- freely available
Pharmaceuticals 2010, 3(3), 702-724; doi:10.3390/ph3030702
Published: 16 March 2010
Abstract: Affective disorders represent the most common psychiatric diseases, with substantial co-morbidity existing between major depressive disorders (MDD) and anxiety disorders. The lack of truly novel acting compounds has led to non-monoaminergic based research and hypotheses in recent years. The large number of brain neuropeptides, characterized by discrete synthesis sites and multiple receptors, represent likely research candidates for novel therapeutic targets. The present review summarises the available preclinical and human evidence regarding the neuropeptide, oxytocin, and its implications in the aetiology and treatment of MDD. While the evidence is not conclusive at present additional studies are warranted to determine whether OXT may be of therapeutic benefit in subsets of MDD patients such as those with comorbid anxiety symptoms and low levels of social attachment.
Major depressive disorder (MDD) is a major health concern, with lifetime prevalence in the United States estimated to be as high as 16.2% . Furthermore, the World Health Organisation states that MDD is the second largest global health burden [2,3]. Despite a biological basis for MDD being postulated as early as the 5th century BC by Hippocrates, together with substantial research efforts, the underlying aetiology of mood disorders remains poorly elucidated [4,5,6]. Currently, according to the Diagnostic and Statistical Manual of Mental Disorders Edition IV, only depressed mood and anhedonia (loss of interest or pleasure in previously rewarding stimuli) are considered as core symptoms of MDD. However, there are also prominent additional symptoms, at least in subsets of depressed patients, which include sleep disturbance , anxiety and sexual dysfunction .
Although a number of pharmacological agents are available to treat depression, approximately 30–40% of patients do not respond to these  and in those who do benefit there is a delayed onset of action. Therefore, a major emphasis in modern psychiatric research is to uncover the underlying aetiology of mood disorders, and to develop novel efficacious antidepressant treatments. Neuropeptides, which have discrete synthesis and receptor sites, have emerged as viable research candidates, with respect to both the pathophysiology and treatment of MDD. In this context, interest has mainly focussed on the brain neuropeptides corticotrophin releasing hormone (CRH) and vasopressin (AVP), which both exert anxiogenic and depression-like effects. Numerous review papers are recommended for the interested reader [10,11,12,13]. However, the nonapeptide oxytocin (OXT), which only differs from AVP by two amino acids, has recently received a great deal of interest in complex behaviours and is the focus of this review.
Originally considered as a “maternal hormone” based on its role in the regulation of reproductive functions and maternal behaviour, OXT has recently been implicated in a plethora of other behaviours and neurochemical processes (see  for a review). OXT is mainly synthesised in magnocellular neurons of the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei and is secreted into the periphery via the posterior pituitary where it mediates effects on uterine contractions, milk ejection in lactation and cardiovascular control, among others. These actions are mediated via the OXT receptor (OXT-R) of which only one has been identified to date. The receptor is a member of the G protein-coupled receptor (GPCR) family and is coupled to phospholipase C . In addition, there is widespread distribution of the OXT-R throughout the central nervous system and independent central and peripheral release of OXT has been shown . Recent evidence has implicated OXT in numerous complex behaviours, particularly anxiolysis [17,18,19,20,21]. Thus, given that half of the patients diagnosed with MDD meet criteria for co-morbid anxiety disorder , OXT may be of therapeutic benefit in these patients, as well as those with only anxiety. The following review will assess the literature on other potential roles of OXT in the pathophysiology and treatment of MDD.
2. Evidence from Animal Studies
2.1. Animal models of depression
The first report of an antidepressant-like effect of OXT came from Arletti and Bertolini  who demonstrated that intra-peritoneal (i.p.) administration both, acutely, and after ten daily-repeated injections decreased immobility time in the forced swim test (FST) in mice: the most widely utilised animal model of depression . The FST results were recapitulated in aged (26 month) Wistar rats following i.p OXT administration . In addition, subcutaneous OXT was reported to decrease the number of escape failures in the learned helpless test , which is indicative of an antidepressant-like effect . In these studies OXT was given peripherally, but we have to keep in mind that neuropeptides like OXT can only cross the blood-brain barrier (BBB) in very low amounts when supra-physiological concentrations of exogenous OXT are administered in adult rodents [26,27]. However, it is also possible that active OXT fragments can cross the BBB to produce central effects . In support, findings of other OXT-mediated effects, such as decreased blood pressure can also be observed following both peripheral and central OXT administration . Recently, the FST findings were recapitulated in mice in the tail suspension test (TST), a test with a similar construct . Furthermore, the antidepressant-like effect was also shown after intracerebral OXT administration in the TST . However, a novel non-peptidergic OXT agonist, WAY-267464, while having an anxiolytic profile, did not replicate the OXT effect in the FST . These results suggest that, at least in mice, systemic or central administration of OXT has antidepressant-like properties.
In rats exposure to forced swimming stimulates the release of OXT within the central amygdala (CeA) again suggesting a link between OXT and depression. However, local administration of an OXT-R antagonist (OXT-A) revealed that the OXT release was linked to a more passive stress-coping style, i.e., depressive-like behaviour . As central OXT actions have also been linked to the promotion of sleep  in male rats, the possibility exists that brain OXT contributes to a generally reduced arousal and activity. While this supports a pro-depressive effect of OXT, this may be region specific as we recently demonstrated in animals selectively bred for high or low anxiety-related behaviour  that neither acute nor chronic icv OXT infusion altered behaviour in the FST . Taken together, the present evidence from the few studies assessing OXT in animal models of depression is inconclusive regarding a potential antidepressant-like effect of OXT. More studies are needed in order to determine whether the findings in the early studies can be replicated and extended to central administration and additional models. These previous studies have only examined the effect of OXT in the FST and TST, or after peripheral administration. Therefore, studies assessing the potential role of central OXT in models that assess different endophenotypes are warranted. For example, replication of the learned helplessness results following central administration, anhedonia (see below), or in sleep disturbances, and in such tests following chronic stress exposure would provide better indication of any potential antidepressant-like properties of OXT.
2.2. OXT and the reward system
As mentioned above anhedonia is a core symptom of depression and it is also one, which is easily assessable in animal studies . The conditioned place preference paradigm is widely used to study drugs of abuse, such as cocaine. Here, animals spend preferentially more time in an environment that has previously been associated with the drug indicative of its rewarding properties. OXT, when infused subcutaneously in rats, was shown to result in a place preference, suggesting that peripheral infusion of OXT results in a positive hedonic state . Contrastingly, a more recent study assessing intracerebral OXT infusion did not replicate these findings ; although the latter study was performed in mice. However, OXT injection into the ventral tegmental area (VTA), ventral subiculum and posteromedial cortical nucleus of the amygdala causes increased dopamine release in the nucleus accumbens [36,37]. This again suggests that OXT may itself have rewarding properties given that drugs of abuse also result in increased DA release in this region .
The brain OXT system shows high activation during the peripartum period with increased synthesis, intracerebral release in response to birth and suckling and receptor presence, and OXT is known to be an important mediator of maternal behaviour [39,40]. In a recent fMRI study, suckling was shown to increase activity in numerous regions of the reward circuitry in lactating rat dams; particularly the VTA-accumbens-prefrontal cortical pathway . This increase was prevented by pre-administration of an OXT-A, and suggests that suckling is rewarding for the mother via OXT release, encouraging her to continue engaging in the behaviour. This finding also fits with a series of experiments from Morrell and co-workers showing that, in early lactation, dams find pups more rewarding than cocaine but that this reverses in mid-to-late lactation [42,43]. These findings suggest that OXT, either via exogenous application or endogenous release in response to specific stimuli, results in a positive hedonic state. Therefore, OXT may help to alleviate the severity of anhedonia observed in MDD patients. Moreover, they suggest that altered OXT system activity may be involved in postpartum depression (see OXT in the peripartum period section).
