Sex-specific effects of intranasal oxytocin on autonomic nervous system and emotional responses to couple conflict

“…influence on individual stress resilience (Robles and Kiecolt-Glaser, 2003), health (Uchino, 2006; Thoits, 2011) and longevity (House et al., 1988; Holt-Lunstad et al., 2010), making couple relationships, as the most prominent social relationship for nearly all adults, an important predictor of…”

“…have a substantial influence on individual stress resilience (Robles and Kiecolt-Glaser, 2003), health (Uchino, 2006; Thoits, 2011) and longevity (House et al., 1988; Holt-Lunstad et al., 2010), making couple relationships, as the most prominent social relationship for nearly all adults, an…”

“They also correspond to ‘befriending’ mechanisms in women, as opposed to the fight-or-flight physiology in men, as suggested by Taylor et al. (2000), and to the anxiolytic effects which were found in previous research in humans (Meyer-Lindenberg et al., 2011).”

“OT is synthesized in the hypothalamus, from where it exerts its effects on widespread areas in the central nervous system (CNS) (Gimpl and Fahrenholz, 2001; de Bono, 2003; Landgraf and Neumann, 2004).”

“Consequently, research interest has turned to the neurobiological mechanisms underlying the effects of couple interaction on stress and individual health-relevant outcomes (Uchino et al., 1996; Robles and Kiecolt-Glaser, 2003; Karelina and DeVries, 2011).”

“…and affectionate social interactions have a substantial influence on individual stress resilience (Robles and Kiecolt-Glaser, 2003), health (Uchino, 2006; Thoits, 2011) and longevity (House et al., 1988; Holt-Lunstad et al., 2010), making couple relationships, as the most prominent social…”

“…this and in contrast to positive couple interaction (cf. Grewen et al., 2003; Coan et al., 2006; Ditzen et al., 2007; Holt-Lunstad et al., 2008), ongoing couple conflicts have been suggested to constantly increase stress and, thereby, to impair individual health (Kiecolt-Glaser and Newton, 2001).”

“Using this technique, an increasing number of human studies suggest effects of OT on the level of behavioral and neural systems, including social interaction, social memory and stress reactivity (Heinrichs et al., 2009; Bos et al., 2011; Meyer-Lindenberg et al., 2011).”

“Among other factors, this research points to the neuropeptide oxytocin (OT), which has been shown to improve social affiliation and attachment and to reduce anxiety and stress (Young et al., 2001; Donaldson and Young, 2008; Ross and Young, 2009; Insel, 2010).”

“On a central level, OT might modulate ANS responses via the amygdala-cingulate circuit processing of emotional and cognitive responses to stress (Kirsch et al., 2005; Domes et al., 2007).”

“As parallel data on OT effects in both men and women are still rare and, in part, conflicting (for an overview, see Bartz et al., 2011), it is particularly important to investigate both sexes within the same research design.”

“In order to reflect ANS activity and, more precisely, sympathetic activity (Ehlert et al., 2006; Nater et al., 2006; Nater and Rohleder, 2009), sAA was repeatedly assessed from saliva samples.”

“…and timing of the nasal spray administration were chosen based on published research on intranasal OT, behavior and emotions in humans (Meyer-Lindenberg et al., 2011) and on Born and colleagues’ results on cerebrospinal fluid levels after intranasal vasopressin administration (Born et al., 2002).”

“In line with this and in contrast to positive couple interaction (cf. Grewen et al., 2003; Coan et al., 2006; Ditzen et al., 2007; Holt-Lunstad et al., 2008), ongoing couple conflicts have been suggested to constantly increase stress and, thereby, to impair individual health (Kiecolt-Glaser and Newton, 2001).”

“Within the context of social interaction research, couple conflict is a valuable research paradigm, because for all subjects it involves a highly relevant social interaction partner during instructed and observable real-time behavior.”

“Research in couples shows that women tend to express demand behavior more frequently, while men tend to show withdraw behavior (Gottman and Krokoff, 1989; Christensen and Heavey, 1990; Bodenmann et al., 1998), the latter being a behavioral pattern that is consistently predictive of decreases Fig.”

