Not just a four-letter word: The role of neuroendocrine factors in romantic love

Introduction

In his poem ‘Love’s Trinity’, Victorian poet laureate Alfred Austin presents a holistic view of love, describing its impact on both our psyche and physiology:1,2

‘Soul, heart, and body, we thus singly name,
Are not in love divisible and distinct,
But each with each inseparably link’d’
(A Austin).3

Romantic love has influenced literature and the arts for generations, and has recently become topical in neurobiology.2,4,5 Both the presence and the absence of romantic love can be shown to impact on emotional and physical wellbeing. Love is associated with feelings of positivity and reward.4–6 It has been the major factor in some of history’s greatest achievements.7 In contrast, loss of love can be profoundly detrimental to a person’s wellbeing.2 The end of a romantic relationship can be very distressing; bereavement of a spouse has been linked to increased overall mortality for numerous causes (including cancer, stroke, accidents and violence),8 as well as specific ailments such as Takotsubo cardiomyopathy (broken heart syndrome).2,9 This exemplifies the power of love as an emotion. Its impact transcends the individual, its role in forming lasting relationships facilitating mankind’s ability to thrive.1,2,5

Over the past two decades, advances in medical imaging technology have allowed neurobiologists to investigate the neural correlates of psychological processes. Through the use of functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), regions of the brain involved in romantic love have been identified, including parts of the dopamine reward system, and  areas rich in oxytocin and anti-diuretic hormone (ADH) receptors.4,5,10,11

Understanding the neurobiology of romantic love has important implications, such as the scientific basis of relationships and why disruption in a relationship can have profound physiological effects.2 This essay will discuss the role that oxytocin and ADH play in romantic love through their influence on dopamine, and the implications of this knowledge. The limitations in current literature will also be addressed.

Oxytocin and ADH

Oxytocin and ADH production
Figure 1 – Oxytocin and ADH production

Oxytocin and ADH are neurohypophysial hormones synthesised in magnocellular neurones in the supraoptic and paraventricular nuclei of the hypothalamus. The axonal projections of these neurones travel to the posterior pituitary gland, where the hormones are released into the systemic circulation (Figure 1).12–15 Oxytocin plays a key role in reproduction through uterine muscle contraction during birthing and milk ejection when breastfeeding;10,16 ADH is an important hormone in cardiovascular function and regulation of the body’s fluid volume.13,17 Both hormones are also neuropeptides, acting locally within the brain when produced from extrahypothalamic sites.14,18 Through this activity, oxytocin and ADH have been implicated in regulation of a range of social behaviours, e.g. attraction and social bonding.10,14

The prairie vole model on oxytocin and ADH in pair-bonding

Animal research has greatly informed our understanding of the roles of these hormones in romantic love, the vast majority having been done in prairie voles.4,5,10 A small mammal native to North America, the prairie vole has long been a subject of interest in studies of social behaviour due to its monogamous nature.19 Monogamy is found only in approximately 3% of mammals,20 hence studies often compare the prairie vole to species of similar anatomy and physiology but differing in this behavioural aspect, such as the promiscuous montane vole.10 Table 1 lists some behavioural differences between the species.

Behaviour Prairie Vole Montane Vole
Mating System Monogamous Promiscuous
Parental Care Biparental Maternal
Partner Preference High Low
‘Selective’ Aggression High Low
Social Construct High Low
Table 1 – Social behaviour differences in the Prairie and Montane vole species – adapted from Young et al.20

One factor implicated in mating behaviour in these species is a difference in the expression of oxytocin and ADH receptors.20–22 To date, one oxytocin and three ADH receptors have been identified; the oxytocin receptor and V1a ADH receptor are found in the brain, whilst the V1b and V2 ADH receptors are found in the pituitary gland and kidney respectively.23 In the brain, these receptors are distributed throughout regions involved in the dopamine reward system.4,5 A higher distribution of brain oxytocin receptors has been found in prairie voles than in montane voles, especially in regions associated with reward (e.g. the prelimbic cortex and nucleus accumbens), and emotional memory (e.g. the amygdaloid complex).10,20,21 However, in the montane vole, receptors for oxytocin and ADH are not as abundant in regions associated with reward,4 but may be more abundant in the lateral septum, an area involved in emotion and stress response.10,21,24 This distribution variation is evident in other species of monogamous and promiscuous voles, and thus could be key to the different mating habits.21

The prairie vole model becomes even more interesting when the concentrations of oxytocin and ADH, or their receptors, are manipulated. When prairie voles mate, a release of neural oxytocin and ADH occurs, enhancing pair-bonding.25 However, studies have shown that if the release of these hormones is blocked, the monogamous nature of prairie voles is disrupted, and pair-bonding does not occur.26,27 In contrast, if the V1a receptor is expressed in a species that does not show monogamous behaviour naturally, e.g. the montane vole, they start to show attachment behaviours.26 As there is no functional difference between V1a receptors in prairie and montane voles, this change must be attributable to the difference in receptor distribution across the brain.

