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Central nervous system actions of oxytocin and modulation of behavior in humans
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Central nervous system actions of oxytocin and modulation of behavior in humans The posterior pituitary hormone oxytocin has modulatory effects on neural functioning that are significant to the regulation of behavior. Basic research in animals has established the importance of oxytocin in affiliation, including mating, pair bonding and parenting behaviors. It is also an important regulator of feeding, grooming and responses to stress. The actions of oxytocin in the brain are regulated by gonadal steroid hormones, particularly estrogen. Oxytocin might also influence normal behavior in humans, and dysfunctions in the oxytocin system might be involved in the etiology and expression of neuropsychiatric disorders. INTEREST in the neuropsychological significance of the neuropeptide oxytocin has increased tremendously in the last decade. Research in a variety of rodents, sheep and primates, including humans, has revealed a constellation of behavioral effects mediated by this uniquely mammalian hormone (Table 1). Oxytocin was originally recognized as one of two neurohypophyseal hormones, along with Vasopressin, released from the posterior pituitary and into the general circulation to exert an action on distant target organs. In the female, these include the smooth muscle of the breast to facilitate the milk let-down reflex and smooth muscle of the uterus to stimulate uterine contractions during parturition. In males, these organs include the smooth muscle of the reproductive tract (Fig. 1). The major source of oxytocin is the paraventricular and supraoptic nuclei of the hypothalamus (Fig. 2). Widespread intracerebral projections of oxytocin-producing neurons subserve its role as a neurotransmitter and/or neuromodulator, and oxytocin is an important modulator of behavioral responses. These would include maternal, paternal, sexual and social behaviors, all of which involve interactions with members of the same species. In addition, oxytocin is implicated as a neurotransmitter regulating feeding, grooming, stress and anxiety. Because of its apparently unique role in the regulation of social behaviors, there has been increased interest in a cross-species comparative approach for understanding the effects of oxytocin. The distribution of oxytocin receptors in the brain appears to be relatively conserved; they are found at highest density in the limbic system (Fig. 3b). However, the regulation of the receptor by steroid hormones varies substantially across species and could be the mechanism by which different species meet the particular demands of social construction. Given our current understanding of oxytocin in mammalian behavior, the question arises regarding the potential significance of oxytocin to normal and pathological behavior in humans. In general, research into the significance of oxytocinergic neurotransmission in humans is relatively sparse. This review therefore focuses
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Sexual behavior
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Maternal behavior
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Pair bonding
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Grooming
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Nociception Anxiety
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Feeding
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briefly on the relevant information in animals and then addresses the more problematic issue of what significance this has to the understanding of human behavior. Behavioral effects of oxytocin in animals Stimulation of the genitals, whether it be by copulation, parturition or manually, results in the release of endogenous oxytocin into the circulation in a variety of mammalian species ~. Although it is not definitively established in all cases, there is compelling evidence for coordination of independent intracerebral and peripheral oxytocin release. This coordination, in turn, allows for integration of behavioral responses with peripheral physiological events, i.e. maternal behavior and suckling stimulation. The role of oxytocin in maternal, sexual
Glossary Basal nucleus of Meynert - The principal source of cholinergic fibers to the cerebral cortex. Behavioral despair - A behavioral paradigm that results in a loss of defensive reactions; it is considered to be an animal model of depression. Hypothalamic-pituitary-adrenal axis - A coordinated system involving the brain, pituitary and adrenal gland; it regulates the synthesis and secretion of glucocorticoids into the bloodstream. Learned helplessness - A behavioral paradigm that results in a loss of defensive reactions; similar to behavioral despair but involves a different experimental protocol. Mesolimbic pathway - A collection of dopaminergic neurons in the midbrain that project to the limbic system; it has been implicated in schizophrenia. Oxytocin neurophysin - An inactive carrier protein that binds oxytocin and is often released along with it. Tic disorders - Disorders characterized by the habitual, repeated contraction of certain muscles, resulting in stereotyped, individualized actions. m
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and social behaviors of animals has been the subject of many excellent and recent reviews-'.3.
Table 1. Behaviors regulated by oxytocin Behavior
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Effect of o.~ytocin on sexual behavior of animals Unlike humans, the overwhelming majority of animals breed only during certain times of the year, and the expression of sexual behavior is under strict endocrine control. Simply put, male and female animals mate only when circulating steroid hormone levels are at appropriate concentrations. For steroid hormones to influence behavior, they must fundamentally alter neurotransmission in the brain. Numerous studies have clearly established that intracerebral infusion of oxytocin into the hypothalamus facilitates sexual behavior in female rats primed with subthreshold levels of estrogen. There are dense collections of oxytocin receptors in this brain region and their density and binding affinity are increased by estrogen and progesterone. Oxytocin also facilitates male sexual responses in rodent models. Central administration of oxytocin significantly reduces the latency to achieve ejaculation and shortens the post-ejaculatory interval. This effect is even more pronounced in aged male rats and might be related to decreases in circulating testosterone (reviewed in Ref. 2).
