Sex, Receptors, and Attachment: A Review of Individual Factors Influencing Response to Oxytocin.

0.66 MB·English

by  MacDonald, Kai S.

MINIREVIEWARTICLE
published:10January2013
doi:10.3389/fnins.2012.00194
Sex, receptors, and attachment: a review of individual
factors influencing response to oxytocin
KaiS.MacDonald*
DepartmentofPsychiatry,UniversityofCaliforniaMedicalCenter,SanDiego,CA,USA
Editedby: As discussed in the larger review in this special issue (MacDonald and Feifel), intranasal
IdanShalev,DukeUniversity,USA oxytocin (OT) is demonstrating a growing potential as a therapeutic agent in psychiatry.
Reviewedby: Importantly,researchsuggeststhatavarietyofindividualfactorsmayinfluenceaperson’s
RenéHurlemann,UniversityofBonn,
responsetoOT.Inthismini-review,Iprovideareviewofthree:(1)sexandhormonalstatus;
Germany
BenjaminA.Tabak,Universityof (2) genetic variation in aspects of the OT system (i.e., OT receptors); and (3) attachment
CaliforniaLosAngeles,USA history.Eachofthesefactorswillbeimportanttomonitoraswestrivetodeveloparicher
*Correspondence: understandingofOT’sroleinhumandevelopment,brain-baseddisease,andthepotential
KaiS.MacDonald,Departmentof forindividualized,OT-targetedtreatments.
Psychiatry,UCSDMedicalCenter,
200WestArborDrive,SanDiego,CA Keywords:oxytocin,sexfactors,attachment,oxytocinreceptorgene,CD38/ADP-ribosylcyclaseactivity
92103-8216,USA.
e-mail:[e-mail]
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-
MacDonaldandFeifelinthisspecialedition),severalindividual dence OT’s“darker”side (Shamay-Tsoory et al., 2009; De Dreu
factors may influence a person’s response to oxytocin. Three of etal.,2010,2011,2012;Declercketal.,2010).ThoughOTisonly
thesefactorsarereviewedbelow. onesmallpieceofthecomplexpsychobiologyofgender,somehave
positeddifferentOT-biasedrelationalstrategiesforthesexes,with
SEXANDHORMONALSTATUS femalesmoreproneto“tendandbefriend”(Tayloretal.,2000;but,
ThecentralOTsystemactsasbutonecomponentof acomplex seeSmithetal.,2012b),whereasmorewarrior-prone,hierarchy-
neurochemicalmilieuinwhichgonadalsteroidsalsoplayasignif- boundmales“competeanddefeat”(DavidandLyons-Ruth,2005;
icantpart.Asextensivelydiscussedinrecentfull-lengthreviews, Smeetsetal.,2009;VanVugt,2009;Gaboretal.,2012).
gonadalsteroidhormones(i.e.,estrogen,progesterone,andtestos- More evidence for sex-specific differences in the OT system
terone),andthetwononapeptides–OTandargininevasopressin 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 asgender-specificbehavioralcorrelationswithOT(Gordonetal.,
etal.,2012).Intoto,thereissubstantialevidenceindicatingthat 2010; Zhong et al., 2012; but, see Szeto et al., 2011 for critique
atleastsomeofoxytocin’seffectsarecorrelatedwithanindivid- of plasma OT measurement techniques). Coming from the per-
ual’ssex,inpartviatheinfluenceof gonadalhormones.Wecan spective of genetic variations in nonapeptide receptors, Walum
onlygivethisimportanttopicbriefreview,anddirectthereader et al. (2012) have found an association between the OTR vari-
tomorecomprehensivetreatments(vanAndersetal.,2011;Bos ant rs7632287 and pair-bonding behaviors in women but not
etal.,2012;Gaboretal.,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(Walumetal.,2008).Furthermore,numerousstudiesin
Cho et al.,1999;Bales and Carter,2003;Bales et al.,2007),and thegrowingOTRliteraturenotesex-specificassociationsbetween
the histological structure for OT neurons is sexually dimorphic, geneticvariantsintheOTRgeneandpersonalitycharacteristics
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 etal.,2010),andempathy(Wuetal.,2012),thoughotherstudies
etal.,2006;Cholerisetal.,2008),whereastestosteronepromotes inthisareahavefailedtofindasexbias(Rodriguesetal.,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
(vanHonkandSchutter,2007;Zaketal.,2009;Bosetal.,2010), etal.,2012),bothputativeclinicaltargetsforintranasaloxytocin
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MacDonald Individualfactorsandresponsetooxytocin
(INOT)(SlatteryandNeumann,2010;NeumannandLandgraf, geneticvariationswithindifferentaspectsoftheOTsystem(Kum-
2012). staandHeinrichs,2012),whatonecouldcall“neuropeptidergic
FocusingonclinicalOTtrialsusingINOT,gender-dependent individuality.”Thistermisannexedfrom–andasubsetof–what
effects have been demonstrated in some single-dose studies Cravchik has called “neurochemical individuality”: genetically
(Hurlemannetal.,2010),includingstudiesofeffectsontheyamyg- 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(Liuetal.,2012)but–consistentwiththevariabilityin neurotransmitter systems (i.e., dopamine, serotonin) (Cravchik
thisliterature–manyothersingle-dosestudieshavenotfoundan andGoldman,2000).
