of time in physical contact and proximity (Mason, 1966). Furthermore, involuntary separation of pair-mates results in a separation distress response similar to that seen in infants in that there is an increase in separation distress vocalizations and HPA activity (Cubicciotti and Mason, 1975, Mendoza and Mason, 1986a, Mason and Mendoza, 1998, Ragen et al., 2012). By examining the effects of opioid manipulation in a primate species that also exhibits a monogamous social structure, we will be able to answer the question whether the contrasting findings between voles and macaques are due to a monogamous social structure or phylogenetic differences. We will also be able to determine whether opioids regulate the separation distress response in an adult attachment compared to an infant–mother attachment.

If opioid manipulation in titi monkeys is more akin to those in other nonhuman primate species, opioid blockade with naloxone would increase affiliative behavior while activation would decrease it. Additionally, opioid activation with morphine would be able to suppress the separation distress response experienced upon brief social separation. We also sought to determine whether opioid manipulation could affect hormones involved in attachment, including cortisol, OT, and AVP. Based on previous studies we hypothesized that naloxone would increase cortisol and OT while morphine would decrease cortisol and OT; however we made no specific hypothesis in relation to AVP since previous findings have been inconsistent (Fabre-Nys et al., 1982, Zis et al., 1984, Parrott and Thornton, 1989, Van Wimersma Greidanus and Van De Heijning, 1993, Wand et al., 1998, Vuong et al., 2010).

Section snippets

Subjects

Subjects were eight titi monkey (Callicebus cupreus) males, housed at the California National Primate Research Center. Subjects were a mean age of 9.3 years (range = 5.4–14.1) and had been housed together with their female pair-mates for a mean (±SEM) of 33.3 ± 10.9 months. Subjects’ mean (±SEM) weight was 1.41 ± 0.06 kg. Female pair-mates were a mean age of 7.3 years (range = 4.1–13.8) and a mean (±SEM) weight of 1.16 ± 0.06 kg. All females had previously given birth with either the current or previous

Behavior

There was a significant effect of Treatment on Grooming, Male Approach, and Male Leave but not for other affiliative/social behaviors (for all comparisons, see Table 3). There was a significant effect of Treatment on Grooming [F(4, 27) = 3.72, p < 0.05]. Compared to vehicle, there was less Grooming in response to naloxone [F(1, 27) = 6.55, p < 0.05], the low [F(1, 27) = 6.45, p < 0.05], medium [F(1, 27) = 10.05, p < 0.01], and high [F(1, 27) = 11.42, p < 0.01] doses of morphine. There was a significant effect of

Discussion

The present study examined whether the opioid system was involved in affiliative behavior and the separation distress response in a monogamous primate and whether manipulation of this system is more similar to nonmonogamous primates or a monogamous rodent. We also investigated the effects of opioid manipulation on plasma OT, AVP, and cortisol concentrations. We did not find any changes in the majority of social behaviors in response to morphine or naloxone in titi monkeys. However, we did find

Role of the funding source

Funding for this research was provided by the Good Nature Institute, NICHD: HD053555, Office of Research Infrastructure programs: Grant P51OD01107, and the American Society of Primatologists Small Grant. Funding sources had no role in designing the study, data analysis, interpretation of the data, writing of the report or the decision to submit the paper for publication.

Conflict of interest

None of the authors had any conflicts of interest.

Acknowledgments

Funding was provided by the Good Nature Institute and NICHD: HD053555 to K.L.B., Office of Research Infrastructure programs: Grant P51OD01107 to the CNPRC, and the American Society of Primatologists Small Grant to B.R. We would like to acknowledge California National Primate Research Center research services and husbandry for their daily care of the animals. We are grateful for the invaluable help of Rebecca Simon, Thomas Schaefer, Gillian Meyers and Sarah Carp in running test sessions as well

References (67)

  • K.D. Laugero et al.

    Plasma omega 3 polyunsaturated fatty acid status and monounsaturated fatty acids are altered by chronic social stress and predict endocrine responses to acute stress in titi monkeys

    Prost. Leukotr. Ess.

    (2011)
  • F.L. Martel et al.

    Opioid receptor blockade reduces maternal affect and social grooming in rhesus monkeys

    Psychoneuroendocrinology

    (1993)
  • S.P. Mendoza et al.

    Contrasting responses to intruders and to involuntary separation by monogamous and polygynous New World monkeys

    Physiol. Behav.

