A Review of Individual Factors Influencing Response to Oxytocin

MINI REVIEW ARTICLE published: 10 January 2013 doi: 10.3389/fnins.2012.00194 Sex, receptors, and attachment: a review of individual factors inﬂuencing response to oxytocin

Kai S. MacDonald*

Department of Psychiatry, University of California Medical Center, San Diego, CA, USA

Edited by: As discussed in the larger review in this special issue (MacDonald and Feifel), intranasal Idan Shalev, Duke University, USA oxytocin (OT) is demonstrating a growing potential as a therapeutic agent in psychiatry. Reviewed by: Importantly, research suggests that a variety of individual factors may inﬂuence a person’s René Hurlemann, University of Bonn, Germany response to OT.In this mini-review, I provide a review of three: (1) sex and hormonal status; Benjamin A. Tabak, University of (2) genetic variation in aspects of the OT system (i.e., OT receptors); and (3) attachment California Los Angeles, USA history. Each of these factors will be important to monitor as we strive to develop a richer *Correspondence: understanding of OT’s role in human development, brain-based disease, and the potential Kai S. MacDonald, Department of for individualized, OT-targeted treatments. Psychiatry, UCSD Medical Center, 200 West Arbor Drive, San Diego, CA Keywords: oxytocin, sex factors, attachment, oxytocin receptor gene, CD38/ADP-ribosyl cyclase activity 92103-8216, USA. e-mail: [email protected]

INTRODUCTION though more recent conceptualizations of the parochial, “us vs. Aside from a wide range of drug-specific factors (discussed in them” aspect of OT make this picture more complex, and evi- MacDonald and Feifel in this special edition), several individual dence OT’s “darker” side (Shamay-Tsoory et al., 2009; De Dreu factors may influence a person’s response to oxytocin. Three of et al., 2010, 2011, 2012; Declerck et al., 2010). Though OT is only these factors are reviewed below. one small piece of the complex psychobiology of gender,some have posited different OT-biased relational strategies for the sexes, with SEX AND HORMONAL STATUS females more prone to“tend and befriend”(Taylor et al., 2000; but, The central OT system acts as but one component of a complex see Smith et al., 2012b), whereas more warrior-prone, hierarchy- neurochemical milieu in which gonadal steroids also play a signif- bound males “compete and defeat” (David and Lyons-Ruth, 2005; icant part. As extensively discussed in recent full-length reviews, Smeets et al., 2009; Van Vugt, 2009; Gabor et al., 2012). gonadal steroid hormones (i.e., estrogen, progesterone, and testos- More evidence for sex-specific differences in the OT system terone), and the two nonapeptides – OT and arginine vasopressin come from research indicating that men and women show dif- (AVP) – coevolved, all playing a vital role in mammalian social ferences in plasma OT levels (Ozsoy et al., 2009; Gordon et al., development through their unique influence on parental bond- 2010; Holt-Lunstad et al., 2011; Weisman et al., 2012b), as well ing, mate choice, and attachment (van Anders et al., 2011; Bos as gender-specific behavioral correlations with OT (Gordon et al., et al., 2012). In toto, there is substantial evidence indicating that 2010; Zhong et al., 2012; but, see Szeto et al., 2011 for critique at least some of oxytocin’s effects are correlated with an individ- of plasma OT measurement techniques). Coming from the per- ual’s sex, in part via the influence of gonadal hormones. We can spective of genetic variations in nonapeptide receptors, Walum only give this important topic brief review, and direct the reader et al. (2012) have found an association between the OTR vari- to more comprehensive treatments (van Anders et al., 2011; Bos ant rs7632287 and pair-bonding behaviors in women but not et al., 2012; Gabor et al., 2012). in men, whereas an earlier study found an association of an As background, animal studies indicate that sex-specific dif- AVP receptor polymorphism and pair-bonding in men but not ferences in response to OT are common (Williams et al., 1994; women (Walum et al., 2008). Furthermore, numerous studies in Cho et al., 1999; Bales and Carter, 2003; Bales et al., 2007), and the growing OTR literature note sex-specific associations between the histological