Effects of o.~3'tocit7on maternal behavior of animals The expression of normal maternal behavior by rats that have recently given birth also requires a prior period of exposure to estrogen, and exogenous oxytocin can facilitate this response in the virgin or pregnant mouse, rat and ewe. Region-specific changes in oxytocin receptor binding in the brain have been related to the establishment of maternal responsiveness; the natural occurrence of the behavior can be blocked by oxytocin receptor antagonists or antiserum to oxytocin. Oxytocin release at parturition plays an important role in the establishment of maternal behavior in sheep, but also facilitates the development of a selective mother-infant bond (reviewed in Ref. 2).
Effects of o.~3.'tocin on social behal,ior of allimals In trying to understand the significance of oxytocin to human behavior, it is perhaps the role of oxytocin in animal social behavior that is the most intriguing. However, the precise quantification of social behavior in animals is difficult because of the involvement of a collection of related behaviors that includes pair bonding and attachment. One convenient parameter used to assess behaviors related to affiliation is the duration of physical contact between two individuals. For example, continuous infusion of oxytocin into male rats paired with females induced increased durations of physical contact, even in the absence of sexual interactions. In another social rodent species, the prairie vole, oxytocin infusion not only increased physical contact between males and females, but reduced agonistic interactions between them as well4. Futhermore, oxytocin infusions will lead to formation of partner preference for a particular male by female voles; this effect appears to be gender specific because vasopressin modulates pair-bonding in male voles, but not in females5. The complexity of neurotransmitter actions on social behavior is well illustrated by studies in the squirrel monkey, in which the effects of exogenous oxytocin depended on the prior social status of individuals. Dominant males responded to oxytocin administration with increased sexual and aggressive behavior, whereas subordinate males displayed a significant increase in the frequency of associative behaviors such as approaching, touching or huddling with another animal. The fact that dominant animals had serum testosterone titers
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over twice as high as the subordinate males might be a key underlying variable6.
Effects of o.xytocin on stress and anxiety in animals In rodents, oxytocin is a stress hormone in that it is released peripherally in response to both physical and psychological stressors. This stimulated release of oxytocin appears to function, in part, to facilitate the activation of the hypothalamic-pituitary-adrenal axis and increase glucocorticoid release 7. A logical and testable prediction of stress-induced central release of oxytocin is that it functions to ameliorate the symptoms associated with stress, i.e. anxiety. A continuous stress response can ultimately be deleterious and reducing that reaction under appropriate circumstances has substantial advantages. Central administration of oxytocin in male rats has been reported to have an anxiolytic action that is similar to that of the benzodiazepines, and the anxiolytic action of oxytocin in female mice was enhanced by estrogen. Compounds found to have anxiolytic actions in animals are also often effective in animal models of depression, and oxytocin has antidepressant action in two such models: learned helplessness and behavioral despair. In addition, the anti-nociceptive action of oxytocin is consistent with its antidepressant action. Finally, there is evidence in animal models that oxytocin can inhibit the development of opiate tolerance, dependence and self-administration, as well as tolerance to cocaine. Some of these effects appear to be mediated by a neuromodulatory action of oxytocin on dopaminergic neurotransmission in limbic brain regions, which might also be related to the the anxiolytic action of oxytocin in this brain system (reviewed in Ref. 8).
Effects of o.~3'tocin on.feeding and grooming in animals Both peripherally and centrally administered oxytocin reduce feeding, an effect that has led to it being called a 'satiety hormone'. Current theory holds that activation of neurons in the paraventricular nucleus (PVN) that project to the dorsal motor nucleus of the vagus nerve activate inhibitory efferents projecting directly to the gut, which then inhibit gastric motility. Both food and anorexiainducing agents, such as cholecystokinin, induce oxytocin release and reduce food intake, leading to the suggestion that both nausea and satiety activate a common hypothalamic oxytocinergic pathway that controls the inhibition of ingestion 9. Evidence in
Hypothalamus
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Figure 1. Sites of oxytocin action in humans. Oxytocin acts on multiple organ systems in men and women to regulate various physiological processes. In women, these include the milk let-down response by the smooth muscle of the breast, and uterine contractions; in men, they include contractions of the smooth muscles of the reproductivetract. Oxytocin is also involved in regulationof water balance by the kidneys, and is releasedby central neurons to influence behavior.