There is also high co-morbidity between MDD and drug abuse, and withdrawal from such drugs leads to the appearance of many symptoms observed in MDD. This has led some authors to postulate that similar neurobiological mechanisms may underlie the disorders . Low doses of 3,4-methylene-dioxymethamphetamine (MDMA; ecstasy) have been shown to increase the level of plasma OXT in both rodents and humans, and administration of an OXT-A was shown to prevent the increased social behaviour induced by MDMA in rodents (reviewed in ). This suggests that OXT may also be involved in the rewarding effects of acute MDMA, again supporting a role of OXT in reward and positive hedonic states. Contrastingly, the literature suggests that OXT actually decreases abuse and withdrawal symptoms of drugs such as cocaine and methamphetamine [35,46]. For example, icv administration of OXT decreased the abuse of opiates and cocaine in rodents [47,48]. OXT has also been shown to decrease methamphetamine-induced hyperactivity and place preference by altering mesolimbic DA turnover [35,49]. Similar findings have been reported regarding OXT preventing the increase in DA release following apomorphine , cocaine  and morphine  administration. Importantly, OXT was also able to prevent the reinstatement of methamphetamine-place preference induced by restraint stress but not by methamphetamine administration . These findings suggest that OXT works to prevent the reinstatement of drugs by a stressor, which is in agreement with the known hypothalamic-pituitary-adrenal (HPA) axis attenuating properties of OXT (see below). A potential reason for the ability of OXT infusion to decrease the abuse potential of drugs of abuse and withdrawal symptoms is the reported decrease in OXT mRNA and OXT-fibers in the nucleus accumbens and VTA following seven days of Δ-9-tetrahydrocannabinol administration  or in the PVN and SON following morphine infusion . This contrasts to the increased excitability of OXT neurones in the SON precipitated by naloxone infusion in morphine-withdrawal in rats . However, these findings again implicate alterations in the OXT system underlying physiological changes as a result of drug withdrawal. Additionally, lithium administration was shown to prevent the withdrawal symptoms from cannabinoids by increasing OXT mRNA expression in the PVN and SON . When an OXT-A was given, lithium administration was no longer able to prevent the withdrawal syndrome, while icv OXT was able to mimic the lithium effects alone . Therefore, OXT could represent a viable treatment option in patients with co-morbid drug abuse, and also to reduce the depressive-like symptoms precipitated by drug withdrawal, which can in turn lead to the development of MDD . Studies using intra-cranial self stimulation under basal and drug-withdrawal conditions could provide a greater insight into the postulated role of OXT in anhedonia . Similarly, studies assessing central OXT on sucrose preference after chronic stress with an antidepressant as a control could determine whether central OXT could attenuate the anhedonic-phenotype observed in such paradigms.
2.4. OXT and 5-HT interactions
The monoamine hypothesis of depression predominated much scientific research into MDD, both academic and pharmaceutical, from the 1960s until recently . Although new hypotheses have been postulated, all currently approved antidepressants with the exception of agomelatin, the melatonin-based compound that was licensed last year, have a primary mechanism of action of increasing the activity of monoamine systems. Therefore, a possible mechanism for a role of OXT in the pathophysiology and treatment of MDD is its interaction with the serotonergic system. It was shown in conscious rat dams that 5-HT injections potentiated the regular OXT bursts that occur in response to the suckling stimulus as assessed by electrical activity of OXTergic neurones . Moreover, 5-HT receptor antagonist treatment or 5-HT depletion by administration of p-chlorophenylalanine (pCPA) inhibited the suckling response. D-Fenfluramine, a 5-HT releasing agent, has also been reported to increase c-fos expression in OXT neurones of both the PVN and SON . These effects may be mediated by 5-HT1A- and 2A receptors as specific agonists for these receptors were shown to dose-dependently increased plasma OXT levels. The effects of the agonists were blocked by pre-treatment with NAN-190 (a 5-HT1A receptor antagonist) or ritanserin (5-HT2A/2C) compounds, respectively [66,67]. Interestingly, plasma AVP levels were not altered by activation of either receptor subtype, supporting a specific role of the serotonergic system for manipulating OXT release [66,67]. The stimulatory effect of activation of the serotonergic system appears to occur also at the level of gene transcription as 5-HT1A- 1B, - 2A- and 2C receptor agonist administration was shown to increase OXT mRNA expression in the PVN and SON . These data are also in agreement with evidence showing that stimulation of the dorsal raphe nucleus leads to an increase in neuronal activity of magnocellular PVN neurones . In a series of lesion studies, p-chloroamphetamine and fenfluramine, increased plasma OXT levels in control and SON-lesioned animals, but not in those with PVN-lesions. Interestingly, the effects in control animals were prevented by administration of fluoxetine, which suggests that, at least acutely, re-uptake of 5-HT into the nerve terminals is required to stimulate OXT secretion into the plasma . In contrast to these findings a study assessing the effect of i.p. citalopram, a more selective 5-HTT blocker than fluoxetine, and a structurally different SSRI, zimeldine, on plasma OXT levels revealed an increase following both acute and chronic (2 week) administration . Further anatomical evidence was shown by Emiliano et al.,  who demonstrated that the density of 5-HTT fibres followed the distribution of OXT-containing neurones in the PVN and SON in macaques. Together with some of the data outlined above, this observation lead the authors to speculate that efficacy of SSRI’s to restore social interactions/bonding may be in part due to the activation of the OXT system .
One of the main reasons in the clinical setting for patients stopping SSRI treatment is the loss of libido and anorgasmia caused by their use. Sexual stimulation in men and women causes an increase in plasma OXT levels [73,74]. In male rats, successful mating is accompanied by increased intra-PVN-release of OXT, and such central OXT is necessary for male sexual behaviour  and the anxiolytic effect of mating . Chronic fluoxetine administration in male rats has also been shown to decrease ejaculation frequency and administration of OXT prior to the test specifically prevented this effect . This data fit with that of Li et al., [78,79,80] showing that chronic fluoxetine administration decreased the affinity of 5-HT1A- and 2A-receptors on OXT neurones. Therefore, it is possible that an initial increase in OXT system activity by SSRI treatment gives way to a decrease following chronic up-regulation of the serotonergic system. Thus combining SSRI treatment with OXT may help to decrease the coincidence of sexual dysfunction caused by the former and, therefore, greater tolerability of the patients to continue with the antidepressant treatment.
There has also been recent evidence showing that the well-documented anxiolytic action of OXT may be mediated via OXT-induced 5-HT receptor activation . In this elegant study, a yellow fluorescent protein, Venus, was placed under control of the regulatory region of the gene encoding the OXT-R in order to determine the expression pattern of OXT-R throughout the brain . In these mice, widespread expression of OXT-R-containing cells was observed but most strikingly a large co-localisation of Venus with tryptophan hydroxylase-positive neurones in the raphe nuclei was shown . Intra-raphe infusion of OXT increased 5-HT release within the median raphe, which was inhibited by 5-HT2A/2C receptor antagonists. This led the authors to speculate that the increased serotonergic activity induced by OXT may underlie its anxiolytic effects , and given the use of SSRI’s in MDD, these findings may also relate to their antidepressant-like effects. It would be interesting to determine whether the increased 5-HT release is maintaining following chronic OXT administration, and therefore, support another possible role for OXT in the treatment of MDD.
2.5. OXT and stress responsivity
Numerous stressors including both social and physical, have been shown to increase central OXT release in regions known to be involved in stress-responsivity including the PVN, CeA and lateral septum [31,82,83,84,85,86]. Such local release has been linked to an inhibitory effect of OXT on HPA axis (re)activity in male and virgin female rats [18,87]. We could show that OXT neurons respond to emotional, physical, or pharmacological stressors with elevated peripheral and somato-dendritic release within the hypothalamus and the amygdala in male and virgin female rats . Endogenous OXT has also been shown to inhibit the activity of the HPA axis locally in the PVN, amygdala, or medio-lateral septum . In support, in mice lacking OXT, exposure to stress has been shown to lead to an increase in CRH mRNA expression within the PVN  and elevated corticosterone levels ; indicative of an elevated stress response . The time around birth is accompanied by complex behavioural, physiological and neuronal adaptations of the maternal brain, which ensure reproductive functions and the mental health of the mother. Two major adaptations are the attenuation of the HPA axis to a variety of stressors and anxiolysis, which are mediated, at least in part, via the increased activity of the OXT system . This suggests that OXT may mediate stress-hyporesponsiveness over a longer duration than those observed in the acute studies mentioned above. Additional support comes from a study showing that chronic icv OXT administration (10 ng/h; 7 day) decreases neuronal and neuroendocrine responses to acute restraint stress exposure in ovariectomized virgin rats . Chronic hypertonic saline has been shown to increase OXT in the PVN  but surprisingly, there have been very few other studies examining the effect of chronic psychological stress on the OXT system [93,94] with the exception of the aforementioned studies on effects of isolation stress in female prairie voles [60,62]. Taken together, these findings suggest that the OXT system acts as a stress-buffering factor, at least to acute stimuli. Therefore, given that, long-term and especially chronic stress is a well-documented risk factor for the development of psychiatric disorders in predisposed individuals; contribution of a dysfunctional OT system is suggested (see below). Additionally, these studies suggest that OXT may represent a therapeutic benefit in MDD patients with abnormal stress responses, such as observed in patients with paradoxical outcome of the dexamethasone suppression/CRH challenge test . However, it is clear that more studies are required to assess the role of chronic stress on the OXT system and whether chronic OXT administration would be beneficial in protecting against the detrimental effects of chronic stress exposure.