structure for OT neurons is sexually dimorphic, genetic variants in the OTR gene and personality characteristics suggesting that sex steroids play a role in early morphogenesis (Stankova et al., 2012), neural responses to emotionally salient of this system (de Vries, 2008). Estrogen upregulates OT and cues (Tost et al., 2010), hypothalamic gray matter volume (Tost OT receptor (OTR) production (Patisaul et al., 2003; Windle et al., 2010), and empathy (Wu et al., 2012), though other studies et al., 2006; Choleris et al., 2008), whereas testosterone promotes in this area have failed to find a sex bias (Rodrigues et al., 2009; both OTR binding in the hypothalamus (Johnson et al., 1991) Saphire-Bernstein et al., 2011; Feldman et al., 2012). A final set as well as production of AVP (Delville et al., 1996), which has of salient investigations found that amygdala-prefrontal cortical many opponent actions to OT (Neumann and Landgraf, 2012). connectivity – which can be impacted by OT in normal sub- In humans, moreover, testosterone seems from one perspective jects (Sripada et al., 2012) and anxiety patients (Labuschagne to have opposite behavioral effects to the prosocial impact clas- et al., 2011) – may be related in a gender-specific way to sically associated with OT: decreasing trust, generosity, empathy the development of anxiety and depressive disorders (Burghy (van Honk and Schutter, 2007; Zak et al., 2009; Bos et al., 2010), et al., 2012), both putative clinical targets for intranasal oxytocin

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(IN OT) (Slattery and Neumann, 2010; Neumann and Landgraf, genetic variations within different aspects of the OT system (Kum- 2012). sta and Heinrichs, 2012), what one could call “neuropeptidergic Focusing on clinical OT trials using IN OT, gender-dependent individuality.” This term is annexed from – and a subset of – what effects have been demonstrated in some single-dose studies Cravchik has called “neurochemical individuality”: genetically (Hurlemann et al.,2010),including studies of effects on they amyg- determined factors that underlie individual differences in brain dala (Domes et al., 2010; Rupp et al., 2012), and interpersonal function. Exemplars include variations in aspects of the major behavior (Liu et al., 2012) but – consistent with the variability in neurotransmitter systems (i.e., dopamine, serotonin) (Cravchik this literature – many other single-dose studies have not found an and Goldman, 2000). effect of sex (see Bartz et al., 2011b for review). A recently investi- In terms of OTs part in “neuropeptidergic individuality,” a gated individual factor at least partly related to sex (due to different recent, rapidly expanding body of literature indicates that genetic sexual selection strategies between males and females; Ihara and differences in aspects of the functional OT system (the OTR itself Aoki, 1999) is the relationship status of the person receiving the and the ectoenzyme CD38, which contributes to OT secretion) drug. Specifically, Scheele et al.(2012) found in a group of 86 nor- (Figure 1) contribute to measurable aspects of an individual’s mal heterosexual males that IN OT preferentially stimulated men personality (Kumsta and Heinrichs, 2012). Though the specific in a monogamous relationship – but not single males – to main- cellular and functional consequences of these genetic variations tain more personal space from women (but not men). Whether have not been fully explicated, a convergent picture of their phe- these effect would cross over to females and same-sex relationships notypic consequences is emerging, indicating that in neurotypical in interesting and unexplored. subjects, genetic differences in the OT system impacts positive Though the suggestion of gender effects in single-dose studies personality factors and social behavior (Bakermans-Kranenburg of normal subjects may be informative, as discussed in the accom- and van Ijzendoorn, 2008; Rodrigues et al., 2009; Montag et al., panying larger review (MacDonald and Feifel), these results do not 2011; Saphire-Bernstein et al., 2011; Walter et al., 2012), differen- speak directly to the clinical question of whether sex differences tial responses to stress and maltreatment (Kim et al., 2010; Bradley moderate the