effectofsex(seeBartzetal.,2011bforreview).Arecentlyinvesti- In terms of OTs part in “neuropeptidergic individuality,” a
gatedindividualfactoratleastpartlyrelatedtosex(duetodifferent recent,rapidlyexpandingbodyofliteratureindicatesthatgenetic
sexualselectionstrategiesbetweenmalesandfemales;Iharaand differencesinaspectsofthefunctionalOTsystem(theOTRitself
Aoki,1999)istherelationshipstatusof thepersonreceivingthe and the ectoenzyme CD38, which contributes to OT secretion)
drug.Specifically,Scheeleetal.(2012)foundinagroupof86nor- (Figure 1) contribute to measurable aspects of an individual’s
malheterosexualmalesthatINOTpreferentiallystimulatedmen personality (Kumsta and Heinrichs, 2012). Though the specific
inamonogamousrelationship–butnotsinglemales–tomain- cellular and functional consequences of these genetic variations
tain more personal space from women (but not men).Whether havenotbeenfullyexplicated,aconvergentpictureoftheirphe-
theseeffectwouldcrossovertofemalesandsame-sexrelationships notypicconsequencesisemerging,indicatingthatinneurotypical
ininterestingandunexplored. subjects, genetic differences in the OT system impacts positive
Thoughthesuggestionofgendereffectsinsingle-dosestudies personality factors and social behavior (Bakermans-Kranenburg
ofnormalsubjectsmaybeinformative,asdiscussedintheaccom- and van Ijzendoorn,2008;Rodrigues et al.,2009;Montag et al.,
panyinglargerreview(MacDonaldandFeifel),theseresultsdonot 2011;Saphire-Bernsteinetal.,2011;Walteretal.,2012),differen-
speakdirectlytotheclinicalquestionof whethersexdifferences tialresponsestostressandmaltreatment(Kimetal.,2010;Bradley
moderatetheeffectsofchronicOTtreatmentinclinicallyillpop- etal.,2011;Chenetal.,2011b;Thompsonetal.,2011;Brune,2012;
ulations.Thefirststudytointimatesuchasexmoderationeffect Normanetal.,2012),brainanatomy(Inoueetal.,2010;Furman
wasarandomized,double-blind,within-subjectscrossoverstudy etal.,2011),anddifferencesinthefunctionofstressandemotion-
ofOT(40IUBIDfor3weeks)inpatientswithgeneralizedanxi- relatedbrainareas(Tostetal.,2010;Loveetal.,2012).Moreover,
etydisorder(GAD)(Feifeletal.,2011).Thistrialdemonstrateda geneticvariationintheOTsystemhasbeenimplicatedinseveral
trendleveldose-by-gendereffectsuchthatmalestreatedwithOT of the disease states where OT has shown the most therapeutic
showedasignificantclinicalimprovementinHAM-Ascoreswith promise: schizophrenia (Teltsh et al.,2011; Montag et al.,2012)
OT,whereasfemalesshowedhigherHAM-Ascoresduring3weeks andautism(Ebsteinetal.,2012).