Human studies and the role of oxytocin in romantic love

The effects of oxytocin on romantic love in humans are less established than in other mammals.10,28 However, in recent years, studies have started to emerge that describe its role in socialising, paternalism and romantic attachment.29–31 A number of double-blind, placebo-controlled trials have looked at the effects of intranasal oxytocin administration, reporting increased feelings of attachment, improved communication within romantic couples, and increased attraction to a romantic partner.32–34 A 2012 meta-analysis concluded that its use leads to improved emotional perception (i.e. recognition of facial expressions) and increased trust in known persons, but does not increase trust in strangers (supporting the theory that oxytocin influences a mother to protect her young from predators).35,36 The drug could therefore benefit trusting relationships, and enhance the effects of behaviour therapies for marital problems. However, there is evidence that oxytocin administration may lead to increased envy, hence the hormone may be implicated in a range of emotional responses.37

Studies have also compared plasma oxytocin concentration in people in relationships to people without romantic attachment. A 2012 study by Schneiderman et al.38 reported a significantly higher plasma oxytocin concentration in 60 new couples compared to 43 non-attached singles. This difference was still statistically significant at six months. The results of this study were in keeping with previous findings that oxytocin levels and attachment anxiety (as measured by the ‘Experiences in Close Relationships’ questionnaire) are positively correlated in romantic love.39 These findings suggest a possible role for oxytocin in initial romantic attachment on finding a suitable partner. However, there is evidence that plasma levels of oxytocin and ADH are not indicative of their neuropeptide concentrations, hence the use of plasma concentration as a biomarker needs clarification.39,40

Dopamine

Oxytocin and ADH production
Figure 1 – Oxytocin and ADH production

Dopamine is a neurotransmitter involved in movement, affect (expressed emotion) and neuroendocrine secretion. Its action is mediated by its five receptor subtypes (D1-D5), split into two major groups: the D1-like receptors and D2-like receptors.41 D1 receptor activation is linked to neuroplasticity and reward-related memory and learning, whilst D2 receptor activity is involved with activation of complex downstream pathways in pair-bonding.42–44 The dopamine reward pathway (Figure 2) plays an important role in emotional attachment.4,5,45 In species that show pair-bonding, this system is densely populated with oxytocin and ADH receptors, and hence is sensitive to the concentration of these hormones.10 When oxytocin and ADH bind to their receptors dopamine is released, thus causing a feeling of reward when romantic love is experienced.46

The prairie vole model on dopamine in pair-bonding

The role of dopamine in romantic love has also been highlighted by the prairie vole model.47 Activation of D2 receptors in the nucleus accumbens of prairie voles (a region of the brain that plays a central role in the dopamine reward pathway – Figure 2) shows partner preference in the absence of mating,48–50 whilst stimulation of D1 receptors has an opposite effect.48 Furthermore, if a D2 receptor antagonist (haloperidol) is infused, social bonding does not occur, even with the presence of oxytocin.49 It is therefore likely that the role of oxytocin in pair-bonding is somewhat reliant on normal dopamine activity. Studies using female voles support this theory: infusing an oxytocin receptor antagonist stops D2 receptor-mediated bonding, whilst blocking D2 receptors interrupts partner preference facilitated by oxytocin.42,51

Studies have also reported that administering a moderate amount of dopamine facilitates pair-bonding, whilst administering a large amount has no effect.47,48 It is thought that this is due to dopamine’s higher affinity for D2 receptors than for D1. Thus, when all the D2 receptors are occupied, dopamine binds to D1 receptors, disrupting the facilitation of pair-bonding.43 Similar activity of dopamine receptors has been reported in addiction studies in rats, in which cocaine-seeking behaviour was facilitated by D2 receptor activity, and inhibited by D1.52 Aragona et al. (2003) reported an upregulation of D1 receptor density in the nucleus accumbens after pair-bond formation for a prairie vole had occurred. Administering D1 receptor antagonists to the nucleus accumbens of male prairie voles has been shown to prevent aggression and promote promiscuous behaviour towards new females.48 It is therefore hypothesised that, having formed a bond with another prairie vole, upregulation of D1 receptors occurs to prevent the forming of new (or multiple) bonds, facilitating monogamy.10