effects of chronic OT treatment in clinically ill pop- et al., 2011; Chen et al., 2011b; Thompson et al., 2011; Brune, 2012; ulations. The first study to intimate such a sex moderation effect Norman et al., 2012), brain anatomy (Inoue et al., 2010; Furman was a randomized, double-blind, within-subjects crossover study et al., 2011), and differences in the function of stress and emotion- of OT (40 IU BID for 3 weeks) in patients with generalized anxi- related brain areas (Tost et al., 2010; Love et al., 2012). Moreover, ety disorder (GAD) (Feifel et al., 2011). This trial demonstrated a genetic variation in the OT system has been implicated in several trend level dose-by-gender effect such that males treated with OT of the disease states where OT has shown the most therapeutic showed a significant clinical improvement in HAM-A scores with promise: schizophrenia (Teltsh et al., 2011; Montag et al., 2012) OT,whereas females showed higher HAM-A scores during 3 weeks and autism (Ebstein et al., 2012). of treatment. The three extant studies using multiple weeks of OT Though no published studies have examined the role of genetic treatment in patients with schizophrenia demonstrated a male variation in the OT system to a psychiatrically ill person’s clinical bias in recruitment (62 males treated vs. 13 females), though none response to OT, several recent studies in normal subjects indicate showed a sex-by-drug effect (Feifel et al., 2010; Pedersen et al., that we should be alert for such effects. For example: subjective 2011; Modabbernia et al., 2012). Notable in this context are studies responses to infant’s faces were moderated by the (rs53576G) by Rubin et al.(2010, 2011) indicating that female but not male allele of the OTR (Marsh et al., 2012); there is an association patients with schizophrenia show a correlation between plasma between several genetic variations in the OTR (rs53576,rs2254298, OT concentrations, perception of facial emotion expression, and rs2228485) and performance on the Reading the Mind in the Eyes psychopathology, as well as evidence that women with borderline Test (RMET) (Lucht et al., 2012); and the OXTR (rs2268498) personality disorder have reduced plasma OT levels, even after polymorphism modulated neural responses to emotional faces controlling for hormonal factors (Bertsch et al., 2012). (O’Connell et al., 2012). Moreover, as evidence of the overlap In terms of future clinical studies with IN OT, the abovemen- between central dopaminergic and oxytocinergic systems, female tioned sex-specific variables may have at least two repercussions. OTR (rs4813625) carriers demonstrated greater stress-induced First,they highlight the importance of monitoring/measuring hor- dopamine release, higher attachment and trait anxiety, and lower mone levels,menstrual phase,and oral contraceptive status in trials emotional well-being scores (Love et al., 2012). with IN OT,given these parameters may impact OT levels (Salonia A relatively new component of the central OT system – but et al., 2005, but, see Rubin et al., 2011) and psychiatric symptoms one which is rapidly galvanizing interest – is the transmembrane (Rubin et al., 2010). Secondly, given that there are sex differences enzyme CD38, whose role was discovered by observing the social in the incidence of many of the disease states for which OT is a behavior of CD38 knock-out mice. These socially hapless mice putative treatment (i.e., autism, postpartum depression), further forget the location of their pups as well as previous social encoun- delineation of the role of sex in the effects of chronic OT treatment ters, and synthesize, but don’t properly secrete OT. Notably, these will be critical. behavioral and hormonal deficits are restored with either (a) viral transfection of a functional CD38 gene or (b) exogenous OT (Jin NEUROPEPTIDERGIC INDIVIDUALITY: GENETIC VARIATIONS et al.,2007). In humans,variants in the CD38 gene have been tied to IN OTR AND CD38 OT secretion (Kiss et al., 2011), social processing (Higashida et al., Aside from sex, a second individual factor of import in relation 2012a; Sauer et al., 2012), sensitive parenting (Feldman, 2012), to IN OT treatment involves phenotypically relevant individual and potentially autism (Higashida et al., 2011, 2012b for review).

