The Oxytocin–Vasopressin Pathway in the Context of Love and Fear
Oxytocin (OT) and vasopressin (VP) are components of an integrated in the vasotocin/vasopressin system: relationship to neurochemical. Difference between Vasopressin and Oxytocin. Vasopressin and Oxytocin are neurohormones produced by the neuro secretory cells of hypothalamus reach the. we discuss the relationship between oxytocin, vasopressin, and various neurotransmitter.
This silences the fetal brain for the period of delivery and reduces its vulnerability to hypoxic damage. This population of oxytocin neurons is absent in Prader-Willi syndromea genetic disorder that leads to uncontrollable feeding and obesity, and may play a key role in its pathophysiology.
Oxytocin has been implicated in the etiology of autism, with one report suggesting autism is correlated with genomic deletion of the chromosome containing the oxytocin receptor gene OXTR.
Behavioral Roles of Oxytocin and Vasopressin
Vasopressin appears to have a similar effect in males. In a study, both humans and dog oxytocin levels in the blood rose after five to 24 minutes of a petting session. This possibly plays a role in the emotional bonding between humans and dogs. Female rats given oxytocin antagonists after giving birth do not exhibit typical maternal behavior.
Oxytocin can increase positive attitudes, such as bonding, toward individuals with similar characteristics, who then become classified as "in-group" members, whereas individuals who are dissimilar become classified as "out-group" members.
Race can be used as an example of in-group and out-group tendencies because society often categorizes individuals into groups based on race Caucasian, African American, Latino, etc.
One study that examined race and empathy found that participants receiving nasally administered oxytocin had stronger reactions to pictures of in-group members making pained faces than to pictures of out-group members with the same expression.
Moreover, individuals of one race may be more inclined to help individuals of the same race than individuals of another race when they are experiencing pain. Oxytocin has also been implicated in lying when lying would prove beneficial to other in-group members.
In a study where such a relationship was examined, it was found that when individuals were administered oxytocin, rates of dishonesty in the participants' responses increased for their in-group members when a beneficial outcome for their group was expected.
Oxytocin is not only correlated with the preferences of individuals to associate with members of their own group, but it is also evident during conflicts between members of different groups. During conflict, individuals receiving nasally administered oxytocin demonstrate more frequent defense-motivated responses toward in-group members than out-group members. Further, oxytocin was correlated with participant desire to protect vulnerable in-group members, despite that individual's attachment to the conflict.
Further, oxytocin influences the responses of individuals in a particular group to those of another group. The in-group bias is evident in smaller groups; however, it can also be extended to groups as large as one's entire country leading toward a tendency of strong national zeal.
A study done in the Netherlands showed that oxytocin increased the in-group favoritism of their nation while decreasing acceptance of members of other ethnicities and foreigners.
Thus, oxytocin appears to affect individuals at an international level where the in-group becomes a specific "home" country and the out-group grows to include all other countries. Drugs[ edit ] Drug interaction: Impact on effects of alcohol and other drugs: According to several studies in animals, oxytocin inhibits the development of tolerance to various addictive drugs opiatescocainealcoholand reduces withdrawal symptoms.
AVP released in high concentrations may also raise blood pressure by inducing moderate vasoconstriction.
- The Oxytocin–Vasopressin Pathway in the Context of Love and Fear
AVP also may have a variety of neurological effects on the brain. It may influence pair-bonding in voles. The high-density distributions of vasopressin receptor AVPr1a in prairie vole ventral forebrain regions have been shown to facilitate and coordinate reward circuits during partner preference formation, critical for pair bond formation. This occurs through increased transcription and insertion of water channels Aquaporin-2 into the apical membrane of collecting tubule and collecting duct epithelial cells.
This effect is mediated by V2 receptors. Vasopressin also increases the concentration of calcium in the collecting duct cells, by episodic release from intracellular stores. Vasopressin, acting through cAMP, also increases transcription of the aquaporin-2 gene, thus increasing the total number of aquaporin-2 molecules in collecting duct cells. These receptors are also involved in the central control of cardiovascular activity.