Human studies and the role of dopamine in romantic love

Intranasal oxytocin administration studies in humans have implicated regions of the brain involved in the dopamine reward system in romantic love (e.g. the nucleus accumbens and ventral tegmental area),34 and other functional imaging studies into the neural correlates of romantic love support these findings.5,11,53 Neural activation on account of one’s romantic partner has been noted in a number of regions of the dopamine rewards pathway including the right tegmental area, right caudate nucleus and the medial orbitofrontal cortex (a region also implicated in maternal love5  and perception of facial beauty54).11,53,55,56 In supporting animal studies,4,10 these results may suggest that romantic love in humans uses the body’s reward pathway to focus on an individual, enabling all mating effort to be directed towards a single mate.53,55

Limitations to research

Substantial research has been conducted into the roles of oxytocin, ADH and dopamine in prairie voles,4,10 however extrapolating these findings to human physiology may be inappropriate.2 Although research in humans is increasing, it is still sparse.10 Results of intranasal oxytocin trials may support the theory of oxytocin being involved in romantic attachment in humans but more research is necessary; current studies are limited by sample size and methodological differences, as well as producing conflicting results.35 Furthermore, some tools used to measure romantic attachment are subjective, and studies may be at risk of positive partner response bias (people are more likely to speak positively about their romantic partner).32,34 Some studies have linked elevated plasma oxytocin concentration to romantic love; however it is debatable whether peripheral oxytocin levels are an indicator of neural oxytocin activity.40 Furthermore, there have been no trials assessing the impact of ADH on romantic love in humans. It may also be necessary to look at the effects of these hormones along with others that are known to be implicated in romantic love, e.g. serotonin and nerve growth factor.10

Conclusion

The past two decades have seen an increase in research into the neurobiology of romantic love. Animal models have informed our understanding; research using prairie voles has shown that oxytocin and ADH cause dopamine release, facilitating monogamy through D2 receptor activity in the reward pathway.4,5,10 Variation in distribution of dopamine receptors in other species has been implicated in their lack of monogamous behaviour.20–22 Intranasal oxytocin studies in humans have reported benefits to communication and perceived attractiveness in romantic couples.35 The use of functional imaging could be of great benefit in future research, and has already provided evidence for the role of the dopamine reward pathway in romantic love.4,10

To date, research in humans is limited. Future studies should aim to confirm which regions of the human brain are implicated in romantic love, to enable assessment of the applicability of animal models to humans. Utilising a longitudinal study design would enable assessment of changes in hormone levels and in romantic attachment over time. Current studies into psychiatric medications influencing dopamine should also assess changes in participants’ relationships. Furthermore, with results suggesting that oxytocin may be involved in other emotions, e.g. envy, it is important to look for other effects of the hormone before considering its use as a relationship aid.35,37 Love is a complex emotion, and in a species as highly evolved as humans, concepts such as monogamy are dictated by many factors, e.g. social construct.10 Although results of current studies look promising with regard to the role of neuroendocrine factors, whether a simple biological mechanism can explain romantic love is debatable.