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point of interest in this context is that retinoids (vitamin-A related compounds) can be used to increase CD38 expression (Riebold et al., 2011), thus providing an alternative way to stimulate the OT system or potentially augment IN OT treatment (Ebstein et al., 2011). Though the focus here is only on variation in the OTR and CD38 gene, other potential contributors to neuropeptidergic individuality include: (1) differences in baseline and dynamic levels of OT release in the brain and/or secretion into the plasma, the latter found to correlate with personality and brain structure (Andari et al., 2012); as well as (2) differences in regional OTR and AVPR receptor density, a factor which influences the social behavior of rodents (Hammock and Young, 2006; Ross et al., 2009; Ophir et al., 2012). Though a few studies have examined postmortem OTR density in the human CNS (Loup et al., 1989, 1991), as mentioned in the accompanying review (MacDonald and Feifel), synthesis of a small-molecule radioligand for the OTR (Smith et al., 2012a), would greatly facilitate our understanding of the role of OTR density and location in living humans. Of critical import in the field of psychiatric genetic association studies are the issues of replicability and effect size (discussed at length in Gershon et al., 2011; Ebstein et al., 2012). For example, in contrast to several of the positive associations noted above, studies have failed to find associations between genetic variations in the OTR and prosocial behavior in the trust or dictator game (Apicella et al., 2010), optimism (Cornelis et al., 2012), and autism (Tansey et al., 2010). Replication studies and larger sample sizes in a variety of populations using different varieties of associations (i.e., different combinations of haplotypes) (Yamasue et al., 2012) are therefore necessary to more fully explore and quantify the strength of the abovementioned associations. Returning to the clinical implications of neuropeptidergic individuality, it is possible that individual variation in aspects of the OT system may in the future be thought of as clinicians currently conceptualize individual variations in dopamine and serotonin systems. One brings to mind the association of DRD4 variants with approach-related traits (Munafo et al., 2008) and response to dopaminergic medication (Hamarman et al., 2004), or the association of serotonin receptor polymorphisms with susceptibility to adverse clinical outcomes (van Ijzendoorn et al., 2012), as well as response to serotonergic antidepressants (Mrazek et al., 2009). Aside from its import in terms of understanding individual variability in both neurotypical and clinically ill populations, neuropeptidergic individuality may have implications in terms of psychiatric pharmacogenetics: the use of information about individual’s genotype in the selection of psychiatric treat- FIGURE 1 |Three individual factors which mediate response to oxytocin ment (Malhotra et al., 2007). Though this approach is currently are (1) sex and hormonal status; (2) genetic variations in the oxytocin speculative in terms of OT, it has growing clinically relevance receptor and CD38 system; and (3) early attachment experiences. The for antidepressants (McMahon et al., 2006) and antipsychotics extent to which these factors play a role in a person’s response to (Zhang et al., 2010). Looking forward, large clinical trials are oxytocin-targetted therapeutics for brain-based disease requires further exploration (see MacDonald and Feifel in this special section). needed to investigate the possibility that genetic variations in the abovementioned aspects of the OT system may influence clinical response to OT treatment. That said, the decreasing cost and Similarly to the OTR studies above, a recent imaging genetics study increasing efficiency of gene sequencing technologies, coupled in neurotypical males suggested that variation in the CD38 gene with larger clinical trials of clinical use of OT (ClinicalTrials.gov), influenced behavioral and neuronal measures of social processing will certainly inform the relevance of this proposed genotype- and amygdala response to IN OT (Sauer et al., 2012). A clinical informed treatment. Moreover, identification of “OT sensitive”