3. Evidence from Human Studies
3.1. OXT in the peripartum period
Similar to the findings from animal studies, OXT has been implicated in decreasing stress-responsivity in humans. Indeed, a series of experiments performed in the 1980s revealed that systemic OXT administration attenuated both basal and pharmacologically-induced ACTH and cortisol responses in healthy volunteers (summarised in ). Breast-feeding was shown to increase plasma OXT in women [97,98], likely to be accompanied by central OXT release [39,99]. Accordingly, Heinrichs et al.,  determined whether breastfeeding prior to an acute stressor exposure may underlie the decreased stress responsivity observed in the peripartum period. Lactating women were asked to either breast-feed or hold their child for a 15 min period, 30 min before they were subjected to the Trier Social Stress Test (TSST) in which they have to give an unprepared speech and perform mental arithmetic in front of an audience . Breast-feeding attenuated the TSST-induced plasma cortisol rise when compared with the lactating holding group  indicating a possible involvement of an activated brain OXT system  along with many other alterations. Additionally, a recent study in first-time mothers showed that those who had low adult attachment ratings (a risk factor for MDD) prior to birth also displayed lower activation of the reward circuitry and lower plasma OXT levels when interacting with their infants . These mothers also displayed the lowest attachment to their infants. This suggests that a certain level of activity of the OXT system, which, in humans, can only be estimated by plasma (or CSF) concentrations, is required for the rewarding aspects of adult attachment and mother-infant relations. Plasma OXT levels are also decreased in cocaine-addicted mothers who are more likely to have psychiatric disorders and less attachment to their infants . Together these studies suggest that OXT is important for the decreased stress reactivity observed in lactation and general reward-related behaviour, and as such represent an important factor in the aetiology of postpartum depression (PPD). To date, the underlying mechanisms of PPD remain poorly elucidated but it has been suggested that altered activity of the OXT system may play an important role . Moreover, given the importance of early-life experiences on adult mental health these findings also suggest that infants of mothers with low OXT system activity may be more vulnerable to develop MDD or related disorders in adulthood (see next section). Future clinical studies could examine whether OXT could be of therapeutic value in PPD, and longer term to less the risk of the development of psychiatric disorders in the children of such mothers.
3.2. OXT and adverse early-life events
Early life stress has repeatedly been demonstrated in preclinical findings to result in increase anxiety- and/or depression-related behaviour and the severity of the response to stress exposure in adulthood [102,103]. Moreover, in rodent studies, stress to the dam resulted in increased anxiety-related behaviour in the offspring and lower levels of OXT-R compared with pups from similar high-caring mothers . These findings suggest that negative early-life events may lead to alterations in the OXT system, which mediate, at least in part, the increased risk of developing psychiatric disorders in adulthood.
Similarly, numerous human studies have implicated negative early-life experiences to be a risk factor for the development of psychiatric disorders in adulthood (see  for a review). In contrast, positive social interactions have been shown to promote health and protect against the development of psychiatric disorders [106,107]. It has also been shown that adults who suffer from a lack of social contact with their parents in childhood, such as may occur following a divorce or a death, are also at an increased risk for the development of psychiatric disorders . A pilot study revealed that men who had experienced disrupted early-life parenting demonstrated less sensitivity to the basal plasma cortisol-reducing effect of intra-nasal OXT . Intra-nasal administration of neuropeptides has previously been shown to cause a resultant increase in their CSF levels . Therefore, it is possible that adverse early-life experiences resulted in altered activity of the brain OXT system in adulthood, especially its receptors, and thereby, increase the likelihood of developing mental disorders. In support, OXT has recently been shown to increase the feeling of attachment security in adult males who suffer from insecure attachment patterns, which are usually the result of early-life experiences and can also lead to the development of MDD [111,112]. Furthermore, a positive correlation has recently been reported in a group of MDD patients with high levels of separation anxiety and a single-nucleotide polymorphism in the OXT-R . In a recent study, 22 females with no psychiatric illness who had experienced childhood traumas were shown to have lower levels of CSF OXT compared with controls . Although not suffering from psychiatric disorder, there was also a negative correlation observed between CSF OXT levels and current anxiety ratings. These findings suggest that the decreased OXT activity may be a susceptibility factor for the increased likelihood of developing psychiatric disorders including MDD following adverse early-life experiences.
3.4. MDD and plasma OXT
A number of clinical studies have attempted to correlate the level of circulating plasma OXT with depressive symptomology. In the first such studies reduced plasma OXT concentrations were observed in MDD patients compared with controls [125,126]. A similar finding was recently reported for a female cohort of depressed patients but was not confirmed in males . However, in the latter study, the number of patients in the male cohort was very low compared with women and may have lead to the negative finding. The patients were then treated with electroconvulsive therapy (ECT), venlafaxine, an SSRI, or a tricyclic antidepressant and after a positive response as measured by the Hamilton Depression Rating Scale (HDRS), plasma OXT levels were re-assessed. However, no alterations in plasma OXT levels were observed. This again may be due to the low number of patients as well as the treatments, which were not separately analysed but grouped together. It would be interesting to perform a similar study with a larger cohort of patients given the earlier findings and also the animal literature suggesting a link between OXT and SSRIs. A study by Van Londen et al.,  comparing 52 MDD patients with 37 controls found no difference in mean plasma OXT levels between the groups but did observe more variation within the MDD group. Similarly, Cyranowski et al.,  reported greater variability in pulsatile OXT release over two 1 h sessions in women with MDD compared with controls. This may suggest an altered circadian release of OXT in MDD but no follow-up studies have examined this hypothesis. In addition, OXT concentrations obtained during an affiliation-associated imagery session positively correlated with the severity of MDD in this group again suggesting an association between the OXT system and sociality in depressed patients . Further, in a group of 60 depressed outpatients of mixed heterogeneity, plasma OXT levels were assessed in relation to a Temperament and Character inventory, which assesses reward dependence, novelty seeking, harm avoidance and persistence. In this sample set a positive correlation between plasma OXT and reward dependency and novelty seeking was found . A negative correlation between OXT and depression- and anxiety- symptom severity in depressed patients has also been reported . Therefore, it appears that plasma OXT may be correlated with a number of symptom clusters in MDD. Additionally, and particularly in women, plasma OXT levels may be lower or more varied in MDD compared with controls but larger studies assessing plasma OXT across the whole day are required to assess this. While further studies on the role of OXT and AVP in human social behaviour are warranted, it is not obvious that measurement of peptides in the periphery will provide any useful information.
3.5. MDD and CSF OXT
For the interpretation of human plasma OXT concentrations we have to keep in mind that intracerebal and peripheral release of neurohypophysial neuropeptides like OXT and AVP may occur in a co-ordinated or independent manner depending on the quality of the stimulus (for review see . Consequently, alterations in plasma OXT levels do not necessarily reflect similar alterations in the (locally specific) activity of the brain OXT system. However, in strict contrast to the dynamics of central versus peripheral AVP release, to date, most physiological, stressful or pharmacological stimuli, which were shown to trigger central OXT release were also identified to induce OXT secretion into the blood [84,85]. Quantification of neuropeptide content in the cerebrospinal fluid (CSF) integrates processes of central release, diffusion and degradation of OXT, and should, therefore, be a better assessment of the activity of a given brain neuropeptide system.
A number of studies have, therefore, assessed the OXT concentration in the CSF of depressed patients. Demitrack and Gold  found no significant difference in CSF levels of OXT between MDD and control subjects.Pitts et al.,  assessed CSF levels of OXT in a heterogeneous population of MDD patients (10 men and nine woman) who were further separated into dexamethasone non-suppressors and suppressors and described a trend towards lower OXT levels in the CSF of dexamethasone suppressors compared with healthy controls. Together with the studies assessing plasma OXT, these findings suggest that the OXT system may be dys-regulated in psychiatric disorders. However, larger studies are required to strengthen the association.
3.6. Post-mortem studies
In contrast to the majority of plasma and CSF data obtained, post-mortem studies assessing OXT neuronal number or mRNA levels have suggested that the OXT system within the hypothalamus is increased in MDD. Purba et al.,  were the first to assess the number of OXT-containing neurones in the PVN of MDD and bipolar tissue samples. There was a significant increase in OXT-immunoreactivity in patients with MDD and bipolar compared with controls; while there was no difference between MDD and bipolar patients. More recently, using in situ hybridisation increased OXT mRNA levels where reported in the PVN, but not SON, of melancholic MDD patients compared with non-melancholic subjects . While a trend was also reported for a similar increase in melancholic patients compared with controls this did not reach significance, but the small sample size may have occluded a significant finding. Following this study, Wang et al.,  performed laser-capture microscopy on snap-frozen tissue to obtain PVN and SON tissue punches from seven MDD/bipolar patients and seven age-matched controls and then assessed a number of genes including OXT by quantitative PCR. Similar to the study by Meynen et al.,  they found a trend towards an increase in OXT mRNA levels in the PVN of the mood disorder group compared with controls . Taken together, the available data suggests that the OXT system in MDD may be over-active at the level of the PVN. However, more careful selection criteria and larger samples may help to elucidate the proposed correlations. These findings, together with those observed in plasma and CSF studies suggest that an up-regulation of OXT synthesis at the hypothalamic level may occur to compensate for the reduced OXT release. Therefore, exogenous application of OXT in MDD could restore the system and as a result have antidepressant effects. It would also be beneficial to have tools to assess the OXT system in patients with depression, such as PET or SPECT tracers. Such tools would enable the role of OXT in MDD and following antidepressant treatment to be assessed in a more timely and accurate manner.