References

  1. Ward JE. Sealed with a Kiss. Lulu.com; 2009.
  2. Young LJ. Being human: love: neuroscience reveals all. Nature. 2009 Jan 8;457(7226):148.
  3. Carter CS, Porges SW. The biochemistry of love: an oxytocin hypothesis. EMBO Rep. 2013 Jan;14(1):12–6.
  4. Zeki S. The neurobiology of love. FEBS Lett. 2007 Jun 12;581(14):2575–9.
  5. Bartels A, Zeki S. The neural correlates of maternal and romantic love. NeuroImage. 2004 Mar;21(3):1155–66.
  6. Esch T, Stefano GB. The neurobiological link between compassion and love. Med Sci Monit Int Med J Exp Clin Res. 2011 Feb 25;17(3):RA65–75.
  7. Bianchi-Demicheli F, Grafton ST, Ortigue S. The power of love on the human brain. Soc Neurosci. 2006;1(2):90–103.
  8. Jones MP, Bartrop RW, Forcier L, Penny R. The long-term impact of bereavement upon spouse health: a 10-year follow-up. Acta Neuropsychiatr. 2010 Oct 1;22(5):212–7.
  9. Golabchi A, Sarrafzadegan N. Takotsubo cardiomyopathy or broken heart syndrome: A review article. J Res Med Sci Off J Isfahan Univ Med Sci. 2011 Mar;16(3):340–5.
  10. de Boer A, van Buel EM, Ter Horst GJ. Love is more than just a kiss: a neurobiological perspective on love and affection. Neuroscience. 2012 Jan 10;201:114–24.
  11. Takahashi K, Mizuno K, Sasaki AT, Wada Y, Tanaka M, Ishii A, et al. Imaging the passionate stage of romantic love by dopamine dynamics. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391262/ (accessed 21/12/2015)
  12. Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev. 2001 Apr;81(2):629–83.
  13. PubMed Health. How does the pituitary gland work?. http://www.ncbi.nlm.nih.gov/books/PMH0072573/ (accessed 19/12/2015)
  14. Lim MM, Young LJ. Neuropeptidergic regulation of affiliative behavior and social bonding in animals. Horm Behav. 2006 Nov;50(4):506–17.
  15. Campbell NE, Reece JB. Biology. 8th edition. San Francisco: Pearson Benjamin Cummings; 2008.
  16. Zeeman GG, Khan-Dawood FS, Dawood MY. Oxytocin and its receptor in pregnancy and parturition: current concepts and clinical implications. Obstet Gynecol. 1997 May;89(5 Pt 2):873–83.
  17. Earley LE. Influence of hemodynamic factors on sodium reabsorption. Ann N Y Acad Sci. 1966 Nov 22;139(2):312–27.
  18. de Vries GJ, Miller MA. Anatomy and function of extrahypothalamic vasopressin systems in the brain. Prog Brain Res. 1998;119:3–20.
  19. Cormier Z. Gene switches make prairie voles fall in love. http://www.nature.com/news/gene-switches-make-prairie-voles-fall-in-love-1.13112 (accessed 19/12/2015)
  20. Young LJ, Wang Z, Insel TR. Neuroendocrine bases of monogamy. Trends Neurosci. 1998 Feb 1;21(2):71–5.
  21. Insel TR, Shapiro LE. Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):5981–5.
  22. Insel TR, Wang ZX, Ferris CF. Patterns of brain vasopressin receptor distribution associated with social organization in microtine rodents. J Neurosci Off J Soc Neurosci. 1994 Sep;14(9):5381–92.
  23. Zingg HH. Vasopressin and oxytocin receptors. Baillières Clin Endocrinol Metab. 1996 Jan;10(1):75–96.
  24. Singewald GM, Rjabokon A, Singewald N, Ebner K. The Modulatory Role of the Lateral Septum on Neuroendocrine and Behavioral Stress Responses. Neuropsychopharmacology. 2011 Mar;36(4):793–804.
  25. Carter CS, DeVries AC, Getz LL. Physiological substrates of mammalian monogamy: the prairie vole model. Neurosci Biobehav Rev. 1995;19(2):303–14.
  26. Lim MM, Young LJ. Vasopressin-dependent neural circuits underlying pair bond formation in the monogamous prairie vole. Neuroscience. 2004;125(1):35–45.
  27. Liu Y, Curtis JT, Wang Z. Vasopressin in the lateral septum regulates pair bond formation in male prairie voles (Microtus ochrogaster). Behav Neurosci. 2001 Aug;115(4):910–9.
  28. McGraw LA, Young LJ. The prairie vole: an emerging model organism for understanding the social brain. Trends Neurosci. 2010 Feb;33(2):103.
  29. Riem MME, Bakermans-Kranenburg MJ, Pieper S, Tops M, Boksem MAS, et al. Oxytocin modulates amygdala, insula, and inferior frontal gyrus responses to infant crying: a randomized controlled trial. Biol Psychiatry. 2011 Aug 1;70(3):291–7.
  30. Magon N, Kalra S. The orgasmic history of oxytocin: Love, lust, and labor. Indian J Endocrinol Metab. 2011 Sep;15(Suppl3):S156–61.
  31. Lancaster K, Carter CS, Pournajafi-Nazarloo H, Karaoli T, Lillard TS, et al. Plasma oxytocin explains individual differences in neural substrates of social perception. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362216/ (accessed 21/12/2015)