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phenotypes may optimize patient selection for treatment and Focusing specifically on the OT treatment literature, several trials. studies indicate that aversive early attachment experiences and attachment style impact stress systems, CSF, and plasma OT levels EARLY EXPERIENCE, EPIGENETICS, AND NEUROPLASTICITY (Heim et al., 2009; Strathearn et al., 2009, 2012; Bertsch et al., 2012; In addition to abovementioned genetically determined factors, a Weisman et al., 2012a) as well as later response to IN OT (Huffmei- third influence on a person’s response to IN OT concerns the way jer et al., 2011, 2012; Simeon et al., 2011; van Ijzendoorn et al., that that an individual’s unique attachment history has sculpted 2011; Bakermans-Kranenburg et al., 2012; Pierrehumbert et al., the function of their OT system (Gordon et al., 2011; Bales and 2012). For example, neurotypical patients’ generosity in response Perkeybile, 2012). More specifically, convergent translational and to IN OT is moderated by parental love-withdrawal (Huffmeijer developmental research in a variety of fields indicates that the et al., 2012), and patients with aversive early attachment repre- central OT system is similar to the HPA axis in being an environ- sentations had a negative response to IN OT compared to those mentally influenced plastic brain system whose function is directly with more positive representations (Bartz et al., 2010). Other lit- and perhaps permanently impacted by early experience (Gunnar erature suggests that variation in the OT system may mediate and Quevedo, 2008; Brune, 2012; McCrory et al., 2012). Clinically, gene-environment interactions between early adversity and out- it is clear that maladaptive early experiences impact the “pheno- comes (Kim et al., 2010; Bradley et al., 2011; Chen et al., 2011a; type”of several psychiatric disorders that may benefit from IN OT, Thompson et al., 2011). including depression (Saveanu and Nemeroff, 2012) and schizo- In toto, data reviewed here support the hypothesis that an phrenia (Read and Hammersley, 2005; van Os et al., 2010). Recent individual’s early attachment experiences – carried forward in imaging studies indicate that early adversity impacts brain sys- OT-responsive neural networks and the dynamic function of the tems of import to both psychiatric disease and OT treatment (i.e., central OT system – may impact a person’s response to IN OT. To amygdala and hippocampus; Dannlowski et al., 2012; Teicher et al., date, in keeping with the general trend noted throughout this and 2012). the accompanying larger review (MacDonald and Feifel, this issue) Research on the environmental plasticity of the OT system the evidence that early experience impacts OT response in clini- began with sentinel animal research indicating intergenerational cal populations is sparse. The only published study in this area transmission of behavior in more- and less-attentive rat moth- demonstrated that patients with borderline personality disorder ers (Champagne and Meaney, 2001; Champagne et al., 2001; and anxious attachment showed less trust than those with more Meaney, 2001). Some of these changes, notably, are mediated via secure attachment after IN OT (Bartz et al., 2011a). Despite the epigenetic modulation of the OT system (Cushing and Kramer, overall lack of studies of IN OT in patient groups, the findings 2005; Stolzenberg et al., 2012). More recently, human experi- cited above suggest that clinical trials examining putative ther- ments support the hypothesis that dynamic changes in com- apeutic effects of OT will be wise to include an assessment of ponents of the OT system (i.e., methylation of the OTR gene; attachment style and early trauma as individual factors that may Jack et al., 2012; Unternaehrer et al., 2012) and possibly neu- influence response to OT. rodevelopmental changes in OT sensitive brain structures (see CONCLUSION Andari et al., 2012 for discussion) are some of the proximate Given the paucity of clinical trials with IN OT, the suggestion that effectors through which early parental care impacts an individ- the above factors may be moderators of clinical response to IN ual throughout life (Champagne et al., 2001; Champagne, 2008; OT should be viewed with circumspection. Both larger-scale ther- Gordon et al., 2011; Bales and Perkeybile, 2012 for reviews). Other apeutic trials with IN OT as well as investigations of the role of convergent evidence comes from attachment-informed behavioral aspects of the central OT system in different disease states will research which indicates parallels and reciprocal influence between be necessary to determine their ultimate clinical and therapeutic parental and infant OT levels and the species-specific behav- relevance. iors associated with secure attachment and optimal psychosocial development (Feldman, 2012). As mentioned above, these fac- ACKNOWLEDGMENTS tors appear to be influenced by both genetic variations in the OT Thanks to Bruce Ammons for editorial suggestions and Maribel system and by IN OT (Naber et al., 2010, 2012; Weisman et al., Santos for the illustration. Some of the author’s work is supported 2012a). by the Goodenough Neuroscience Research Fund.