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":.,ix Figure 2. The source of oxytocin. Oxytocin is supplied to the posterior pituitary from neurons located in the paraventricular and supraoptic nuclei of the hypothalamus. It is then released from the pituitary into the circulation in response to appropriate stimuli. These same neurons, in addition to accessory oxytocinergic neurons located elsewhere in the brain, project broadly throughout the central nervous system. Receptors for oxytocin are discretely distributed in the brain and, in most mammalian species, are found in the hypothalamus and components of the limbic system. m
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Figure3. (a) Predictedstructureof the humanoxytocinreceptor.The geneencodingthe humanoxytocinreceptorhas beencloned13and encodesa protein withtheseventransmembrane domaintypical s of a G-protein-coupledreceptor. Theaminoacidsmarkedwithatriangleindicatepositionswheresubstitutions canbetoleratedwithoutalteringthe functionalpropertiesof the receptor.(b) Oxytocinreceptorbindingin rat brain, showing thehighestconcentratioofn receptors(red)in theventromedinucleus al of the hypothalamusandamygdala. animal models also suggests that central oxytocin mediates osmolality-related inhibition of appetite for salt, which might impact importantly on the actions of oxytocin as a satiety agenfl °. One of the first consistent behavioral effects reported in animals for central oxytocin administration was a pronounced increase in auto-grooming 11. Subsequent studies indicate that oxytocin increases several aspects of grooming but increases genital grooming more than other components. The ability of oxytocin to facilitate grooming involves activation of dopamine neurotransmission in the mesolimbic pathway and might be the result of direct activation of dopamine neurons in the ventral tegmental area by oxytocin. As discussed above, oxytocin is released in response to stress, and the induction of grooming might be part of a homeostatic mechanism for reducing anxiety. An additional potential function of oxytocin-induced 272
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grooming is the facilitation of pair bonds, whether between mother and infant or between mating partners, by increased transfer of odors between individualsL
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Behavioral effects of oxytocin in humans Compared with the very active investigation of behavioral effects of oxytocin in rodents, sheep and primates, relatively little data have been collected in humans. A number of difficulties have inhibited studies of oxytocin in humans, including (1) difficulty in obtaining brain tissue, (2) the extremely low basal plasma levels of the hormone and (3) a lack of oxytocin agonists or antagonists that can penetrate the blood-brain barrier. Informative sampling of hormone levels can only be performed in humans by lumbar puncture; this allows access to cerebrospinal fluid (CSF) where levels of oxytocin are higher. Alternatively, administration of pharmacological agents and/or psychophysiological challenges can stimulate secretion of oxytocin into the plasma; this secretion is likely to be a reflection of relative central oxytocin activity, but the relationship of peripheral to central secretion of oxytocin remains to be fully described. Another difficulty in the study of behavioral effects of oxytocin in humans is that behavior in humans is powerfully influenced by nonhormonal factors, particularly cultural expectations. The majority of our informative observations in humans are therefore derived by comparing measures of oxytocin in healthy subjects to measures in subjects with a variety of neuropsychiatric illnesses. Although oxytocin is expected to have behavioral effects in humans analogous to those seen in animals, substantial differences do exist between rats and humans in the regulation, function and neuroanatomical distribution of oxytocin-containing neurons. Initial studies of oxytocin receptor binding in humans differ from receptor binding studies in rats in several respects, including intense receptorbinding in humans in the basal nucleus of Meynert and a lack of oxytocin binding in humans in the hippocampus, amygdala, entorhinal cortex and olfactory bulb 12. However, the human oxytocin receptor has now been cloned ~3 and studies confirm that this 88-residue polypeptide is a typical seven-transmembrane domain, G-proteincoupled receptor (Fig. 3a). The rat oxytocin receptor has also been cloned and the predicted amino acid sequence is 93% identical to the human sequence ~4. Both human and rat oxytocin receptors have multiple transcripts that differ in the length of their 3' untranslated regions and appear to be the product of a single gene. A portion of the 3' untranslated region of the human receptor contains a 30 base-pair (bp) CA repeat polymorphism with two alleles occurring with frequencies of 0.77 and 0.23 in a sample of Caucasians. This polymorphism was also used to map the human oxytocin receptor to chromosome 3p25-3p26 but the functional significance of the polymorphism remains unknown ~5. Unlike rodents, primates (including humans) have a circadian rhythm of oxytocin in the CSF with peak values occuring at midday 16. Neither rodents nor primates have a circadian rhythm of oxytocin in the plasma. Despite these differences in pituitary secretion and differing effects on pituitary adrenocorticotrophic hormone (ACTH) release, oxytocin secretion is stimulated in humans by estrogen, a finding consistent with animal studies. Release of oxytocin into the plasma can be induced by estrogen administration, oral contraceptives and pregnancy. Basal oxytocin levels also rise at the midpoint of the menstrual cycle, at the time of ovulation ~7A8.In addition, women have increased basal plasma oxytocin secretion during labor and lactation, and plasma secretion in response to nipple stimulation
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during pregnancy and the luteal phase of the menstrual cycle ~9.There are some notable species differences with regard to the ability of other stimuli to induce peripheral oxytocin release. In rats, oxytocin release is stimulated in response to a wide variety of stressors, and secretion of ACTH and corticosterone are enhanced in response to oxytocin. By contrast, in humans oxytocin is released in response to relatively few stressors, and oxytocin inhibits, rather than stimulates, ACTH and cortisol secretion 2°. Plasma oxytocin secretion can be stimulated in men and women by hypoglycemia:~--'3,and infusion of angiotensin II (Ref. 24) and apomorphine 2-~.'-6,but not by hypertonic saline infusion -'7 or exercise stress 28. Many of these same stimuli will induce oxytocin release in rats. However, despite these apparent species differences in pituitary secretion of oxytocin, indirect evidence cited below suggests that behavioral effects of oxytocin are similar across species.