3.7. OXT and Electroconvulsive therapy (ECT)
OXT also received substantial interest in relation to ECT at the start of the 1990’s. While ECT is one of the most effective treatments for severe MDD with a relatively rapid onset of action the underlying mechanism of its action is poorly understood. It was first postulated by Scott et al.,  that the release of OXT in response to ECT may be indicative of a positive clinical outcome, which was supported by later studies [138,139]; although the clinical outcome was not reported in these studies. Scott and co-workers followed up their initial study by assessing the effect of ECT on plasma vasopressin-associated neurophysin I (hNpI) and OXT-associated neurophysin II (hNpII) over the course of repeated sessions. While hNpI or II release did not alter during the improvement of depressive symptoms from the first to last ECT session, hNpII secretion during the first ECT treatment correlated positively with clinical improvement . However, another study assessing the relationship between ECT, plasma OXT and clinical outcome did not find any correlation between plasma OXT and clinical outcome . A larger study by Devanand et al.,  employing 55 patients observed no correlation between plasma OXT levels and the therapeutic effects of ECT. This suggests that the acute increase in plasma OXT is merely a consequence of the stressful ECT therapy experience and is not in any way related to its therapeutic benefit. In this context, estimation of the effects of ECT on central OXT via CSF levels seems to be essential in order to draw further conclusions.
3.8. OXT and drug discovery
There are currently a number of clinical studies assessing the role of OXT in a number of psychiatric disorders (summarised in Table 1; further information can be found at www.clinicaltrials.gov). Although some of the current endeavours are not directly related to MDD, with further research they may become relevant to the disorder. It is of particular interest to note that many studies are assessing the role of OXT in social functions or anxiety-related disorders and if the results are positive it could lead to the study of OXT in MDD patients. These studies will provide a greater understanding of OXT in complex psychiatric disorders and hopefully, verify the information outlined in this review gathered from the preclinical and human studies performed to date. However, as stated above, such studies should also assess the level of the neuropeptide in the central compartment to validate the findings.
|Table 1. Current drug discovery status of OXT and endophenotypes of depression.|
|Study Center||Study aims|
|University of North Carolina||Social functioning / decrease paranoia and psychotic symptoms in schizophrenia|
|University of California / Stanley Medical Research Institute||Augmentation of antipsychotics in schizophrenia patients|
|Lawson Health Research Institute / Alzheimer’s Society London & Middlesex||Social cognition in frontotemporal dementia|
|Sheba Medical Center||Prevention of post-traumatic stress disorder|
|University of Maryland / NIMH||Social affliation, anxiety and cognition|
|Harvard School of Public Health / Brigham and Women’s Hospital||Amelioration of the neuroendocrine and cardiovascular effects of stress|
|University of California||Add-on for stable anxiety patients|
|NIDA / University of Maryland||Drug dependence|
|NIMH||Functioning of neurocognitive symptoms in mood disorders (together with AVP)|
|NIMH||Affectionate writing in response to acute stress|
Overall, the evidence from animal and clinical studies suggests a potential role of the OXT system in the pathophysiology of MDD, as well as a potential therapeutic benefit of OXT in at least some subsets of MDD patients. Its significant involvement in multiple aspects of behavioural and neuroendocrine regulation including anxiolytic and anti-depressive properties, promotion of various social interactions and reward as well as attenuation of behavioural and hormonal stress responses, makes the brain OXT system an ideal candidate central to possible therapeutics. The potential for these synergistic actions and multiple interactions with other neurotransmitter and neuropeptide systems underline the importance of OXT for the fine-tuned balance of emotionality, stress coping and complex social interactions, which shape our personality and mental health. The most promising indications from studies to date include the role of OXT in social behaviour, stress-attenuation and interactions with the serotonergic system. However, the studies to date are not conclusive with regard to the role of OXT in the aetiology and potential treatment of MDD. For example, we are only beginning to understand detailed molecular mechanisms of OXT actions at the neuronal level. Thus studies such as those demonstrating the detailed neuronal intracellular signalling pathways involved in the anxiolytic and spatial memory-enhancing effects of OXT [143,144] are necessary in the context of MDD. These studies should include the assessment of central OXT administration in chronic stress paradigms, in drug-withdrawal paradigms, and in conjunction with antidepressant administration. Moreover, assessment of the role of OXT in additional endophenotypes of depression is sorely warranted, for examine cognitive dysfunction and sleep disturbances under control and stess-altered conditions. Of interest, is the development of the non-peptidergic OXT agonist, WAY-267464, which replicated the anxiolytic, but not antidepressant-like, properties of OXT. Further studies with this, or similar, compounds would also substantially improve the assessment of the OXT system in MDD as they could be applied peripherally. This would solve a major problem of the human studies to date, which have assessed intra-nasal effects of OXT without verifying the levels in the brain. Interestingly, at present there is greater knowledge from human studies revealing OXT to be candidate system in the aetiology and treatment of MDD; at least at the level of certain endophenotypes. Replication of these studies, and translation to preclinical models would give greater cause for optimism in the use of OXT as an antidepressant with a novel mechanism of action. Thus, whereas CRF and AVP with their described anxiogenic and depression-like effects could represent Scylla and Charybdis in behaviour regulation, OXT like Circe counteracts these effects and mediates anxiolysis, calmness, rewarding and the positive consequences of social support [13,107].
References and Notes
- Kessler, R.C.; Berglund, P.; Demler, O.; Jin, R.; Koretz, D.; Merikangas, K.R.; Rush, A.J.; Walters, E.E.; Wang, P.S. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003, 289, 3095–3105. [Google Scholar]
- Licinio, J.; Wong, M.L. Depression, antidepressants and suicidality: a critical appraisal. Nat. Rev. Drug Discov. 2005, 4, 165–171. [Google Scholar]
- Murray, C.J.; Lopez, A.D. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 1997, 349, 1498–1504. [Google Scholar]
- Cryan, J.F.; Slattery, D.A. Animal models of mood disorders: Recent developments. Curr.Opini. Psychiat. 2007, 20, 1–7. [Google Scholar]
- Nemeroff, C.B.; Vale, W.W. The neurobiology of depression: inroads to treatment and new drug discovery. J. Clin. Psychiat. 2005, 66, 5–13. [Google Scholar]
- Slattery, D.A.; Hudson, A.L.; Nutt, D.J. Invited review: the evolution of antidepressant mechanisms. Fundam. Clin. Pharm. 2004, 18, 1–21. [Google Scholar]
- Nutt, D.; Wilson, S.; Paterson, L. Sleep disorders as core symptoms of depression. Dialogues Clin. Neurosci. 2008, 10, 329–336. [Google Scholar]
