**4.3. OXT and human paternal behavior**

54 Neuroendocrinology and Behavior

may extend beyond the initial stages of maternal care.

anxiety disorder [85], and research in this area is ongoing.

**4.2. OXT and male human aggression** 

**4. Oxytocin in male humans** 

during orgasm [76-78].

**4.1. OXT and male human affiliation** 

in social recognition [65]. In sheep, a functioning OXT circuit in the olfactory bulb is required for offspring recognition [52]. These effects of OXT on offspring recognition are mediated by GABA, norepinephrine, and acetylcholine and are crucial to the role of OXT in maternal care induction [66]. It has also been postulated that the effects of OXT in pair bonding involve a social recognition function [67]. Similar to studies of the roles of dopamine and AVP in rodent maternal memory (the ability of a dam to quickly return to maternal care following a separation from her pups) [68, 69], central OXT is involved in the consolidation of maternal memory [70]. One hypothesis is that the effects of both OXT and AVP are mediated by their actions on dopamine. Although some studies of ongoing maternal care conclude that OXT is not necessary once offspring care has been established [11, 52, 71], these data on maternal memory indicate that its importance to maternal care

The investigations of OXT and affiliation in humans do not necessarily examine affiliation directly. For instance, intranasal OXT promotes trust and prosocial behaviors which are critical to human bonding and it is also associated with trustworthiness [72, 73]. Intranasal OXT increases cooperation following unreciprocated cooperation in a social experiment and this behavioral effect was associated with increased fMRI activity in OXT regions associated with affiliation [74]. Studies investigating affiliation and/or sexual behavior conclude that the effects of OXT are often mediated by direct physical contact as increased plasma OXT has been recorded in men during social contact with a partner [75], and

Impaired affiliation has been associated with decreased plasma OXT in autistic patients [79]. Normal affiliative expression is especially impaired in autistic males, and some autistic males have deficits in OXT receptor expression [80, 81]. Several cases were associated with hypermethylation of the OXT receptor gene and a decrease in OXT receptor mRNA. Furthermore, clinical studies have reported enhanced social interactions (eye contact, social memory) in autistic patients following intranasal OXT [82]. Several labs have investigated the use of OXT for the treatment of social behavior deficits in autism [82-84] and social

Compared to the interest in OXT and human prosocial behavior, there are few studies of the role of OXT on male aggression. The established effects on affiliation and prosocial behavior in animals and humans support the hypothesis that OXT has inhibitory effects on aggression. Conversely, some have postulated that OXT's anxiolytic effects could result in increased aggression, but there are no behavioral data in support of this theory. One

potential clinical role of OXT is in the treatment of PTSD associated aggression.

There is some evidence that OXT mediates human paternal care as well as maternal care. Plasma and salivary OXT has been associated with paternal social engagement, affect synchrony, and positive communication sequences, and fathers who exhibit high levels of stimulatory contact with 4-6 month old infants have elevated OXT levels compared to fathers that do not exhibit high levels of contact [86]. Intranasal OXT increases the responsiveness of fathers during play with their children, and may decrease hostility, which supports a causal role for OXT and positive paternal behavior [87]. The decrease in hostility offers indirect support for an inhibitory effect on male aggression. Finally, both maternal and paternal plasma OXT levels predict coordination of behaviors between parents and their children, indicating that OXT may have a positive effect on family interactions [88, 89]. Collectively, these recent studies indicate that OXT modulates several forms of family associated social behavior.

## **4.4. OXT and male human depression and anxiety**

The interest in OXT as a potential treatment for mood disorders is based on the animal literature supporting the involvement of OXT in reward mediated and social behaviors [90, 91], which are often impaired in depressed individuals. Reduced plasma OXT has been observed in humans suffering from depression [92, 93], and detailed investigations of depressive symptoms indicate that high levels of plasma OXT are associated with a decrease in the severity of symptoms [94]. However, some studies have been unable to find depression related differences in plasma OXT [95]. Since OXT has both central behavioral effects and peripheral physiological effects, the exact functions of elevated plasma OXT are not clear. The few studies which have measured OXT activity in postmortem samples of depressed patients have reported increases in depression associated OXT immunoreactivity [96] and OXT mRNA in the PVN [97]. The increase in OXT mRNA in melancholic patients compared to non-melancholic depressives suggests that changes in OXT are specific to the type of depression. With anxiety, intranasal OXT has minor effects in male patients with seasonal affective disorder [85]. Given the strength of the animal work on the prosocial and reward mediated actions of OXT, it is surprising that there is not more interest in this target for treating depression and/or anxiety.

#### **4.5. OXT and male human learning and memory**

Intranasal OXT facilitates socially reinforced learning and emotional empathy in men [98], consistent with the data from animal models and the initial studies of the effects of OXT in autistic patients. Another study reported that OXT's effects were specific to the social stimuli of facial expressions, and did not affect financial associations in an associative learning task [99]. The available evidence supports the conclusion that OXT facilitates social reinforced learning and memory in human males, and these effects may be mediated at the amygdala [98].