In lactating mammalian mothers, OXT initiates milk letdown in the mammary glands, and the release of OXT is stimulated by suckling.
OXT has one known receptor which has several alleles. While some of these actions are mediated the PVN and SON, several other behaviorally active brain regions will also be discussed.
The behavioral roles of oxytocin and vasopressin have been studied and characterized in several animal species over the past few decades, and these findings have recently stimulated related work in humans. While the specific direction of the effects often vary between species, the general behavioral functions of AVP and OXT, as well as several related ancestral peptides, are conserved across taxa.
The study of the diversity of these systems in birds [ 1 ] and fish [ 2 ] has been particularly useful in identifying the mechanisms of the effects of these peptides on behavior. Although the behavioral roles of OXT and AVP are good examples of effective translation from animal models to clinical study for some topics, such as autism, there is still a need for increased communication and collaboration on many relevant issues, especially gender differences and stress related mood disorders.
Both animal and human studies on depression and anxiety indicate that these neuropeptides have gender specific roles, and administering treatments developed in male animals and humans to females may be ineffective or have adverse consequences. The objectives of this review chapter are to present an updated summary of the gender specific behavioral roles of OXT and AVP in both animals and humans and stimulate translationally relevant gender specific studies on these hormones.
The need for more female specific studies in this area is great, and this need will be underscored throughout the chapter. Clinical topics discussed include depression, anxiety, addiction, and autism. Due to the broad scope of these objectives, this review chapter will highlight selected research and review papers on each topic, but will not be comprehensive.
Oxytocin in male animals 2. OXT and male animal affiliation While most studies of both AVP and OXT conclude that OXT is a more important mediator of affiliative behavior in females than males, there is considerable evidence that OXT may serve important social behavior functions in males as well.
The most convincing evidence for the role of OXT in affiliative behavior in animals is pair bonding in prairie voles Microtus ochrogaster. These voles are relatively unique in their monogamous social structure, which is mediated by OXT and AVP activity in the brain.
Central OXT infusions facilitate prairie vole pair bonding [ 3 ], which has been linked to gender specific developmental effects in male voles [ 4 ]. The distribution of OXT receptors in the brain mediates divergent social strategies in monogamous and polygamous vole species [ 5 ]. Studies of social recognition and memory in male mice, processes important for the establishment of affiliative behavior, conclude that OXT actions on social behavior are mediated by changes in recognition and social memory [ 67 ].
In pair bonded tamarin monkeys, peripheral OXT levels vary with levels of affiliation and sexual behavior in both genders [ 9 ]. Specifically, OXT levels in male tamarins were correlated strongly with sexual behavior. In fish it has been postulated that isotocin the teleostean homologue of OXT is involved in courtship displays and territorial defense [ 10 ], and many of the social behavior effects of OXT are conserved across taxa [ 11 ]. OXT and male animal aggression The recent data from stickleback fish suggest that the affiliative actions of OXT in vertebrates are associated with aggression [ 10 ].
OXT levels are highest in male sticklebacks that aggressively defend eggs and in subordinate males that fight to change their social status. Disruption of the OXT gene in male mice decreases aggression [ 12 ], yet OXT knockout mice display elevated aggression which is postulated to be the result of decreased fearfulness [ 13 ]. One potential explanation for this inconsistency is indirect effects through AVP due to the neuroanatomical and biochemical similarities between the two neuropeptide systems.
OXT and animal paternal behavior In polygamous male meadow voles Microtus pennsylvanicuspaternal experience is associated with increases in OXT receptor binding in the accessory olfactory nucleus, bed nucleus of the stria terminalis, lateral septum, and lateral amygdala [ 14 ].