  32. Dreu D, K.w C. Oxytocin modulates the link between adult attachment and cooperation through reduced betrayal aversion. Psychoneuroendocrinology. 2012 Jul 1;37(7):871–80.
  33. Ditzen B, Schaer M, Gabriel B, Bodenmann G, Ehlert U, Heinrichs M. Intranasal oxytocin increases positive communication and reduces cortisol levels during couple conflict. Biol Psychiatry. 2009 May 1;65(9):728–31.
  34. Scheele D, Wille A, Kendrick KM, Stoffel-Wagner B, Becker B, et al. Oxytocin enhances brain reward system responses in men viewing the face of their female partner. Proc Natl Acad Sci. 2013 Dec 10;110(50):20308–13.
  35. Van IJzendoorn MH, Bakermans-Kranenburg MJ. A sniff of trust: Meta-analysis of the effects of intranasal oxytocin administration on face recognition, trust to in-group, and trust to out-group. Psychoneuroendocrinology. 2012 Mar 1;37(3):438–43.
  36. Sue Carter C. Neuroendocrine perspectives on social attachment and love. Psychoneuroendocrinology. 1998 Nov 1;23(8):779–818.
  37. Shamay-Tsoory SG, Fischer M, Dvash J, Harari H, Perach-Bloom N, Levkovitz Y. Intranasal administration of oxytocin increases envy and schadenfreude (gloating). Biol Psychiatry. 2009 Nov 1;66(9):864–70.
  38. Schneiderman I, Zagoory-Sharon O, Leckman JF, Feldman R. Oxytocin during the initial stages of romantic attachment: relations to couples’ interactive reciprocity. Psychoneuroendocrinology. 2012 Aug;37(8):1277–85.
  39. Marazziti D, Dell’Osso B, Baroni S, Mungai F, Catena M, Rucci P, et al. A relationship between oxytocin and anxiety of romantic attachment. Clin Pract Epidemiol Ment Health CP EMH. 2006 Oct 11;2:28.
  40. Kagerbauer SM, Martin J, Schuster T, Blobner M, Kochs EF, Landgraf R. Plasma Oxytocin and Vasopressin do not Predict Neuropeptide Concentrations in Human Cerebrospinal Fluid. J Neuroendocrinol. 2013 Jul 1;25(7):668–73.
  41. Jaber M, Robinson SW, Missale C, Caron MG. Dopamine receptors and brain function. Neuropharmacology. 1996;35(11):1503–19.
  42. Young LJ, Wang Z. The neurobiology of pair bonding. Nat Neurosci. 2004 Oct;7(10):1048–54.
  43. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: from structure to function. Physiol Rev. 1998 Jan;78(1):189–225.
  44. Withersither. The importance of brain reward pathway. https://currentmedicalresearch.wordpress.com/2014/11/16/the-importance-of-brain-reward-pathway/ (accessed 08/01/2016)
  45. Rosenfeld AJ, Lieberman JA, Jarskog LF. Oxytocin, dopamine, and the amygdala: a neurofunctional model of social cognitive deficits in schizophrenia. Schizophr Bull. 2011 Sep;37(5):1077–87.
  46. Baskerville TA, Douglas AJ. Dopamine and oxytocin interactions underlying behaviors: potential contributions to behavioral disorders. CNS Neurosci Ther. 2010 Jun;16(3):e92–123.
  47. Edwards S, Self DW. Monogamy: dopamine ties the knot. Nat Neurosci. 2006 Jan;9(1):7–8.
  48. Aragona BJ, Liu Y, Curtis JT, Stephan FK, Wang Z. A critical role for nucleus accumbens dopamine in partner-preference formation in male prairie voles. J Neurosci Off J Soc Neurosci. 2003 Apr 15;23(8):3483–90.
  49. Gingrich B, Liu Y, Cascio C, Wang Z, Insel TR. Dopamine D2 receptors in the nucleus accumbens are important for social attachment in female prairie voles (Microtus ochrogaster). Behav Neurosci. 2000 Feb;114(1):173–83.
  50. Wang Z, Yu G, Cascio C, Liu Y, Gingrich B, Insel TR. Dopamine D2 receptor-mediated regulation of partner preferences in female prairie voles (Microtus ochrogaster): a mechanism for pair bonding? Behav Neurosci. 1999 Jun;113(3):602–11.
  51. Liu Y, Wang ZX. Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in female prairie voles. Neuroscience. 2003;121(3):537–44.
  52. Self DW, Barnhart WJ, Lehman DA, Nestler EJ. Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists. Science. 1996 Mar 15;271(5255):1586–9.
  53. Fisher H, Aron A, Brown LL. Romantic love: an fMRI study of a neural mechanism for mate choice. J Comp Neurol. 2005 Dec 5;493(1):58–62.
  54. Ishai A. Sex, beauty and the orbitofrontal cortex. Int J Psychophysiol Off J Int Organ Psychophysiol. 2007 Feb;63(2):181–5.
  55. Aron A, Fisher H, Mashek DJ, Strong G, Li H, Brown LL. Reward, motivation, and emotion systems associated with early-stage intense romantic love. J Neurophysiol. 2005 Jul;94(1):327–37.
  56. Bartels A, Zeki S. The neural basis of romantic love. Neuroreport. 2000 Nov 27;11(17):3829–34.

Leave a Reply

Your email address will not be published. Required fields are marked *