Effects o[ o.~ytocin on sexual behavior in humans There have been several reports that plasma oxytocin secretion is increased during sexual stimulation and arousal, and that it peaks during orgasm in both men and women, leading to the suggestion that oxytocin plays a role in generating sexual arousal and orgasmzg. The intensity of muscular contractions during orgasm correlated with oxytocin plasma level. Men who took naloxone (an opioid antagonist) before sexual self-stimulation had reductions in both oxytocin secretion and the degree of arousal and pleasure during orgasm -~°. Oxytocin was an effective treatment for impotence in one male subject 3~ and a case study reported enhanced sexual arousal and enhanced intensity of orgasm in a woman during intranasal administration of oxytocin. The response could be elicited only while the subject was taking daily doses of an oral contraceptive with estrogenic and progestogenic actions (levonorgestrel) 3-'. Because intranasal oxytocin administration in these cases is unlikely to cross the blood-brain barrier, enhanced sexual arousal and sexual response might occur through direct effects on sexual organs or sensory nerve sensitivity. This possibility has been confirmed as a potential mechanism by studies in the rat. A peak in plasma oxytocin secretion at ovulation combined with high estrogen levels at midcycle could contribute to the increased sexual interest noted in women at midcycle in some studies 33.
Effects of o.~ytocin on maternal behavior in humans Although effects of centrally administered oxytocin on maternal behavior have been clearly demonstrated in animal studies, it is not possible to perform similar investigations in humans. A few studies have compared maternal behavior in lactating and non-lactating postpartum women, on the assumption that lactating women experience higher central secretion of oxytocin. Results suggest that breastfeeding within 1 h of birth, when oxytocin levels are very high, causes long-lasting enhancement of bonding and interactive behavior between the mother and her infant -~4.-~-~.
Effects of o.~ytocin on stress and anxiet3, in humans Indirect evidence that oxytocin reduces anxiety and stress in humans also comes from studies of lactating women. Compared with postpartum women who bottle-feed their infants, lactating women had reduced hormonal responses to exercise stress 36 and had lower heartrate responses to hearing a baby's cry. In addition, women with panic disorder can experience a relief of symptoms during lactation, and the panic disorder tends to relapse after weaning 37, as does their de-
pression 38. Reduced stress responsivity during lactation is adaptive for the mother and infant because stress and anxiety can impair maternal caretaking and reduce release of oxytocin and milk during suckling. Stress and anxiety also exacerbate the experience of pain. Consistent with the analgesic effects of oxytocin in rats, intrathecal administration of oxytocin relieved acute and chronic low back pain. Interestingly, CSF oxytocin levels were elevated in patients with chronic low back pain, perhaps as a compensatory response to the painful condition 39.
Role of oxytocin in neuropsychiatric disorders Obsessive-compulsive disorder ( OCD) Increased oxytocin levels in CSF have been noted in the large subgroup of patients with obsessive-compulsive disorder (OCD) who do not have a history of tic disorders. In this group, symptom severity correlated with oxytocin levels4°. Excessive grooming is often a component of OCD, and exogenous oxytocin induces high levels of self grooming in animals. Notably, puberty and pregnancy - periods of increased gonadal steroid secretion - are associated with a heightened risk for onset of OCD. It is possible that gonadal steroids activate oxytocin receptors during these periods.