- Kennedy, S.H. Core symptoms of major depressive disorder: relevance to diagnosis and treatment. Dialogues Clin. Neurosci. 2008, 10, 271–277. [Google Scholar]
- Matthews, K.; Christmas, D.; Swan, J.; Sorrell, E. Animal models of depression: navigating through the clinical fog. Neurosci. Biobehav. Rev. 2005, 29, 503–513. [Google Scholar]
- Holsboer, F.; Ising, M. Central CRH system in depression and anxiety -- Evidence from clinical studies with CRH1 receptor antagonists. Eur. Pharm. 2008, 583, 350–357. [Google Scholar]
- Nemeroff, C.B. The corticotropin-releasing factor (CRF) hypothesis of depression: new findings and new directions. Mol. Psychiat. 1996, 1, 336–342. [Google Scholar]
- Frank, E.; Landgraf, R. The vasopressin system—From antidiuresis to psychopathology. Eur. J. Pharmacol. 2008, 583, 226–242. [Google Scholar]
- Landgraf, R.; Kessler, M.S.; Bunck, M.; Murgatroyd, C.; Spengler, D.; Zimbelmann, M.; Nussbaumer, M.; Czibere, L.; Turck, C.W.; Singewald, N.; Rujescu, D.; Frank, E. Candidate genes of anxiety-related behavior in HAB/LAB rats and mice: focus on vasopressin and glyoxalase-I. Neurosci. Biobehav. Rev. 2007, 31, 89–102. [Google Scholar]
- Neumann, I.D. Brain oxytocin: a key regulator of emotional and social behaviours in both females and males. J. Neuroendocrinol. 2008, 20, 858–865. [Google Scholar]
- Gimpl, G.; Fahrenholz, F. The oxytocin receptor system: structure, function, and regulation. Physiol. Rev. 2001, 81, 629–683. [Google Scholar] [PubMed]
- Neumann, I.D. Stimuli and consequences of dendritic release of oxytocin within the brain. Biochem. Soc. Trans. 2007, 35, 1252–1257. [Google Scholar]
- Bale, T.L.; Davis, A.M.; Auger, A.P.; Dorsa, D.M.; McCarthy, M.M. CNS region-specific oxytocin receptor expression: importance in regulation of anxiety and sex behavior. J. Neurosci. 2001, 21, 2546–2552. [Google Scholar]
- Neumann, I.D.; Torner, L.; Wigger, A. Brain oxytocin: differential inhibition of neuroendocrine stress responses and anxiety-related behaviour in virgin, pregnant and lactating rats. Neuroscience 2000, 95, 567–575. [Google Scholar]
- Ring, R.H.; Malberg, J.E.; Potestio, L.; Ping, J.; Boikess, S.; Luo, B.; Schechter, L.E.; Rizzo, S.; Rahman, Z.; Rosenzweig-Lipson, S. Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications. PsychoPharmacology 2006, 185, 218–225. [Google Scholar]
- Slattery, D.A.; Neumann, I.D. Chronic icv oxytocin attenuates the pathological high anxiety state of selectively bred Wistar rats. Neuropharmacology 2010, 58, 56–61. [Google Scholar]
- Windle, R.J.; Shanks, N.; Lightman, S.L.; Ingram, C.D. Central oxytocin administration reduces stress-induced corticosterone release and anxiety behavior in rats. Endocrinology 1997, 138, 2829–2834. [Google Scholar]
- Arletti, R.; Bertolini, A. Oxytocin acts as an antidepressant in two animal models of depression. Life Sci. 1987, 41, 1725–1730. [Google Scholar]
- Arletti, R.; Benelli, A.; Poggioli, R.; Luppi, P.; Menozzi, B.; Bertolini, A. Aged rats are still responsive to the antidepressant and memory-improving effects of oxytocin. Neuropeptides 1995, 29, 177–182. [Google Scholar]
- Nowakowska, E.; Kus, K.; Bobkiewicz-Kozlowska, T.; Hertmanowska, H. Role of neuropeptides in antidepressant and memory improving effects of venlafaxine. Pol. J. Pharm. 2002, 54, 605–613. [Google Scholar]
- Cryan, J.F.; Markou, A.; Lucki, I. Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol. Sci. 2002, 23, 238–245. [Google Scholar]
- Ermisch, A.; Ruhle, H.J.; Landgraf, R.; Hess, J. Blood-brain barrier and peptides. J. Cereb. Blood Flow Metab. 1985, 5, 350–357. [Google Scholar]
- Jones, P.M.; Robinson, I.C. Differential clearance of neurophysin and neurohypophysial peptides from the cerebrospinal fluid in conscious guinea pigs. Neuroendocrinology 1982, 34, 297–302. [Google Scholar]
- de Wied, D.; Diamant, M.; Fodor, M. Central nervous system effects of the neurohypophyseal hormones and related peptides. Front. Neuroendocrinology 1993, 14, 251–302. [Google Scholar]
- Petersson, M.; Alster, P.; Lundeberg, T.; Uvnas-Moberg, K. Oxytocin causes a long-term decrease of blood pressure in female and male rats. Physiol. Behav. 1996, 60, 1311–1315. [Google Scholar]
- Ring, R.H.; Schechter, L.E.; Leonard, S.K.; Dwyer, J.M.; Platt, B.J.; Graf, R.; Grauer, S.; Pulicicchio, C.; Resnick, L.; Rahman, Z.; Sukoff Rizzo, S.J.; Luo, B.; Beyer, C.E.; Logue, S.F.; Marquis, K.L.; Hughes, Z.A.; Rosenzweig-Lipson, S. Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist. Neuropharmacology 2010, 58, 69–77. [Google Scholar] [CrossRef] [PubMed]
- Ebner, K.; Bosch, O.J.; Kromer, S.A.; Singewald, N.; Neumann, I.D. Release of oxytocin in the rat central amygdala modulates stress-coping behavior and the release of excitatory amino acids. Neuropsychopharmacology 2005, 30, 223–230. [Google Scholar]
- Lancel, M.; Kromer, S.; Neumann, I.D. Intracerebral oxytocin modulates sleep-wake behaviour in male rats. Regul. Pept. 2003, 114, 145–152. [Google Scholar]
- Landgraf, R.; Wigger, A. High vs low anxiety-related behavior rats: an animal model of extremes in trait anxiety. Behav. Genet. 2002, 32, 301–314. [Google Scholar]
- Liberzon, I.; Trujillo, K.A.; Akil, H.; Young, E.A. Motivational properties of oxytocin in the conditioned place preference paradigm. Neuropsychopharmacology 1997, 17, 353–359. [Google Scholar]
- Qi, J.; Yang, J.Y.; Wang, F.; Zhao, Y.N.; Song, M.; Wu, C.F. Effects of oxytocin on methamphetamine-induced conditioned place preference and the possible role of glutamatergic neurotransmission in the medial prefrontal cortex of mice in reinstatement. Neuropharmacology 2009, 56, 856–865. [Google Scholar]
- Melis, M.R.; Melis, T.; Cocco, C.; Succu, S.; Sanna, F.; Pillolla, G.; Boi, A.; Ferri, G.L.; Argiolas, A. Oxytocin injected into the ventral tegmental area induces penile erection and increases extracellular dopamine in the nucleus accumbens and paraventricular nucleus of the hypothalamus of male rats. Eur. Neurosci. 2007, 26, 1026–1035. [Google Scholar]
- Melis, M.R.; Succu, S.; Sanna, F.; Boi, A.; Argiolas, A. Oxytocin injected into the ventral subiculum or the posteromedial cortical nucleus of the amygdala induces penile erection and increases extracellular dopamine levels in the nucleus accumbens of male rats. Eur. J. Neurosci. 2009, 30, 1349–1357. [Google Scholar]
- Wise, R.A. Brain reward circuitry: insights from unsensed incentives. Neuron 2002, 36, 229–240. [Google Scholar]
- Neumann, I.; Ludwig, M.; Engelmann, M.; Pittman, Q.J.; Landgraf, R. Simultaneous microdialysis in blood and brain: oxytocin and vasopressin release in response to central and peripheral osmotic stimulation and suckling in the rat. Neuroendocrinology 1993, 58, 637–645. [Google Scholar]
- Slattery, D.A.; Neumann, I.D. No stress please! Mechanisms of stress hyporesponsiveness of the maternal brain. J. Physiol. 2008, 586, 377–385. [Google Scholar]
- Febo, M.; Numan, M.; Ferris, C.F. Functional magnetic resonance imaging shows oxytocin activates brain regions associated with mother-pup bonding during suckling. J. Neurosci. 2005, 25, 11637–11644. [Google Scholar]
- Seip, K.M.; Morrell, J.I. Increasing the incentive salience of cocaine challenges preference for pup- over cocaine-associated stimuli during early postpartum: place preference and locomotor analyses in the lactating female rat. Psychopharmacology 2007, 194, 309–319. [Google Scholar]
- Seip, K.M.; Pereira, M.; Wansaw, M.P.; Reiss, J.I.; Dziopa, E.I.; Morrell, J.I. Incentive salience of cocaine across the postpartum period of the female rat. Psychopharmacology 2008, 199, 119–130. [Google Scholar]
- Paterson, N.E.; Markou, A. Animal models and treatments for addiction and depression co-morbidity. Neurotox. Res. 2007, 11, 1–32. [Google Scholar]