It was concluded that central OXT infusion increased the tolerance of the offspring by the father. It appears that male prairie vole paternal behavior may rely on the neural effects of both peptides. Mandarin voles Lasiopodomys mandarinuswhich are biparental and express parental behavior towards foster pups, increase central OXT expression following the development of male alloparental behavior. This increased expression may be mediated by elevated estrogen receptor alpha [ 16 ].
In support of this association between OXT and mammalian paternal expression, a recent primate study reported that icv OXT increased the transfer of food from fathers to their offspring [ 17 ].
Similar effects of OXT in male primates are supported by clinical data which will be discussed later in this review. OXT and male animal models of depression and anxiety Peripheral OXT has antidepressant effects in both young and old rats, and the effects in older rats are associated with enhanced memory [ 1819 ]. In the mouse tail suspension test, both systemic and central OXT decrease immobility time, which indicates that OXT decreased helplessness [ 20 ].
In contrast to these results, intracerebroventricular icv OXT did not affect behavior in the forced swim test of depressive like behavior in male rats selected for high or low anxiety, although it did have an anxiolytic effect [ 21 ].
Furthermore, isolated prairie vole males exhibit both anhedonia and increased plasma OXT following a resident intruder test of aggression [ 22 ].
As has been hypothesized for OXT elevation following maternal aggression, this increase could be due to the stress of the interaction, and may not be a causal factor for anhedonia. It is possible that anhedonia targeting tests of depressive behavior, such as saccharin preference or a naturally occurring reward mediated behavior sexual behavior, maternal behaviorwould reveal consistent anti-depressive actions of OXT.
OXT and male animal learning and memory Most of the research on OXT and learning and memory has been limited to male models [ 23 ]. OXT mediates social recognition in several species [ 24 ], and male OXT knockout mice exhibit social amnesia [ 6 ], while other forms of memory are not affected. This effect on social recognition is reversed by OXT treatment [ 7 ] and is mediated by the transmembrane protein CD38 [ 25 ].
A single dose of OXT can specifically impair memory retention [ 26 ], and further study indicates that exogenous OXT inhibits cholinergic mechanisms that are necessary for memory retention [ 27 ]. Another mechanism implicated in the amnesiac effects of OXT is glucocorticoid release, as dexamethasone is able to reverse the effects of OXT on memory [ 28 ].
While OXT may facilitate memory and social interactions in certain contexts such as pair bonds at certain levels, robust levels of OXT may impair social memory due to substantial glucocorticoid release or impaired cholinergic activity.
Oxytocin in female animals 3. OXT and female animal affiliation OXT mediates the establishment and support of social bonds in several female mammalian species. Central injection of OXT specifically facilitates pair bonding in female prairie voles, similar to the role of AVP in males [ 32930 ]. Studies of OXT receptor distributions in voles have identified expression patterns linked to species patterns of social organization, which support the manipulative studies [ 511 ]. It has been postulated that the role of OXT in female rodent affiliation may be related to its effects on maternal behavior [ 31 ].
In primates, affiliation has been correlated with urinary OXT levels, including a relationship between the solicitation of sex and increased OXT levels [ 9 ]. OXT and female animal aggression The data on the role OXT in female aggression are mixed, including several studies specifically on maternal aggression [ 32 ]. Other studies reporting a positive association between OXT and female aggression postulate that OXT increases aggression by attenuating fear [ 343637 ], but it is also possible that elevated OXT levels following maternal aggression are a result of the stress of the encounter [ 36 ].
[The role of oxytocin and vasopressin in central nervous system activity and mental disorders].
In contrast, maternal separation decreases OXT immunoreactivity in lactating female mice, and this decrease was associated with an decreased latency to attack a novel male intruder [ 38 ], supporting earlier studies reporting an inhibitory effect of OXT on maternal aggression [ 39 - 41 ].
Several studies of the effects of cocaine on maternal aggression and oxytocin have also concluded that oxytocin has inhibitory effects on aggression [ 42 - 44 ]. In multiparous rats which are more aggressive than primiparous dams, OXT or OXT receptor levels are decreased in several behaviorally relevant brain regions compared to primiparous animals [ 45 ]. In general, the majority of the manipulative studies support the conclusion that OXT is inhibitory towards female aggression. OXT receptor knockout mice exhibit deficits in maternal care [ 51 ].