Eating disorders Oxytocin release in response to a meal, which has been noted in a number of different animals, does not seem to occur in humans. There has been one report of increased basal oxytocin levels in obese individuals, with a reduction in oxytocin levels after surgical gastric banding and the subsequent restriction of caloric intake. Conversely, in women with anorexia nervosa, CSF levels of oxytocin are reduced during the starvation phase of the illness and return to normal as the patients increase their food intake 41. Plasma oxytocin responses to stimulation with estrogen and hypoglycemia are also reduced in underweight anorectic women, and normalize with weight restoration 42. Reduced brain and plasma levels of oxytocin during the 'starvation phase' of the illness might contribute to the symptom profile of anxiety, loss of libido, amenorrhea and increased activation of the hypothalamic-pituitary-adrenal hormonal stress axis. In patients with Prader-Willi syndrome (a severe disorder characterized by an extreme appetite for food, obesity, hypogonadism, mental retardation and hypogenitalism), investigators found a 42% decrease in the number of hypothalamic neurons producing oxytocin; these cells also had smaller cell volumes than hypothalamic oxytocin-producing cells in unaffected controls 43.
Depression Pederson has speculated that diminished oxytocin release or insensitivity to oxytocin might occur during depression and contribute to activation of the hypothalamic-pituitary-adrenal stress axis. He bases this hypothesis on a report in primates that repeated exposure to uncontrollable stress decreased oxytocin blood levels and that dexamethasone administration, which suppresses hypothalamicpituitary-adrenal axis activation, increased oxytocin secretion. A 23% increase in the number of oxytocin-producing cells in the hypothalamus was detected by immunocytochemistry in postmortem samples from patients with depression 44. The increased detection of oxytocin-producing neurons might be the result of decreased release of the neuropeptide or might reflect a higher rate of oxytocinergic activity in these patients. 273
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The outstandingquestions • Do oxytocin and/or oxytocin analogs have anxiolytic effects in humans? • Does steroid hormone modulation of oxytocin binding occur in the human brain and does this induce gender differences in normal behavior? • Are gender differences in neuropsychiatric illnesses related to hormonal modulation of oxytocin? • Are polymorphisms in the gene encoding the oxytocin receptor, or polymorphisms in genes that regulate the oxytocin receptor, associated with particular psychiatric illnesses? • Will nonpeptide oxytocin agonists and antagonists have beneficial effects in humans with some neuropsychiatric illnesses?
Schizophrenia
In light of oxytocin-induced activation of social behaviors in animals, impairments in the function of oxytocin or its receptor could be hypothesized to play a role in the profound social deficits that occur in autism and schizophrenia. Increased oxytocin and oxytocin neurophysin have been found in the plasma and CSF of schizophrenic patients in some, but not all, studies 4-~.46.This finding is not easy to interpret, but might represent a compensatory increase in oxytocin secretion in the context of impaired oxytocin-receptor function. Alzheimer's
disease
There has been speculation that oxytocin might play a role in Alzheimer's disease because pre-clinical studies in animals suggest that oxytocin impairs memory functions. Tissue levels of oxytocin were increased in the hippocampus and temporal cortex of patients with Alzheimer's disease 47, while the number of hypothalamic cells expressing oxytocin were normal in two other sets of patients with Alzheimer's disease 48.49. Studies of oxytocin levels in the CSF of patients with Alzheimer's disease have produced mixed results. Interestingly, the nucleus basalis of Meynert in the basal forebrain, which is the major nucleus for cortical cholinergic neurons and degenerates in Alzheimer's disease, is also one of the densest concentrations of oxytocin receptors in humans ~2. Future directions Animal models have proved critical in elucidating the mechanisms of neurohormonal regulation of complex behaviors. Attempting to determine a 'cause and effect' relationship between a neurochemical and social behavior in humans would be virtually impossible without the guidelines and directions set by basic research in animals. This has been particularly true in the case of oxytocin and the regulation of social behaviors. In future years, new techniques should lead to further substantial advances in our understanding of how oxytocin modulates complex multivariate behaviors in humans and animals. Nonpeptide oxytocin agonists and antagonists that can enter the brain should become available for use in acute and long-term studies. In addition, these compounds could be labeled to allow imaging of brain oxytocin-receptor populations at baseline and in a variety of other conditions. Investigations into the signal transduction pathways regulated by oxytocin will be informative, and genetic research might reveal changes in the genes encoding and regulating oxytocinreceptor function in any of a number of psychiatric illnesses, such as 1