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Weisman, O., Zagoory-Sharon, O., Windle, R. J., Gamble, L. E., Kershaw, J., Efremidze, L., et al. (2009). that could be construed as a potential and Feldman, R. (2012a). Oxy- Y. M., Wood, S. A., Lightman, Testosterone administration conflict of interest. tocin administration to parent S. L., and Ingram, C. D. (2006). decreases generosity in the ulti- enhances infant physiological and Gonadal steroid modulation of matum game. PLoS ONE 4:e8330. Received: 05 December 2012; paper behavioral readiness for social stress-induced hypothalamo- doi:10.1371/journal.pone.0008330 pending published: 18 December 2012; engagement. Biol. Psychiatry 72, pituitary-adrenal activity and Zhang, J. P., Lencz, T., and Malhotra, A. accepted: 20 December 2012; published 982–989. anxiety behavior: role of cen- K. (2010). D2 receptor genetic varia- online: 10 January 2013. Weisman, O., Zagoory-Sharon, O., tral oxytocin. Endocrinology 147, tion and clinical response to antipsy- Citation: MacDonald KS (2013) Sex, Schneiderman, I., Gordon, I., 2423–2431. chotic drug treatment: a meta- receptors, and attachment: a review of and Feldman, R. (2012b). Plasma Wu, N., Li, Z., and Su, Y. (2012). analysis. Am. J. Psychiatry 167, individual factors influencing response oxytocin distributions in a large The association between oxytocin 763–772. to oxytocin. Front. Neurosci. 6:194. doi: cohort of women and men receptor gene polymorphism Zhong, S., Monakhov, M., Mok, 10.3389/fnins.2012.00194 and their gender-specific asso- (OXTR) and trait empathy. J. Affect. H. P., Tong, T., Lai, P. S., Chew, This article was submitted to Frontiers ciations with anxiety. Psycho Disord. 138, 468–472. S. H., et al. (2012). U-shaped in Neuroendocrine Science, a specialty of neuroendocrinology. doi: Yamasue, H., Yee, J. R., Hurlemann, R., relation between plasma oxy- Frontiers in Neuroscience. 10.1016/j.psyneuen.2012.08.011. Rilling, J. K., Chen, F. S., Meyer- tocin levels and behavior in the Copyright © 2013 MacDonald. This is an [Epub ahead of print]. Lindenberg,A.,et al. (2012). Integra- trust game. PLoS ONE 7:e51095. open-access article distributed under the Williams, J. R., Insel, T. R., Harbaugh, tive approaches utilizing oxytocin doi:10.1371/journal.pone.0051095 terms of the Creative Commons Attribu- C. R., and Carter, C. S. (1994). Oxy- to enhance prosocial behavior: from tion License, which permits use, distrib- tocin administered centrally facili- animal and human social behav- ution and reproduction in other forums, tates formation of a partner prefer- ior to autistic social dysfunction. J. Conflict of Interest Statement: The provided the original authors and source ence in female prairie voles (Micro- Neurosci. 32, 14109–14117. author declares that the research was are credited and subject to any copy- tus ochrogaster). J. Neuroendocrinol. Zak, P. J., Kurzban, R., Ahmadi, conducted in the absence of any right notices concerning any third-party 6, 247–250. S., Swerdloff, R. S., Park, commercial or financial relationships graphics etc.

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