    (1986)
  • S.P. Mendoza et al.

    Parental division of labour and differentiation of attachments in a monogamous primate (Callicebus moloch)

    Anim. Behav.

    (1986)
  • E.E. Nelson et al.

    Brain substrates of infant–mother attachment: contributions of opioids, oxytocin, and norepinephrine

    Neurosci. Biobehav. Rev.

    (1998)
  • M.E. Olds

    Reinforcing effects of morphine in the nucleus accumbens

    Brain Res.

    (1982)
  • J. Panksepp et al.

    Endogenous opioids and social behavior

    Neurosci. Biobehav. Rev.

    (1980)
  • J. Panksepp et al.

    Reduction of distress vocalization in chicks by opiate-like peptides

    Brain Res. Bull.

    (1978)
  • R.F. Parrott et al.

    Opioid influences on pituitary function in sheep under basal conditions and during psychological stress

    Psychoneuroendocrinology

    (1989)
  • S.C. Ribeiro et al.

    Interface of physical and emotional stress regulation through the endogenous opioid system and mu-opioid receptors

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2005)
  • G. Schino et al.

    Opiate receptor blockade in juvenile macaques: effect on affiliative interactions with their mothers and group companions

    Brain Res.

    (1992)
  • I. Schneiderman et al.

    Oxytocin during the initial stages of romantic attachment: relations to couples’ interactive reciprocity

    Psychoneuroendocrinology

    (2012)
  • L.E. Shapiro et al.

    Affiliative behavior in voles: effects of morphine, naloxone, and cross-fostering

    Physiol. Behav.

    (1989)
  • P.D. Skoubis et al.

    Blockade of ventral pallidal opioid receptors induces a conditioned place aversion and attenuates acquisition of cocaine place preference in the rat

    Neuroscience

    (2003)
  • A.S. Smith et al.

    Manipulation of the oxytocin system alters social behavior and attraction in pair-bonding primates, Callithrix penicillata

    Horm. Behav.

    (2010)
  • T.B. Van Wimersma Greidanus et al.

    Opioid control of vasopressin and oxytocin release

    Regul. Pept.

    (1993)
  • G.S. Wand et al.

    Naloxone-induced cortisol predicts mu opioid receptor binding potential in specific brain regions of healthy subjects

    Psychoneuroendocrinology

    (2011)
  • K.A. Young et al.

    The neurobiology of pair bonding: insights from a socially monogamous rodent

    Front. Neuroendocrinol.

    (2011)
  • K.A. Young et al.

    The role of mesocorticolimbic dopamine in regulating interactions between drugs of abuse and social behavior

    Neurosci. Biobehav. Rev.

    (2011)
  • A.P. Zis et al.

    Morphine inhibits cortisol and stimulates prolactin secretion in man

    Psychoneuroendocrinology

    (1984)
  • B.J. Aragona et al.

    A critical role for nucleus accumbens dopamine in partner-preference formation in male prairie voles

    J. Neurosci.

    (2003)
  • K.L. Bales et al.

    Validation of oxytocin and vasopressin plasma assays for primate: what can blood tell us?

    Am. J. Primatol.

    (2005)
  • C.S. Barr et al.

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

    Proc. Natl. Acad. Sci. U. S. A.

    (2008)
  • Cited by (27)

    • Neurobiology of Pair Bonding

      2019, Encyclopedia of Animal Behavior, Second Edition: Volume 1-5
    • Neurobiology of pair bonding

      2019, Encyclopedia of Animal Behavior
    • Pair bond formation leads to a sustained increase in global cerebral glucose metabolism in monogamous male titi monkeys (Callicebus cupreus)

      2017, Neuroscience
      Citation Excerpt :

      Thirty CSF samples were assayed for OT, because there were five samples that did not have sufficient volume to measure both hormones. Plasma cortisol concentrations were estimated in duplicate using commercial radioimmunoassay kits (Siemens Healthcare, Malvern, PA, USA), previously validated for titi monkeys (Mendoza, unpublished data) and has been used many times to analyze cortisol in this species (Hoffman et al., 1995; Bales et al., 2007; Jarcho et al., 2011; Laugero et al., 2011; Ragen et al., 2013). Prior to assay, samples were diluted 1:4 in PBS gel buffer.

    View all citing articles on Scopus
    View full text