oftreatment.ThethreeextantstudiesusingmultipleweeksofOT Thoughnopublishedstudieshaveexaminedtheroleofgenetic
treatment in patients with schizophrenia demonstrated a male variationintheOTsystemtoapsychiatricallyillperson’sclinical
biasinrecruitment(62malestreatedvs.13females),thoughnone responsetoOT,severalrecentstudiesinnormalsubjectsindicate
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;Modabberniaetal.,2012).Notableinthiscontextarestudies responses to infant’s faces were moderated by the (rs53576G)
byRubinetal.(2010,2011)indicatingthatfemalebutnotmale allele of the OTR (Marsh et al., 2012); there is an association
patients with schizophrenia show a correlation between plasma betweenseveralgeneticvariationsintheOTR(rs53576,rs2254298,
OTconcentrations,perceptionoffacialemotionexpression,and rs2228485)andperformanceontheReadingtheMindintheEyes
psychopathology,aswellasevidencethatwomenwithborderline 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
controllingforhormonalfactors(Bertschetal.,2012). (O’Connell et al., 2012). Moreover, as evidence of the overlap
IntermsoffutureclinicalstudieswithINOT,theabovemen- betweencentraldopaminergicandoxytocinergicsystems,female
tionedsex-specificvariablesmayhaveatleasttworepercussions. OTR (rs4813625) carriers demonstrated greater stress-induced
First,theyhighlighttheimportanceofmonitoring/measuringhor- dopaminerelease,higherattachmentandtraitanxiety,andlower
monelevels,menstrualphase,andoralcontraceptivestatusintrials emotionalwell-beingscores(Loveetal.,2012).
withINOT,giventheseparametersmayimpactOTlevels(Salonia A relatively new component of the central OT system – but
etal.,2005,but,seeRubinetal.,2011)andpsychiatricsymptoms onewhichisrapidlygalvanizinginterest–isthetransmembrane
(Rubinetal.,2010).Secondly,giventhattherearesexdifferences enzymeCD38,whoserolewasdiscoveredbyobservingthesocial
intheincidenceof manyof thediseasestatesforwhichOTisa behavior of CD38 knock-out mice. These socially hapless mice
putativetreatment(i.e.,autism,postpartumdepression),further forgetthelocationoftheirpupsaswellasprevioussocialencoun-
delineationoftheroleofsexintheeffectsofchronicOTtreatment ters,andsynthesize,butdon’tproperlysecreteOT.Notably,these
willbecritical. behavioralandhormonaldeficitsarerestoredwitheither(a)viral
transfectionofafunctionalCD38geneor(b)exogenousOT(Jin
NEUROPEPTIDERGICINDIVIDUALITY:GENETICVARIATIONS etal.,2007).Inhumans,variantsintheCD38genehavebeentiedto
INOTRANDCD38 OTsecretion(Kissetal.,2011),socialprocessing(Higashidaetal.,
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 andpotentiallyautism(Higashidaetal.,2011,2012bforreview).
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MacDonald Individualfactorsandresponsetooxytocin
pointofinterestinthiscontextisthatretinoids(vitamin-Arelated
compounds) can be used to increase CD38 expression (Riebold
etal.,2011),thusprovidinganalternativewaytostimulatetheOT
system or potentially augment IN OT treatment (Ebstein et al.,
2011).
Though the focus here is only on variation in the OTR and
CD38gene,otherpotentialcontributorstoneuropeptidergicindi-
vidualityinclude:(1)differencesinbaselineanddynamiclevelsof
OTreleaseinthebrainand/orsecretionintotheplasma,thelatter
found to correlate with personality and brain structure (Andari
etal.,2012);aswellas(2)differencesinregionalOTRandAVPR
receptordensity,afactorwhichinfluencesthesocialbehaviorof
rodents(HammockandYoung,2006;Rossetal.,2009;Ophiretal.,
2012). Though a few studies have examined postmortem OTR
densityinthehumanCNS(Loupetal.,1989,1991),asmentioned
intheaccompanyingreview(MacDonaldandFeifel),synthesisof
a small-molecule radioligand for the OTR (Smith et al.,2012a),
would greatly facilitate our understanding of the role of OTR
densityandlocationinlivinghumans.