However, central OXT activity may not be a factor in all aspects of maternal care. The initiation of maternal care is impaired by the disruption of central OXT activity by lesions and antagonism of OXT [ 11 ], but since OXT disrupting lesions to the PVN of sheep do not disrupt maternal care once it has been established, OXT appears to be more important in the initiation of maternal care than the maintenance [ 52 ].
Other investigations in sheep have supported the hypothesis that OXT specifically mediates the induction of maternal care [ 53 ]. Comprehensive studies of natural variations in rodent maternal care indicate that OXT receptors mediate these differences, with high levels of OXT activity being associated with elevated levels of maternal care [ 5455 ]. These OXT actions are related to associated changes in dopamine activity [ 56 ] and both OXT receptor levels and maternal care are altered by exposure to gestational stress [ 57 ].
It is postulated that impairments in maternal care following gestational stress may be mediated by decreases in central OXT activity. The actions of OXT receptors in the nucleus accumbens have also been implicated in spontaneous maternal care in prairie voles [ 58 ]. Future animal work which includes the behavioral and physiological effects of OXT in maternal animals may identify treatments for disorders involving deficits in both maternal care and lactation. OXT in female animal models of depression and anxiety Despite the established role of OXT in maternal care, a potent reward mediated behavior; little effort has been directed at studying the role of OXT in female depression and anxiety.
Much of the current focus on translational OXT work is centered on effects on social behavior, and related disorders such as seasonal affective disorder and autism. Central OXT decreases anxiety in pregnant and lactating rats, despite having no effect in virgins [ 59 ].
However, chronic icv OXT is anxiolytic in female rats selected for high levels of anxiety [ 21 ]. Studies using ovariectomized rats indicate that circulating estrogen is required for the anxiolytic effects of OXT, which is likely to involve dynamic estrogen dependent changes in OXT receptor levels [ 60 ].
This dependence on estrogen may explain the divergent results in maternal and nulliparous rats considering the robust hormonal changes of pregnancy and lactation [ 61 ].
These data are relevant to the clinical observation that exposure to stress is a significant predictor of depression in females [ 63 ]. The animal literature on OXT and maternal care and the consistency between animal and human work make this neuropeptide a strong target for human studies of postpartum depression. OXT and female animal learning and memory The majority of the studies on OXT and memory in female animals investigate social recognition.
The disruption of endogenous OXT activity impairs short-term olfactory memory in female rats [ 64 ], and mice with a conditional OXT knockout display impairments in social recognition [ 65 ]. In sheep, a functioning OXT circuit in the olfactory bulb is required for offspring recognition [ 52 ].
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 [ 6869 ], central OXT is involved in the consolidation of maternal memory [ 70 ].
Although some studies of ongoing maternal care conclude that OXT is not necessary once offspring care has been established [ 115271 ], these data on maternal memory indicate that its importance to maternal care may extend beyond the initial stages of maternal care.
Oxytocin in male humans 4. OXT and male human affiliation 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 [ 7273 ]. 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 ]. 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 [ 8081 ].
[The role of oxytocin and vasopressin in central nervous system activity and mental disorders].
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 anxiety disorder [ 85 ], and research in this area is ongoing.
The established effects on affiliation and prosocial behavior in animals and humans support the hypothesis that OXT has inhibitory effects on aggression. OXT and human paternal behavior 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 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 [ 8889 ].
Collectively, these recent studies indicate that OXT modulates several forms of family associated social behavior. 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 [ 9091 ], which are often impaired in depressed individuals.
Reduced plasma OXT has been observed in humans suffering from depression [ 9293 ], and detailed investigations of depressive symptoms indicate that high levels of plasma OXT are associated with a decrease in the severity of symptoms [ 94 ].