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those characterized by anxiety, social deficits, abnormal eating, memory problems or substance abuse. In turn, this information might yield clues to the development of new treatments for these illnesses. Administration of these compounds to humans will help to clarify the importance of oxytocin in determining expression of many of the behaviors suggested by animal studies of oxytocin; these include sexual function, affiliation, aggression, anxiety, eating and grooming. In addition, chronic administration of nonpeptide oxytocin angonists and antagonists might provide relief of symptoms for patients with a variety of psychiatric disorders, including anxiety, autism, eating disorders, drug abuse and aggression. Oxytocin agonists might also prove beneficial for patients with sexual dysfunctions. References
1 Carter,C.S., DcVries,A.C. and Getz, L.L. (1995) Physiologicalsubstrates of mammalian monogamy:the prairie volemodel,NealrJsci. Biobehav Rev. 19, 303-314 2 Pedersen,C.A., Jirikowski,G.E. Caldwell,J.D. and lnsel, T.R. (1992) O.u,tochz h~ Maternal, Sexual and Social Behaviors. Ann. New York Acad. Sci. (Vol.652) 3 lnsel, T.R. (1992) Oxytocin - a neuropeptide for affiliation: evidence from behavioral, receptor autoradiographic, and comparative studies, Psychoneuroendocrinology 17, 3-35 4 Witt, D.M. (1995) Oxytocin and rodent sociosexual responses: from behavior to gene expression, Neurosci. Biobeha~: Rev. 19, 315-324 5 lnsel.T.R. and Hulihan,T.J. (1995) A gender-specificmechanism for pair bonding: oxytncin and partner preference formation in monogamous voles. Behav Neurosci. 109, 782-789 6 Winslow,J.T. and Insel, T.R. (1995) Social and environmental determinants of centrally administered oxytoein effects on male squirrel monkey behavior, Ann. New York Acad. Sci. 652, 452--455 7 Samson, W.K. and Mogg, R.J. (1990) Oxytncin as part of stress responses, in Current Topics in Neuroendocrinology (Vol. 10), pp. 33--60, Springer-Verlag 8 McCarthy,M.M. (1995) Estrogen modulation of oxytocin and its relation to behavior, in O.~3,tocin (lvell, R. and Ressell.J., eds), pp. 235-245, Plenum 90lson, B.R., Dmtarosky, M.D., Stricker, E.M and Verbalis, J.G. (1991) Brain oxytocin receptor antagonism blunts the effects of anorexigenic treatments in rats: evidence for central oxytocin inhibition of food intake, Endocrinology 129, 785-791 10 Blackburn, R.E. et al. (1993) Central oxytocin inhibition of salt appetite in rats: evidence for differential sensing of plasma sodium and osmolality, Proc. Natl. Acad. Sci. U. S. A. 90, 10380-10384 11 Delanoy,R.L., Dunn, AJ. and Tintner, R. (1978) Behavioral responses to intracerebroventricularly administered neurohypophyseal peptides in mice, Norm. Beha~ 11,348-362 12 Loup, E et al. (1991) Localization of high-affinity binding sites for nxytocin and vasnpressin in the human brain. An autnradiographic study, Brain Res. 555,220-232 13 Kimura, T. et al. (1992) Structure and expression of a human oxytocin receptor. Nature 356, 526-529 14 Rozen, F., Russo,C.. Banville,D. and Zingg, H.H. (1995) Structure, characterization, and expression of the rat oxytocin receptor gene. Proc. Natl. Acad. Sci. U. S. A. 92, 200-204 15 Michelini,S. et al. (1995) Pnlymorphism and genetic mapping of the human oxytocin receptor gene on chromosome 3. Am. J. Med. Genet. 60, 183-187 16 Amico, J.A. et al. (1983) A time-dependent peak of oxytocin exists in cerebrospinal fluid but not in plasma of humans, J. Clin. EndocrinoL Metab. 57, 947-95 I 17 Shukovski.L.. Healy,D.L. and Findlay,J.K. (1989) Circulating immunoreactive oxytocin during the human menstrual cycle comes from the pituitary and is estradiol dependent, J. Clin. Endocrinol. Metab. 68, 455-460
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18 Uvnas-Moberg, K. et al. ( 19891 Plasma levels of gastrin, somatostatin, VIP, insulin and oxytocin during the menstrual cycle in women (with and without oral contraceptives), A cla Obstet. GynecoL ScamL 68, 165-169 19 Amico. J. and Finely, B.E. (1986) Breast stimulation in cycling women, pregnant women and a woman with induced lactation: pattern of release of oxytocin, prolactin and luteinizing hormone, Clin. EmlocrinoL 25, 97-106 20 Legros, J.J. el al. (19841 Dose--response relationship between plasma oxytocin and cortisol and adrenocorticotropin concentrations during oxytocin infusions in normal men, J. C/in. Endocrinol. Metab. 58, 105-109 21 Seckl. J.R., Johnson, M.R. and Lightman, S.L. (1989) Vasopressin and oxytocin responses to hypertonic saline infusion: effect of the opioid antagonist naloxone, CIhs. EndocrinoL 30. 