“OT is synthesized in the hypothalamus, from where it exerts its effects on widespread areas in the central nervous system (CNS) (Gimpl and Fahrenholz, 2001; de Bono, 2003; Landgraf and Neumann, 2004).”

“Among other factors, this research points to the neuropeptide oxytocin (OT), which has been shown to improve social affiliation and attachment and to reduce anxiety and stress (Young et al., 2001; Donaldson and Young, 2008; Ross and Young, 2009; Insel, 2010).”

“In women, there were no associations of sAA with emotional arousal or with observed conflict behavior.”

“Among other factors, this research points to the neuropeptide oxytocin (OT), which has been shown to improve social affiliation and attachment and to reduce anxiety and stress (Young et al., 2001; Donaldson and Young, 2008; Ross and Young, 2009; Insel, 2010).”

“Using this technique, an increasing number of human studies suggest effects of OT on the level of behavioral and neural systems, including social interaction, social memory and stress reactivity (Heinrichs et al., 2009; Bos et al., 2011; Meyer-Lindenberg et al., 2011).”

“cortisol levels, during a couple conflict task (Ditzen et al., 2009).”

“On a central level, OT might modulate ANS responses via the amygdala-cingulate circuit processing of emotional and cognitive responses to stress (Kirsch et al., 2005; Domes et al., 2007).”

“Social integration and affectionate social interactions have a substantial influence on individual stress resilience (Robles and Kiecolt-Glaser, 2003), health (Uchino, 2006; Thoits, 2011) and longevity (House et al.”

“Research in couples shows that women tend to express demand behavior more frequently, while men tend to show withdraw behavior (Gottman and Krokoff, 1989; Christensen and Heavey, 1990; Bodenmann et al., 1998), the latter being a behavioral pattern that is consistently predictive of decreases Fig.”

“Sex-specific effects of intranasal oxytocin on autonomic nervous system and emotional responses to couple conflict Beate Ditzen,1 Urs M. Nater,2 Marcel Schaer,3 Roberto La Marca,1 Guy Bodenmann,4 Ulrike Ehlert,1 and Markus Heinrichs5 1Department of Psychology, Division of Clinical Psychology and Psychotherapy, Univers…”

“Among other factors, this research points to the neuropeptide oxytocin (OT), which has been shown to improve social affiliation and attachment and to reduce anxiety and stress (Young et al., 2001; Donaldson and Young, 2008; Ross and Young, 2009; Insel, 2010).”

“However, substantial sex differences might be expected here, as women show different amygdala activation in response to OT than men (Domes et al., 2010).”

“In line with this and in contrast to positive couple interaction (cf. Grewen et al., 2003; Coan et al., 2006; Ditzen et al., 2007; Holt-Lunstad et al., 2008), ongoing couple conflicts have been suggested to constantly increase stress and, thereby, to impair individual health (Kiecolt-Glaser and Newton, 2001).”

“Moreover, effects of a single neuropharmacological challenge might differ considerably from endogenous OT mechanisms, which are modulated by number and sensitivity of OT receptors in different areas of the CNS (Bale et al., 2001; Landgraf and Neumann, 2004).”

“Using this technique, an increasing number of human studies suggest effects of OT on the level of behavioral and neural systems, including social interaction, social memory and stress reactivity (Heinrichs et al., 2009; Bos et al., 2011; Meyer-Lindenberg et al., 2011).”

“Kiecolt-Glaser et al. (1993) and, more recently, Nealey-Moore et al. (2007) observed increased heart rate (HR) and blood pressure (BP) in response to couple conflict in both men and women, as did Flor et al. (1995) in chronic pain patients and healthy controls.”

“As no specific central nervous in-vivo markers are yet available, the interpretation of OT measures in humans is limited (Meyer-Lindenberg et al., 2011; Szeto et al., 2011).”

“Rilling et al. (2011) and Gamer and Buchel (2011) also failed to find such changes in HR.”

“In a most recent review paper, McCall and Singer (2012) presented the hypothesis that OT might modulate the motivational states approach and quiescence, and that Table 1 HLM with increases in sAA as dependent variable Fixed effects Coefficient; B SE T-ratio d.f. P-value Intercept 26.28 13.07 2.01…”

“However, neuropeptides have been shown to gain access to the brain following intranasal administration (Born et al., 2002; Chang et al., 2012).”