Ofcriticalimportinthefieldofpsychiatricgeneticassociation
studiesaretheissuesof replicabilityandeffectsize(discussedat
lengthinGershonetal.,2011;Ebsteinetal.,2012).Forexample,in
contrasttoseveralofthepositiveassociationsnotedabove,studies
havefailedtofindassociationsbetweengeneticvariationsinthe
OTRandprosocialbehaviorinthetrustordictatorgame(Apicella
etal.,2010),optimism(Cornelisetal.,2012),andautism(Tansey
etal.,2010).Replicationstudiesandlargersamplesizesinavari-
ety of populations using different varieties of associations (i.e.,
differentcombinationsof haplotypes)(Yamasueetal.,2012)are
thereforenecessarytomorefullyexploreandquantifythestrength
oftheabovementionedassociations.
Returningtotheclinicalimplicationsofneuropeptidergicindi-
viduality, 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
serotoninsystems.Onebringstomindtheassociationof DRD4
variants with approach-related traits (Munafo et al., 2008) and
response to dopaminergic medication (Hamarman et al.,2004),
ortheassociationofserotoninreceptorpolymorphismswithsus-
ceptibility to adverse clinical outcomes (van Ijzendoorn et al.,
2012),aswellasresponsetoserotonergicantidepressants(Mrazek
et al., 2009). Aside from its import in terms of understanding
individualvariabilityinbothneurotypicalandclinicallyillpop-
ulations,neuropeptidergicindividualitymayhaveimplicationsin
terms of psychiatric pharmacogenetics: the use of information
aboutindividual’sgenotypeintheselectionof psychiatrictreat-
ment(Malhotraetal.,2007).Thoughthisapproachiscurrently
FIGURE1|Threeindividualfactorswhichmediateresponsetooxytocin
are(1)sexandhormonalstatus;(2)geneticvariationsintheoxytocin speculative in terms of OT, it has growing clinically relevance
receptorandCD38system;and(3)earlyattachmentexperiences.The for antidepressants (McMahon et al., 2006) and antipsychotics
extenttowhichthesefactorsplayaroleinaperson’sresponseto (Zhang et al., 2010). Looking forward, large clinical trials are
oxytocin-targettedtherapeuticsforbrain-baseddiseaserequiresfurther
neededtoinvestigatethepossibilitythatgeneticvariationsinthe
exploration(seeMacDonaldandFeifelinthisspecialsection).
abovementioned aspects of the OT system may influence clini-
calresponsetoOTtreatment.Thatsaid,thedecreasingcostand
SimilarlytotheOTRstudiesabove,arecentimaginggeneticsstudy increasing efficiency of gene sequencing technologies, coupled
inneurotypicalmalessuggestedthatvariationintheCD38gene withlargerclinicaltrialsofclinicaluseofOT(ClinicalTrials.gov),
influencedbehavioralandneuronalmeasuresofsocialprocessing 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”
www.frontiersin.org January2013|Volume6|Article194|3
MacDonald Individualfactorsandresponsetooxytocin
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
attachmentstyleimpactstresssystems,CSF,andplasmaOTlevels
(Heimetal.,2009;Strathearnetal.,2009,2012;Bertschetal.,2012;
EARLYEXPERIENCE,EPIGENETICS,ANDNEUROPLASTICITY
Weismanetal.,2012a)aswellaslaterresponsetoINOT(Huffmei-
Inadditiontoabovementionedgeneticallydeterminedfactors,a
jer et al.,2011,2012; Simeon et al.,2011; van Ijzendoorn et al.,
thirdinfluenceonaperson’sresponsetoINOTconcernstheway
2011; Bakermans-Kranenburg et al., 2012; Pierrehumbert et al.,
thatthatanindividual’suniqueattachmenthistoryhassculpted
2012).Forexample,neurotypicalpatients’generosityinresponse
the functionof theirOT system(Gordon etal.,2011;Bales and
toINOTismoderatedbyparentallove-withdrawal(Huffmeijer
Perkeybile,2012).Morespecifically,convergenttranslationaland
et al., 2012), and patients with aversive early attachment repre-
developmental research in a variety of fields indicates that the
sentationshadanegativeresponsetoINOTcomparedtothose
centralOTsystemissimilartotheHPAaxisinbeinganenviron-
withmorepositiverepresentations(Bartzetal.,2010).Otherlit-
mentallyinfluencedplasticbrainsystemwhosefunctionisdirectly
erature suggests that variation in the OT system may mediate
andperhapspermanentlyimpactedbyearlyexperience(Gunnar
gene-environmentinteractionsbetweenearlyadversityandout-
andQuevedo,2008;Brune,2012;McCroryetal.,2012).Clinically,
comes(Kimetal.,2010;Bradleyetal.,2011;Chenetal.,2011a;
itisclearthatmaladaptiveearlyexperiencesimpactthe“pheno-
Thompsonetal.,2011).