- McGregor, I.S.; Callaghan, P.D.; Hunt, G.E. From ultrasocial to antisocial: a role for oxytocin in the acute reinforcing effects and long-term adverse consequences of drug use? Br. J. Pharm. 2008, 154, 358–368. [Google Scholar]
- Kovacs, G.L.; Sarnyai, Z.; Szabo, G. Oxytocin and addiction: a review. Psychoneuroendocrinology 1998, 23, 945–962. [Google Scholar]
- Kovacs, G.L.; Sarnyai, Z.; Barbarczi, E.; Szabo, G.; Telegdy, G. The role of oxytocin-dopamine interactions in cocaine-induced locomotor hyperactivity. Neuropharmacology 1990, 29, 365–368. [Google Scholar]
- Kovacs, G.L.; Sarnyai, Z.; Izbeki, F.; Szabo, G.; Telegdy, G.; Barth, T.; Jost, K.; Brtnik, F. Effects of oxytocin-related peptides on acute morphine tolerance: opposite actions by oxytocin and its receptor antagonists. J. Pharm. Exp. Therap. 1987, 241, 569–574. [Google Scholar]
- Qi, J.; Yang, J.Y.; Song, M.; Li, Y.; Wang, F.; Wu, C.F. Inhibition by oxytocin of methamphetamine-induced hyperactivity related to dopamine turnover in the mesolimbic region in mice. Naunyn-Schmiedeberg's Arch. Pharm. 2008, 376, 441–448. [Google Scholar] [CrossRef]
- Succu, S.; Sanna, F.; Melis, T.; Boi, A.; Argiolas, A.; Melis, M.R. Stimulation of dopamine receptors in the paraventricular nucleus of the hypothalamus of male rats induces penile erection and increases extra-cellular dopamine in the nucleus accumbens: Involvement of central oxytocin. Neuropharmacology 2007, 52, 1034–1043. [Google Scholar]
- Butovsky, E.; Juknat, A.; Elbaz, J.; Shabat-Simon, M.; Eilam, R.; Zangen, A.; Altstein, M.; Vogel, Z. Chronic exposure to Delta9-tetrahydrocannabinol downregulates oxytocin and oxytocin-associated neurophysin in specific brain areas. Mol. Cell. Neurosci. 2006, 31, 795–804. [Google Scholar]
- You, Z.D.; Li, J.H.; Song, C.Y.; Wang, C.H.; Lu, C.L. Chronic morphine treatment inhibits oxytocin synthesis in rats. Neuroreport 2000, 11, 3113–3116. [Google Scholar]
- Brown, C.H.; Russell, J.A. Cellular mechanisms underlying neuronal excitability during morphine withdrawal in physical dependence: lessons from the magnocellular oxytocin system. Stress (Amsterdam, Netherlands) 2004, 7, 97–107. [Google Scholar] [PubMed]
- Cui, S.S.; Bowen, R.C.; Gu, G.B.; Hannesson, D.K.; Yu, P.H.; Zhang, X. Prevention of cannabinoid withdrawal syndrome by lithium: involvement of oxytocinergic neuronal activation. J. Neurosci. 2001, 21, 9867–9876. [Google Scholar]
- Slattery, D.A.; Markou, A.; Froestl, W.; Cryan, J.F. The GABAB receptor-positive modulator GS39783 and the GABAB receptor agonist baclofen attenuate the reward-facilitating effects of cocaine: intracranial self-stimulation studies in the rat. Neuropsychopharmacology 2005, 30, 2065–2072. [Google Scholar]
- Carter, C.S.; Grippo, A.J.; Pournajafi-Nazarloo, H.; Ruscio, M.G.; Porges, S.W. Oxytocin, vasopressin and sociality. Prog. Brain Res. 2008, 170, 331–336. [Google Scholar]
- Donaldson, Z.R.; Young, L.J. Oxytocin, vasopressin, and the neurogenetics of sociality. Science 2008, 322, 900–904. [Google Scholar] [CrossRef] [PubMed]
- Goodson, J.L. Nonapeptides and the evolutionary patterning of sociality. Prog. Brain Res. 2008, 170, 3–15. [Google Scholar]
- Young, L.J.; Wang, Z. The neurobiology of pair bonding. Nat. Neurosci. 2004, 7, 1048–1054. [Google Scholar]
- Ferguson, J.N.; Aldag, J.M.; Insel, T.R.; Young, L.J. Oxytocin in the medial amygdala is essential for social recognition in the mouse. J. Neurosci. 2001, 21, 8278–8285. [Google Scholar]
- Grippo, A.J.; Cushing, B.S.; Carter, C.S. Depression-Like Behavior and Stressor-Induced Neuroendocrine Activation in Female Prairie Voles Exposed to Chronic Social Isolation. Psychosom. Med. 2007, 69, 149–157. [Google Scholar]
- Grippo, A.J.; Gerena, D.; Huang, J.; Kumar, N.; Shah, M.; Ughreja, R.; Sue Carter, C. Social isolation induces behavioral and neuroendocrine disturbances relevant to depression in female and male prairie voles. Psychoneuroendocrinology 2009, 32, 966–980. [Google Scholar]
- Krishnan, V.; Han, M.H.; Graham, D.L.; Berton, O.; Renthal, W.; Russo, S.J.; Laplant, Q.; Graham, A.; Lutter, M.; Lagace, D.C.; Ghose, S.; Reister, R.; Tannous, P.; Green, T.A.; Neve, R.L.; Chakravarty, S.; Kumar, A.; Eisch, A.J.; Self, D.W.; Lee, F.S.; Tamminga, C.A.; Cooper, D.C.; Gershenfeld, H.K.; Nestler, E.J. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 2007, 131, 391–404. [Google Scholar]
- Moos, F.; Richard, P. Serotonergic control of oxytocin release during suckling in the rat: opposite effects in conscious and anesthetized rats. Neuroendocrinology 1983, 36, 300–306. [Google Scholar]
- Javed, A.; Kamradt, M.C.; Van de Kar, L.D.; Gray, T.S. D-Fenfluramine induces serotonin-mediated Fos expression in corticotropin-releasing factor and oxytocin neurons of the hypothalamus, and serotonin-independent Fos expression in enkephalin and neurotensin neurons of the amygdala. Neuroscience 1999, 90, 851–858. [Google Scholar]
- Bagdy, G.; Kalogeras, K.T. Stimulation of 5-HT1A and 5-HT2/5-HT1C receptors induce oxytocin release in the male rat. Brain Res. 1993, 611, 330–332. [Google Scholar]
- Uvnas-Moberg, K.; Hillegaart, V.; Alster, P.; Ahlenius, S. Effects of 5-HT agonists, selective for different receptor subtypes, on oxytocin, CCK, gastrin and somatostatin plasma levels in the rat. Neuropharmacology 1996, 35, 1635–1640. [Google Scholar] [PubMed]
- Jorgensen, H.; Kjaer, A.; Knigge, U.; Moller, M.; Warberg, J. Serotonin stimulates hypothalamic mRNA expression and local release of neurohypophysial peptides. J. Neuroendocrinol. 2003, 15, 564–571. [Google Scholar]
- Saphier, D. Paraventricular nucleus magnocellular neuronal responses following electrical stimulation of the midbrain dorsal raphe. Experim. Brain Res. 1991, 85, 359–363. [Google Scholar]
- Van de Kar, L.D.; Rittenhouse, P.A.; Li, Q.; Levy, A.D.; Brownfield, M.S. Hypothalamic paraventricular, but not supraoptic neurons, mediate the serotonergic stimulation of oxytocin secretion. Brain Res. Bull. 1995, 36, 45–50. [Google Scholar] [PubMed]
- Uvnas-Moberg, K.; Bjokstrand, E.; Hillegaart, V.; Ahlenius, S. Oxytocin as a possible mediator of SSRI-induced antidepressant effects. Psychopharmacology 1999, 142, 95–101. [Google Scholar]
- Emiliano, A.B.; Cruz, T.; Pannoni, V.; Fudge, J.L. The interface of oxytocin-labeled cells and serotonin transporter-containing fibers in the primate hypothalamus: a substrate for SSRIs therapeutic effects? Neuropsychopharmacology 2007, 32, 977–988. [Google Scholar] [CrossRef] [PubMed]
- Carmichael, M.S.; Warburton, V.L.; Dixen, J.; Davidson, J.M. Relationships among cardiovascular, muscular, and oxytocin responses during human sexual activity. Arch. Sex. Behav. 1994, 23, 59–79. [Google Scholar] [CrossRef] [PubMed]
- Murphy, M.R.; Seckl, J.R.; Burton, S.; Checkley, S.A.; Lightman, S.L. Changes in oxytocin and vasopressin secretion during sexual activity in men. J. Clin. Endocrinol. Metab. 1987, 65, 738–741. [Google Scholar]
- Argiolas, A.; Collu, M.; D'Aquila, P.; Gessa, G.L.; Melis, M.R.; Serra, G. Apomorphine stimulation of male copulatory behavior is prevented by the oxytocin antagonist d(CH2)5 Tyr(Me)-Orn8-vasotocin in rats. Pharmacol. Biochem. Behav. 1989, 33, 81–83. [Google Scholar]
- Waldherr, M.; Neumann, I.D. Centrally released oxytocin mediates mating-induced anxiolysis in male rats. Proc. Natl. Acad. Sci. USA 2007, 104, 16681–16684. [Google Scholar]
- Cantor, J.M.; Binik, Y.M.; Pfaus, J.G. Chronic fluoxetine inhibits sexual behavior in the male rat: reversal with oxytocin. Psychopharmacology 1999, 144, 355–362. [Google Scholar]