“Interestingly, however, in women, these changes were related to affective content and quality of the interaction, whereas in men, these (overall smaller) changes were related to speech rate (Ewart et al., 1991).”

“In female prairie voles, peripheral OT administration reduced HR responses to social isolation (Grippo et al., 2009) and to social stress (resident intruder test) (Grippo et al., 2012).”

“Sex-specific effects of intranasal oxytocin on autonomic nervous system and emotional responses to couple conflict Beate Ditzen,1 Urs M. Nater,2 Marcel Schaer,3 Roberto La Marca,1 Guy Bodenmann,4 Ulrike Ehlert,1 and Markus Heinrichs5 1Department of Psychology, Division of Clinical Psychology and Psychotherapy, Univers…”

“In women, there were no associations of sAA with emotional arousal or with observed conflict behavior.”

“Moreover, intranasal OT increased both sympathetic activity (assessed by PEP) and parasympathetic activity (assessed by high-frequency HR variability) (Norman et al., 2011).”

“(NE) in blood were found to raise during conflict tasks in the laboratory (Malarkey et al., 1994), although again with sex differences, as revealed by significantly higher responses in EPI levels in women than in men.”

“In order to reflect ANS activity and, more precisely, sympathetic activity (Ehlert et al., 2006; Nater et al., 2006; Nater and Rohleder, 2009), sAA was repeatedly assessed from saliva samples.”

“The authors concluded that ‘gender differences in OT may be evident in different categories of social behaviors’ (Fischer-Shofty et al., 2012).”

“In a recent study, ANS responses were triggered by positive couple interactions (as compared to neutral interactions; Nealey-Moore et al., 2007), an effect which was attributed to the emotional nature of the task.”

“Consequently, research interest has turned to the neurobiological mechanisms underlying the effects of couple interaction on stress and individual health-relevant outcomes (Uchino et al., 1996; Robles and Kiecolt-Glaser, 2003; Karelina and DeVries, 2011).”

“Kiecolt-Glaser et al. (1993) and, more recently, Nealey-Moore et al. (2007) observed increased heart rate (HR) and blood pressure (BP) in response to couple conflict in both men and women, as did Flor et al. (1995) in chronic pain patients and healthy controls.”

“However, the opposite is the case in men, in whom results strikingly resemble the data recently reported by Gamer and Buchel (2011).”

“In female prairie voles, peripheral OT administration reduced HR responses to social isolation (Grippo et al., 2009) and to social stress (resident intruder test) (Grippo et al., 2012).”

“Research in couples shows that women tend to express demand behavior more frequently, while men tend to show withdraw behavior (Gottman and Krokoff, 1989; Christensen and Heavey, 1990; Bodenmann et al., 1998), the latter being a behavioral pattern that is consistently predictive of decreases Fig.”

“In humans, an association of OT receptor gene polymorphism rs53576 with cardiac pre-ejection period (PEP) was recently found in males, with A allele carriers displaying higher levels of sympathetic cardiac control, as revealed by lower resting PEP levels (Norman et al., 2012).”

“However, the underlying mechanisms may be different, because OT decreased sympathetic activity measures during couple conflict in women, but increased sympathetic activity measures in men (Ditzen et al., 2013).”

“But it is likely that effects are not only sex-specific, but task specific (some suggest OT does not change the salience of social-emotional cues) and task-specific between sexes (Ditzen et al., 2012).”

“Initial studies in healthy humans show that oxytocin, a nine– amino acid neuropeptide, reduces anxiety and endocrine responses to social stress (18,19), modulates social memory (20–22), promotes trust in social interactions (23), improves the ability to infer the emotional or mental states of others from subtle facial…”

“Psychoneuroendocrinology 34(6):917–923.”

“…effects on neural underpinnings of social 115cognitive/affective processes in male and female participants (Kirsch et al., 2005; Domes et al., 2010; Ditzen et al., 2012), future research should integrate EEG recording and intranasal administration of OT to clarify whether OT increases or decreases…”

“, 2009, 2012), although the relevant literature in humans is more limited and extensively focused on effects of exogenous OT, which are sometimes sex-specific (Ditzen et al., 2012; Norman et al., 2011; Gamer and Buchel, 2012).”