513-518 22 Nussey, S.S. et aL (1988) Responses of plasma oxytocin and arginine vasopressin to nausea induced by apomorphine and ipecacuanha, Clin. EmlocrhsoL 28, 297-304 23 Legros. J.J. et al. (1992) Apomorphine stimulation of vasopressin- and oxytocin-neurophysins, Evidence for increased oxytocinergic and decreased vasopressinergic function in schizophrenics. Psychoneuroendocrino/ogy 17, 611-617 24 Fisher, B.M., Baylis. P.H. and Frier, B.M (1987) Plasma oxytocin, arginine vasopressin and atrial natriuretic peptide responses to insulin-induced hypoglycaemia in man, C/in. EndocrhloL 26, 179-185 25 Coiro. V. et aL (1988) Oxytocin response to insulin-induced hypoglycemia in obese subjects before and after weight loss, J. EndocrinoL hwest. 11, 125-128 26 Chiodera, P. et aL (1991) Effect of estrogen or insulin-induced hypoglycemia on plasma oxytoein levels in bnlimia and anorexia nervasa, Metabolism 40, 1226--1230 27 Chiodera. P. eta/. (1994) Oxytocin response to challenging stimuli in elderly
men, Reg. Peptides 51,169-176 28 Ahemus, M. et al. (1995) Suppression of hypothalamic-pituitary adrenal axis responses to stress in lactating women, J. C/in. EndocrinoL Metab. 80, 2954-2959 29 Murphy. MR. et al. (1987) Changes in oxytocin and vasoprcssin secretion during sexual activity in men, J. Clin. Endocrinol. Metah, 65,738-741 30 Carmichael, M.S. et al. (1994) Relationships among cardiovascular, muscular and oxytocin responses during human sexual activity, A~z,h. Sex. Behav. 23, 59-79 31 Lidberg, L. (1972) The effect of Syntocinn R on a patient suffering from impotence. Pharmaeopsycltiatt3' 5, 187-190 32 Anderson-Hunt, M. and Dennerstein. L. (1994) Increased female sexual response after oxytoein, Br Med. ,L 309, 929 33 Dennerstein, L. et al. (1994) The relationship between the menstrual cycle and female sexual interest in women with PMS complaints and volunteers, P.~ychmwuroendocrinology 19, 293-304 34 Kennell. J.H. et aL (1974) Maternal behavior one year after early and extended post-partum contract, De~: Meal Child, NeuroL 16, 172-179 35 DeChateau, P. and Wiberg, B. 0977) Long term effect of mother-infant behavior of extra contact during the first hour post partum 1I. Follow up at three months, Acta. Paediatr ScamL 66. 145-15 I 36 Ahemus. M. et al. (1995) Suppression of hypothalamic-pituitary adrenal axis responses to stress in lactating women, ,I. Clin. EndocrinoL Metab. 80, 2954-2959 37 Klein. D.E, Skrobala. AM. and Garfinkel, R.S. (1995) Preliminary, look at the effects of pregnancy on the course of panic disorder. Attriety 1. 227-232 38 Susman. V.L. and Katz, J.L. (1988) Weaning and depression: another postpartum complication, Am. ,L Psychiao3' 145, 498-501 39 Yang,J. (1994) lntrathecal administration of oxytocin induces analgesia in low back pain involving the endogenous opiate peptide system. Spine 19, 867-871 40 Leckman, J.E et aL (1994) Elevated cerebrospinal fluid levels of oxytocin in obsessive-compulsivedisorder, Arch. Gen. Psychiatry 5 I. 782-792
41 Demitrack, M.A. et aL (19901 CSF oxytocin in anorexia nervosa and bulimia nervosa: clinical and pathophysiologic considerations, Am. J. Psychiato, 147, 882-886 42 Chiodera, P. et al. (1991) Effect of estrogen or insulin-induced hypoglycemia on plasma oxytocin levels in bnlimia and anorexia nervosa, Metabolism 40, 1226-1230 43 Swaab, D.E, Purba. J.S. and Hofman, M.A. (19951 Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in Prader-Willi syndrome: a study of five cases, J. Clin. EndocrinoL Metab. 80, 573-579 44 Purba, J.S. et aL (19961 Increased number of vasopressin- and oxytoeinexpressing neurons in the paraventricular nucleus of the hypothalamus in depression, Airh. Gen. Psychiao7 53, 137-143 45 Legros, J.J. et al. (19921 Apomorphine stimulation of vasopressin- and oxytocin-neurophysias. Evidence for increased oxytocinergic and decreased vasopressinergic function in schizophrenics, Psychoneuroendocrinology 17, 611-617 46 Glovinsky, D. et al. 0994) Cerebrospinal fluid oxytoein concentration in schizophrenic patients does not differ from control subjects and is not changed by neuroleptic medication, Schi=ophrenia Res. 1I, 273-276 47 Mazurek, M.E et al. ( 198710xytocin in AIzheimer's disease: postmortem brain levels, Neurology 37. 1001-1003 48 Wierda, M. et aL (1991) Oxytocin cell number in the human paraventricnlar nucleus remains constant with aging and in Alzheimer's disease. NeurobioL Agh~g 12,511-516 49 Fliers, E. et aL (1985) The vasopressin and oxytocin neurons in the human supraoptic and paraventrieular nucleus; changes with aging and in senUe dementia, Brabl Res. 342.45~53
Free biomedical literature searches The NationalCenterfor I~.~,~ ~ ~. Biotechnology / ~ ~ ~ ~ . ~ Information at the National Library of
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an experimental ~~'~N~%~Z~:~. service that allows you ~ -'" to search the biomedical l i t e r a t u r e . ~ ~ PubMed searches the 9 million citations in Medline, pre-Medline citations and citations supplied electronically by publishers. It has been developed in conjunction with publishers of biomedical literature, and allows you free access to literature citations and to full-text versions of some papers at publishers' Web sites. PubMed can be accessed on the World Wide web at: http:I/www4.ncbi.nlm.nih.gov/PubMed/ i