- Li, Q.; Brownfield, M.S.; Battaglia, G.; Cabrera, T.M.; Levy, A.D.; Rittenhouse, P.A.; van de Kar, L.D. Long-term treatment with the antidepressants fluoxetine and desipramine potentiates endocrine responses to the serotonin agonists 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) and (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). J. Pharm. Experim. Therap. 1993, 266, 836–844. [Google Scholar]
- Li, Q.; Levy, A.D.; Cabrera, T.M.; Brownfield, M.S.; Battaglia, G.; Van de Kar, L.D. Long-term fluoxetine, but not desipramine, inhibits the ACTH and oxytocin responses to the 5-HT1A agonist, 8-OH-DPAT, in male rats. Brain Res. 1993, 630, 148–156. [Google Scholar] [CrossRef] [PubMed]
- Li, Q.; Muma, N.A.; van de Kar, L.D. Chronic fluoxetine induces a gradual desensitization of 5-HT1A receptors: reductions in hypothalamic and midbrain Gi and G(o) proteins and in neuroendocrine responses to a 5-HT1A agonist. J. Pharm. Experim. Therap. 1996, 279, 1035–1042. [Google Scholar]
- Yoshida, M.; Takayanagi, Y.; Inoue, K.; Kimura, T.; Young, L.J.; Onaka, T.; Nishimori, K. Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in mice. J. Neurosci. 2009, 29, 2259–2271. [Google Scholar]
- Bosch, O.J.; Meddle, S.L.; Beiderbeck, D.I.; Douglas, A.J.; Neumann, I.D. Brain oxytocin correlates with maternal aggression: link to anxiety. J. Neurosci. 2005, 25, 6807–6815. [Google Scholar]
- Ebner, K.; Wotjak, C.T.; Landgraf, R.; Engelmann, M. A single social defeat experience selectively stimulates the release of oxytocin, but not vasopressin, within the septal brain area of male rats. Brain Res. 2000, 872, 87–92. [Google Scholar] [CrossRef] [PubMed]
- Engelmann, M.; Landgraf, R.; Wotjak, C.T. The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: an old concept revisited. Front. Neuroendocrinol. 2004, 25, 132–149. [Google Scholar]
- Landgraf, R.; Neumann, I.D. Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front. Neuroendocrinol. 2004, 25, 150–176. [Google Scholar]
- Wotjak, C.T.; Ganster, J.; Kohl, G.; Holsboer, F.; Landgraf, R.; Engelmann, M. Dissociated central and peripheral release of vasopressin, but not oxytocin, in response to repeated swim stress: new insights into the secretory capacities of peptidergic neurons. Neuroscience 1998, 85, 1209–1222. [Google Scholar] [CrossRef] [PubMed]
- Neumann, I.D.; Toschi, N.; Ohl, F.; Torner, L.; Kromer, S.A. Maternal defence as an emotional stressor in female rats: correlation of neuroendocrine and behavioural parameters and involvement of brain oxytocin. Eur. J. Neurosci. 2001, 13, 1016–1024. [Google Scholar]
- Nomura, M.; Saito, J.; Ueta, Y.; Muglia, L.J.; Pfaff, D.W.; Ogawa, S. Enhanced up-regulation of corticotropin-releasing hormone gene expression in response to restraint stress in the hypothalamic paraventricular nucleus of oxytocin gene-deficient male mice. J. Neuroendocrinol. 2003, 15, 1054–1061. [Google Scholar]
- Amico, J.A.; Miedlar, J.A.; Cai, H.M.; Vollmer, R.R. Oxytocin knockout mice: a model for studying stress-related and ingestive behaviours. Prog. Brain Res. 2008, 170, 53–64. [Google Scholar]
- Caldwell, H.K.; Stephens, S.L.; Young, W.S., 3rd. Oxytocin as a natural antipsychotic: a study using oxytocin knockout mice. Mol. Psychiat. 2009, 14, 190–196. [Google Scholar]
- Windle, R.J.; Kershaw, Y.M.; Shanks, N.; Wood, S.A.; Lightman, S.L.; Ingram, C.D. Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary-adrenal activity. J. Neurosci. 2004, 24, 2974–2982. [Google Scholar]
- Kiss, A.; Aguilera, G. Regulation of the hypothalamic pituitary adrenal axis during chronic stress: responses to repeated intraperitoneal hypertonic saline injection. Brain Res. 1993, 630, 262–270. [Google Scholar]
- Herman, J.P.; Flak, J.; Jankord, R. Chronic stress plasticity in the hypothalamic paraventricular nucleus. Prog. Brain Res. 2008, 170, 353–364. [Google Scholar]
- Reber, S.O.; Neumann, I.D. Defensive behavioral strategies and enhanced state anxiety during chronic subordinate colony housing are accompanied by reduced hypothalamic vasopressin, but not oxytocin, expression. Ann. NY Acad. Sci. 1148, 184–195. [Google Scholar]
- Ising, M.; Kunzel, H.E.; Binder, E.B.; Nickel, T.; Modell, S.; Holsboer, F. The combined dexamethasone/CRH test as a potential surrogate marker in depression. Prog. Neuro-psychopharmacol. Biol. Psychiat. 2005, 29, 1085–1093. [Google Scholar] [CrossRef]
- Heinrichs, M.; Meinlschmidt, G.; Neumann, I.; Wagner, S.; Kirschbaum, C.; Ehlert, U.; Hellhammer, D.H. Effects of suckling on hypothalamic-pituitary-adrenal axis responses to psychosocial stress in postpartum lactating women. J. Clin. Endocrinol. Metab. 2001, 86, 4798–4804. [Google Scholar]
- Chiodera, P.; Salvarani, C.; Bacchi-Modena, A.; Spallanzani, R.; Cigarini, C.; Alboni, A.; Gardini, E.; Coiro, V. Relationship between plasma profiles of oxytocin and adrenocorticotropic hormone during suckling or breast stimulation in women. Horm. Res. 1991, 35, 119–123. [Google Scholar]
- Nissen, E.; Uvnas-Moberg, K.; Svensson, K.; Stock, S.; Widstrom, A.M.; Winberg, J. Different patterns of oxytocin, prolactin but not cortisol release during breastfeeding in women delivered by caesarean section or by the vaginal route. Early Human Develop. 1996, 45, 103–118. [Google Scholar]
- Neumann, I.; Landgraf, R. Septal and Hippocampal Release of Oxytocin, but not Vasopressin, in the Conscious Lactating Rat During Suckling. J. Neuroendocrinol. 1989, 1, 305–308. [Google Scholar] [CrossRef] [PubMed]
- Strathearn, L.; Fonagy, P.; Amico, J.; Montague, P.R. Adult Attachment Predicts Maternal Brain and Oxytocin Response to Infant Cues. Neuropsychopharmacology 2009, 34, 2655–2666. [Google Scholar] [CrossRef] [PubMed]
- Light, K.C.; Grewen, K.M.; Amico, J.A.; Boccia, M.; Brownley, K.A.; Johns, J.M. Deficits in plasma oxytocin responses and increased negative affect, stress, and blood pressure in mothers with cocaine exposure during pregnancy. Addict. Behav. 2004, 29, 1541–1564. [Google Scholar] [CrossRef] [PubMed]
- Pryce, C.R.; Ruedi-Bettschen, D.; Dettling, A.C.; Weston, A.; Russig, H.; Ferger, B.; Feldon, J. Long-term effects of early-life environmental manipulations in rodents and primates: Potential animal models in depression research. Neurosci. Biobehav. Rev. 2005, 29, 649–674. [Google Scholar]
- Veenema, A.H.; Reber, S.O.; Selch, S.; Obermeier, F.; Neumann, I.D. Early life stress enhances the vulnerability to chronic psychosocial stress and experimental colitis in adult mice. Endocrinology 2008, 149, 2727–2736. [Google Scholar]
- Champagne, F.A.; Meaney, M.J. Stress during gestation alters postpartum maternal care and the development of the offspring in a rodent model. Biol. Psychiat. 2006, 59, 1227–1235. [Google Scholar]
- Heim, C.; Newport, D.J.; Mletzko, T.; Miller, A.H.; Nemeroff, C.B. The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology 2008, 33, 693–710. [Google Scholar]
- House, J.S.; Landis, K.R.; Umberson, D. Social relationships and health. Science (New York) 1988, 241, 540–545. [Google Scholar]
- Neumann, I.D. The advantage of social living: brain neuropeptides mediate the beneficial consequences of sex and motherhood. Front. Neuroendocrinol. 2009, 30, 483–496. [Google Scholar]
- Kendler, K.S.; Neale, M.C.; Kessler, R.C.; Heath, A.C.; Eaves, L.J. Childhood parental loss and adult psychopathology in women. A twin study perspective. Arch. Gen. Psychiat. 1992, 49, 109–116. [Google Scholar]
- Meinlschmidt, G.; Heim, C. Sensitivity to Intranasal Oxytocin in Adult Men with Early Parental Separation. Biol. Psychiat. 2007, 61, 1109–1111. [Google Scholar]
- Born, J.; Lange, T.; Kern, W.; McGregor, G.P.; Bickel, U.; Fehm, H.L. Sniffing neuropeptides: a transnasal approach to the human brain. Nat. Neurosci. 2002, 5, 514–516. [Google Scholar]