“In women, OXT also reduced salivary alpha-amylase, an index of sympathetic activity, whereas in men the peptide increased salivary alpha-amylase levels and emotional arousal during couple conflict (83).”

“, 2013) or increased salivary alpha-amylase, a proxy of stress-related sympathetic activity (Ditzen et al., 2013).”

“Intranasal administration of oxytocin before social interaction also generates distinct responses in men and women, increasing self-reported arousal and sympathetic nervous system activation for men and decreasing arousal and SNS activity for women (Ditzen et al., 2013).”

“For example, previous research has shown that oxytocin effects can vary as a function of emotion regulation skills (Quirin et al., 2011), social context history of childhood maltreatment (Ebert et al., 2013; Flanagan et al., 2015), and sex (Ditzen et al., 2012; Rilling et al., 2014).”

“, 2016; Young and Wang, 2004] and human [Ditzen et al., 2013; Feng et al., 2015; Hoge et al., 2014; Lischke et al., 2012; Scheele et al., 2014b; Yao et al., 2014] studies.”

“Thismay fit into current psychobiological considerations and findings of gender-specific functions of OXT and vasopressin (Ditzen et al., 2013; Meyer-Lindenberg et al., 2011).”

“In addition, OT administration increases ANS activity and emotional responses to couple conflict in males whereas decreases these physiological and subjective responses in females (Ditzen et al. 2012).”

“Findings that marital satisfaction positively correlates with emotional expressiveness (King, 1993), could thus be driven in part by an OXT-induced increase in behavioral synchrony between partners in addition to other changes in communicative style (Ditzen et al., 2009; Ditzen et al., 2013).”

“…in the ability to collect and maintain oxytocin through saliva (Gyurak et al., 2013) and recent studies of the effects of oxytocin on emotional responses to couple conflict (Ditzen et al., 2013) suggest that there is promise in further research of the role of oxytocin in close relationships.”

“Indeed, this finding fits with the crucial function of OT as a female hormone in labor, bonding and parenting both in human- [54], [4] and nonhuman mammals [55] and is in agreement with recent experimental evidence pointing to the sex-dimorphic effects of OT nasal spray in humans [19], [45] [56], [57].”

“The relatively small sample size prevented us from explicitly examining sex differences in oxytocin response (Ditzen et al., 2013; Hoge et al., 2014; Lynn, Hoge, Fischer, Barrett, & Simon, 2014; Rilling et al., 2014), although the similar distribution by sex within groups partially mitigates this…”

“Despite growing evidence for gender differences for OXT actions on physiological and emotional responses (Kubzansky et al., 2012; Ditzen et al., 2013; Fischer-Shofty et al., 2013; Rilling et al., 2014; Hoge et al., 2014; Yao et al., 2014) we found no clear evidence for this in the context of the…”

“…exhibits bidirectional interactions with the hypothalamic pituitary adrenal (HPA) axis, hypothalamic pituitary gonadal axis, the autonomic nervous system, as well as with other neurotransmitters such as dopamine, and serotonin (Ditzen et al., 2013; Windle et al., 2006; Nikolaeva et al., 2007).”

“…the extensive literature linking heightened cortisol reactivity and long-term cortisol levels to numerous negative health risks and outcomes (Ennis et al., 2017; Wells et al., 2014), the current findings lend tentative support to the emerging hypothesis that oxytocin might be more effective…”

“…cues in both sexes (McCall and Singer, 2012), sex has been shown to moderate the effect of oxytocin on social judgments (Hoge et al., 2014), autonomic nervous system and emotional responses to couple conflict (Ditzen et al., 2012), and amygdala response to social judgements (Gao et al., 2016).”

“More specifically, OT enhanced social behavior to support parent-infant bonding (Weisman, Zagoory-Sharon, & Feldman, 2012) and improved positive behavior during an instructed couple interaction task (Ditzen et al., 2009, 2012).”

“10:155. doi: 10.3389/fnins.2016.00155”

“Couples’ positive cognitions about and engagement in a conflict discussion have been related to increased sAA levels in response to the conflict paired with quicker reactivity/recovery dynamics overall (Ditzen et al. 2013; Laurent et al. 2013b).”