type”ofseveralpsychiatricdisordersthatmaybenefitfromINOT,
In toto, data reviewed here support the hypothesis that an
includingdepression(SaveanuandNemeroff,2012)andschizo-
individual’s early attachment experiences – carried forward in
phrenia(ReadandHammersley,2005;vanOsetal.,2010).Recent
OT-responsiveneuralnetworksandthedynamicfunctionofthe
imaging studies indicate that early adversity impacts brain sys-
centralOTsystem–mayimpactaperson’sresponsetoINOT.To
temsofimporttobothpsychiatricdiseaseandOTtreatment(i.e.,
date,inkeepingwiththegeneraltrendnotedthroughoutthisand
amygdalaandhippocampus;Dannlowskietal.,2012;Teicheretal.,
theaccompanyinglargerreview(MacDonaldandFeifel,thisissue)
2012).
theevidencethatearlyexperienceimpactsOTresponseinclini-
Research on the environmental plasticity of the OT system
cal populations is sparse. The only published study in this area
beganwithsentinelanimalresearchindicatingintergenerational
demonstrated that patients with borderline personality disorder
transmission of behavior in more- and less-attentive rat moth-
andanxiousattachmentshowedlesstrustthanthosewithmore
ers (Champagne and Meaney, 2001; Champagne et al., 2001;
secure attachment after IN OT (Bartz et al.,2011a). Despite the
Meaney,2001).Someofthesechanges,notably,aremediatedvia
overall lack of studies of IN OT in patient groups,the findings
epigenetic modulation of the OT system (Cushing and Kramer,
cited above suggest that clinical trials examining putative ther-
2005; Stolzenberg et al., 2012). More recently, human experi-
apeutic effects of OT will be wise to include an assessment of
ments support the hypothesis that dynamic changes in com-
attachmentstyleandearlytraumaasindividualfactorsthatmay
ponents of the OT system (i.e., methylation of the OTR gene;
influenceresponsetoOT.
Jack et al., 2012; Unternaehrer et al., 2012) and possibly neu-
rodevelopmental changes in OT sensitive brain structures (see CONCLUSION
Andari et al., 2012 for discussion) are some of the proximate
GiventhepaucityofclinicaltrialswithINOT,thesuggestionthat
effectors through which early parental care impacts an individ-
the above factors may be moderators of clinical response to IN
ual throughout life (Champagneet al.,2001;Champagne,2008;
OTshouldbeviewedwithcircumspection.Bothlarger-scalether-
Gordonetal.,2011;BalesandPerkeybile,2012forreviews).Other
apeutictrialswithINOTaswellasinvestigationsof theroleof
convergentevidencecomesfromattachment-informedbehavioral
aspects of the central OT system in different disease states will
researchwhichindicatesparallelsandreciprocalinfluencebetween
benecessarytodeterminetheirultimateclinicalandtherapeutic
parental and infant OT levels and the species-specific behav-
relevance.
iorsassociatedwithsecureattachmentandoptimalpsychosocial
development (Feldman, 2012). As mentioned above, these fac- ACKNOWLEDGMENTS
torsappeartobeinfluencedbybothgeneticvariationsintheOT ThankstoBruceAmmonsforeditorialsuggestionsandMaribel
system and by IN OT (Naber et al.,2010,2012;Weisman et al., Santosfortheillustration.Someoftheauthor’sworkissupported
2012a). bytheGoodenoughNeuroscienceResearchFund.
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