- Buchheim, A.; Heinrichs, M.; George, C.; Pokorny, D.; Koops, E.; Henningsen, P.; O'Connor, M.F.; Gundel, H. Oxytocin enhances the experience of attachment security. Psychoneuroendocrinology 2009, 34, 1417–1422. [Google Scholar]
- Sloman, L.; Gilbert, P.; Hasey, G. Evolved mechanisms in depression: the role and interaction of attachment and social rank in depression. J. Affect. Disord. 2003, 74, 107–121. [Google Scholar]
- Costa, B.; Pini, S.; Gabelloni, P.; Abelli, M.; Lari, L.; Cardini, A.; Muti, M.; Gesi, C.; Landi, S.; Galderisi, S.; Mucci, A.; Lucacchini, A.; Cassano, G.B.; Martini, C. Oxytocin receptor polymorphisms and adult attachment style in patients with depression. Psychoneuroendocrinology 2009, 34, 1506–1514. [Google Scholar]
- Heim, C.; Young, L.J.; Newport, D.J.; Mletzko, T.; Miller, A.H.; Nemeroff, C.B. Lower CSF oxytocin concentrations in women with a history of childhood abuse. Mol. Psychiat. 2009, 14, 954–958. [Google Scholar]
- Kirschbaum, C.; Klauer, T.; Filipp, S.H.; Hellhammer, D.H. Sex-specific effects of social support on cortisol and subjective responses to acute psychological stress. Psychosom. Med. 1995, 57, 23–31. [Google Scholar]
- Heinrichs, M.; Baumgartner, T.; Kirschbaum, C.; Ehlert, U. Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol. Psychiat. 2003, 54, 1389–1398. [Google Scholar]
- Ditzen, B.; Schaer, M.; Gabriel, B.; Bodenmann, G.; Ehlert, U.; Heinrichs, M. Intranasal oxytocin increases positive communication and reduces cortisol levels during couple conflict. Biol. Psychiat. 2009, 65, 728–731. [Google Scholar]
- Kirsch, P.; Esslinger, C.; Chen, Q.; Mier, D.; Lis, S.; Siddhanti, S.; Gruppe, H.; Mattay, V.S.; Gallhofer, B.; Meyer-Lindenberg, A. Oxytocin modulates neural circuitry for social cognition and fear in humans. J. Neurosci. 2005, 25, 11489–11493. [Google Scholar]
- Domes, G.; Heinrichs, M.; Glascher, J.; Buchel, C.; Braus, D.F.; Herpertz, S.C. Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol. Psychiat. 2007, 62, 1187–1190. [Google Scholar]
- Domes, G.; Lischke, A.; Berger, C.; Grossmann, A.; Hauenstein, K.; Heinrichs, M.; Herpertz, S.C. Effects of intranasal oxytocin on emotional face processing in women. Psychoneuroendocrinology 2009. [Google Scholar]
- Di Simplicio, M.; Massey-Chase, R.; Cowen, P.J.; Harmer, C.J. Oxytocin enhances processing of positive versus negative emotional information in healthy male volunteers. J. Psychopharmacol. (Oxford, England) 2009, 23, 241–248. [Google Scholar] [CrossRef]
- Harmer, C.J.; Bhagwagar, Z.; Perrett, D.I.; Vollm, B.A.; Cowen, P.J.; Goodwin, G.M. Acute SSRI administration affects the processing of social cues in healthy volunteers. Neuropsychopharmacology 2003, 28, 148–152. [Google Scholar]
- Harmer, C.J.; Mackay, C.E.; Reid, C.B.; Cowen, P.J.; Goodwin, G.M. Antidepressant drug treatment modifies the neural processing of nonconscious threat cues. Biol. Psychiat. 2006, 59, 816–820. [Google Scholar]
- Norbury, R.; Mackay, C.E.; Cowen, P.J.; Goodwin, G.M.; Harmer, C.J. Short-term antidepressant treatment and facial processing. Functional magnetic resonance imaging study. Br. J. Psychiat. 2007, 190, 531–532. [Google Scholar] [CrossRef]
- Frasch, A.; Zetzsche, T.; Steiger, A.; Jirikowski, G.F. Reduction of plasma oxytocin levels in patients suffering from major depression. Adv. Experim. Med. Biol. 1995, 395, 257–258. [Google Scholar]
- Zetzsche, T.; Frasch, A.; Jirikowski, G.F.; Murck, H.; Steiger, A. Nocturnal oxytocin secretion is reduced in major depression. Biol. Psychiat. 1996, 39, 584. [Google Scholar]
- Ozsoy, S.; Esel, E.; Kula, M. Serum oxytocin levels in patients with depression and the effects of gender and antidepressant treatment. Psychiat. Res. 2009, 169, 249–252. [Google Scholar]
- van Londen, L.; Goekoop, J.G.; van Kempen, G.M.; Frankhuijzen-Sierevogel, A.C.; Wiegant, V.M.; van der Velde, E.A.; De Wied, D. Plasma levels of arginine vasopressin elevated in patients with major depression. Neuropsychopharmacology 1997, 17, 284–292. [Google Scholar]
- Cyranowski, J.M.; Hofkens, T.L.; Frank, E.; Seltman, H.; Cai, H.M.; Amico, J.A. Evidence of dysregulated peripheral oxytocin release among depressed women. Psychosom. Med. 2008, 70, 967–975. [Google Scholar]
- Bell, C.J.; Nicholson, H.; Mulder, R.T.; Luty, S.E.; Joyce, P.R. Plasma oxytocin levels in depression and their correlation with the temperament dimension of reward dependence. J. Psychopharmacol. 2006, 20, 656–660. [Google Scholar]
- Scantamburlo, G.; Hansenne, M.; Fuchs, S.; Pitchot, W.; Marechal, P.; Pequeux, C.; Ansseau, M.; Legros, J.J. Plasma oxytocin levels and anxiety in patients with major depression. Psychoneuroendocrinology 2007, 32, 407–410. [Google Scholar]
- Demitrack, M.A.; Gold, P.W. Oxytocin: neurobiologic considerations and their implications for affective illness. Prog. Neuro-psychopharmacol. Biol. Psychiat. 1988, 12 Suppl, S23–S51. [Google Scholar] [CrossRef]
- Pitts, A.F.; Samuelson, S.D.; Meller, W.H.; Bissette, G.; Nemeroff, C.B.; Kathol, R.G. Cerebrospinal fluid corticotropin-releasing hormone, vasopressin, and oxytocin concentrations in treated patients with major depression and controls. Biol. Psychiat. 1995, 38, 330–335. [Google Scholar]
- Purba, J.S.; Hoogendijk, W.J.; Hofman, M.A.; Swaab, D.F. Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. Arch. Gen. Psychiat. 1996, 53, 137–143. [Google Scholar]
- Meynen, G.; Unmehopa, U.A.; Hofman, M.A.; Swaab, D.F.; Hoogendijk, W.J. Hypothalamic oxytocin mRNA expression and melancholic depression. Mol. Psychiatry 2007, 12, 118–119. [Google Scholar] [CrossRef] [PubMed]
- Wang, S.S.; Kamphuis, W.; Huitinga, I.; Zhou, J.N.; Swaab, D.F. Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances. Mol. Psychiat. 2008, 13, 786–799. [Google Scholar]
- Scott, A.I.; Whalley, L.J.; Bennie, J.; Bowler, G. Oestrogen-stimulated neurophysin and outcome after electroconvulsive therapy. Lancet 1986, 1, 1411–1414. [Google Scholar]
- Devanand, D.P.; Lo, E.-S.; Sackeim, H.A.; Ross, F.; Halbreich, U.; Prudic, J.; Cooper, T. Specificity of ECT treatment parameters on plasma vasopressin and oxytocin. In Annual Meeting of the Society for Biological Psychiatry, Montreal, Canada, 7 May 1988.
- Smith, J.E.; Williams, K.; Burkett, S.; Glue, P.; Nutt, D.J. Oxytocin and vasopressin responses to ECT. Psychiat. Res. 1990, 32, 201–202. [Google Scholar]
- Scott, A.I.; Shering, P.A.; Legros, J.J.; Whalley, L.J. Improvement in depressive illness is not associated with altered release of neurophysins over a course of ECT. Psychiat. Res. 1991, 36, 65–73. [Google Scholar]
- Smith, J.; Williams, K.; Birkett, S.; Nicholson, H.; Glue, P.; Nutt, D.J. Neuroendocrine and clinical effects of electroconvulsive therapy and their relationship to treatment outcome. Psychol. Med. 1994, 24, 547–555. [Google Scholar]
- Devanand, D.P.; Lisanby, S.; Lo, E.-S.; Fitzsimons, L.; Cooper, T.B.; Halbreich, U.; Sackeim, H.A. Effects of electroconvulsive therapy on plasma vasopressin and oxytocin. Biol. Psychiat. 1998, 44, 610–616. [Google Scholar]
- Blume, A.; Bosch, O.J.; Miklos, S.; Torner, L.; Wales, L.; Waldherr, M.; Neumann, I.D. Oxytocin reduces anxiety via ERK1/2 activation: local effect within the rat hypothalamic paraventricular nucleus. Eur. J. Neurosci. 2008, 27, 1947–1956. [Google Scholar]
- Tomizawa, K.; Iga, N.; Lu, Y.F.; Moriwaki, A.; Matsushita, M.; Li, S.T.; Miyamoto, O.; Itano, T.; Matsui, H. Oxytocin improves long-lasting spatial memory during motherhood through MAP kinase cascade. Nat. Neurosci. 2003, 6, 384–390. [Google Scholar]
© 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).