“OT seems to strengthen the positive aspects of intimate couple relationships, for example by dampening increased sympathetic activity and increasing positive behavior during couple conflict (Ditzen et al. 2009, 2013).”

“…dynamic sAA reactivity and quick recovery to baseline levels were associated with a higher ratio of positive/negative behaviors and less perceived negativity during couples conflict, as well as positive anticipation of a conflict discussion (Ditzen et al., 2013; Laurent, Powers, & Granger, 2013).”

“In the current study, groups were balanced by sex because sex is known to influence oxytocin responses (Ditzen et al., 2012; Flanagan et al., 2018a; Rilling et al., 2014).”

“Children with autism spectrum disorder (ASD) exhibit diminished attention, engagement and orienting to exogenous stimuli, and it has been suggested that atypical LC-NA activity is involved in aberrant mental focus and responsiveness in children with ASD [3].”

“In the present study, only female participants were chosen, in line with emerging research that posits that when females take no oral contraceptives (or any other medication containing hormones) they are ideal subjects when it comes to OT research (Ditzen et al., 2013; Feldman, Gordon, & Zagoory-Sharon, 2010; Insel &…”

“…distress and the burden of anxiety when such con‐ flict occurs may fall more heavily on females, which might then be re‐ flected in their psychobiological profiles of relatively lower T and higher OT (van Anders et al., 2011; Ditzen et al., 2012; Grebe et al., 2017; Taylor et al., 2006).”

“responses and emotional arousal in females, increases them in males Ditzen et al. (2013)”

“…to generally increase positive behavior during a couple conflict (e.g., eye contact and self-disclosure) in both men and women (Ditzen et al., 2009) and furthermore increases salivary alpha-amylase as a marker of sympathetic activity as well as emotional arousal in men (Ditzen et al., 2012).”

“These findings might fit well with regard to gender-specific functions of OXT in experiencing sexual encounters and perceiving sexual arousal.(2,40) Thus, males may primarily focus on sexual functions or performance, whereas females put more focus on emotional and relationship aspects.”

“For example, sex differences in OT response have been extensively documented (Ditzen et al., 2013; Flanagan et al., 2018a; Lynn et al., 2014; Rilling et al., 2014).”

“On the other hand, intranasal oxytocin has been shown to promote relationship repairing responses more in men than in women (Ditzen et al., 2013; Xu et al., 2017).”

“, 2014), and emotional responses to couple conflict (Ditzen et al., 2013).”

“Der allgemeineWirkmechanismus läge dann in der Stressreduktion, würde jedoch abhängig von Geschlecht und Beziehungskontext moduliert.”

“, 2009), affected emotional and sympathetic responses in a sex-dependent manner (Ditzen et al., 2013), increased pupil dilation (as an indicator of norepinephrine driven processes) and eye-gaze to bonding-related and socially neutral stimuli (Eckstein et al.”

“Moreover, researchers have found that oxytocin administration increased positive communication [124], reduced cortisol and autonomic arousal during couple conflict [127], and increased people’s appraisal of positive aspects of their relationships [128].”

“This is in line with research showing a stronger negative effect of intranasal OT on autonomic arousal (measured with salivary α-amylase (23)), as well as a stronger positive effect on feelings of relaxation in women than in men (58).”

“A critical challenge in intranasal delivery is that the response to neuropeptides like oxytocin and NPY is often sexually dimorphic; for instance, oxytocin has been shown to reduce sympathetic nervous system activity in women while increasing it in men during identical social stressors [183–185].”

“Although some studies [69-72] have underlined the importance of investigating the effects of IN-OT on adult females, given the risk factors (eg, uterine contraction and menstrual cycle disturbance) for female adolescents in non-clinical environments, this experimental research will be conducted…”

“For example, one study found that intranasal doses of OT administered prior to a couple conflict task was associated with a decrease of salivary alpha-amylase (a marker of emotional arousal) in women, but the opposite was true in men (Ditzen et al., 2013).”

“Interestingly, ESTtra*OXTint interactions may have contributed to the modulatory effects of hormonal contraception([66]) and to the sex-specific effects of OXTint that have been found in various domains, including fear-related amygdala reactivity([35]), the perception of competition,([67]) moral decision-making,([30])…”