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Central nervous system actions of oxytocin and modulation of behavior in humans The posterior pituitary hormone oxytocin has modulatory effects on neural functioning that are significant to the regulation of behavior. Basic research in animals has established the importance of oxytocin in affiliation, including mating, pair bonding and parenting behaviors. It is also an important regulator of feeding, grooming and responses to stress. The actions of oxytocin in the brain are regulated by gonadal steroid hormones, particularly estrogen. Oxytocin might also influence normal behavior in humans, and dysfunctions in the oxytocin system might be involved in the etiology and expression of neuropsychiatric disorders. INTEREST in the neuropsychological significance of the neuropeptide oxytocin has increased tremendously in the last decade. Research in a variety of rodents, sheep and primates, including humans, has revealed a constellation of behavioral effects mediated by this uniquely mammalian hormone (Table 1). Oxytocin was originally recognized as one of two neurohypophyseal hormones, along with Vasopressin, released from the posterior pituitary and into the general circulation to exert an action on distant target organs. In the female, these include the smooth muscle of the breast to facilitate the milk let-down reflex and smooth muscle of the uterus to stimulate uterine contractions during parturition. In males, these organs include the smooth muscle of the reproductive tract (Fig. 1). The major source of oxytocin is the paraventricular and supraoptic nuclei of the hypothalamus (Fig. 2). Widespread intracerebral projections of oxytocin-producing neurons subserve its role as a neurotransmitter and/or neuromodulator, and oxytocin is an important modulator of behavioral responses. These would include maternal, paternal, sexual and social behaviors, all of which involve interactions with members of the same species. In addition, oxytocin is implicated as a neurotransmitter regulating feeding, grooming, stress and anxiety. Because of its apparently unique role in the regulation of social behaviors, there has been increased interest in a cross-species comparative approach for understanding the effects of oxytocin. The distribution of oxytocin receptors in the brain appears to be relatively conserved; they are found at highest density in the limbic system (Fig. 3b). However, the regulation of the receptor by steroid hormones varies substantially across species and could be the mechanism by which different species meet the particular demands of social construction. Given our current understanding of oxytocin in mammalian behavior, the question arises regarding the potential significance of oxytocin to normal and pathological behavior in humans. In general, research into the significance of oxytocinergic neurotransmission in humans is relatively sparse. This review therefore focuses
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briefly on the relevant information in animals and then addresses the more problematic issue of what significance this has to the understanding of human behavior. Behavioral effects of oxytocin in animals Stimulation of the genitals, whether it be by copulation, parturition or manually, results in the release of endogenous oxytocin into the circulation in a variety of mammalian species ~. Although it is not definitively established in all cases, there is compelling evidence for coordination of independent intracerebral and peripheral oxytocin release. This coordination, in turn, allows for integration of behavioral responses with peripheral physiological events, i.e. maternal behavior and suckling stimulation. The role of oxytocin in maternal, sexual
Glossary Basal nucleus of Meynert - The principal source of cholinergic fibers to the cerebral cortex. Behavioral despair - A behavioral paradigm that results in a loss of defensive reactions; it is considered to be an animal model of depression. Hypothalamic-pituitary-adrenal axis - A coordinated system involving the brain, pituitary and adrenal gland; it regulates the synthesis and secretion of glucocorticoids into the bloodstream. Learned helplessness - A behavioral paradigm that results in a loss of defensive reactions; similar to behavioral despair but involves a different experimental protocol. Mesolimbic pathway - A collection of dopaminergic neurons in the midbrain that project to the limbic system; it has been implicated in schizophrenia. Oxytocin neurophysin - An inactive carrier protein that binds oxytocin and is often released along with it. Tic disorders - Disorders characterized by the habitual, repeated contraction of certain muscles, resulting in stereotyped, individualized actions. m
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and social behaviors of animals has been the subject of many excellent and recent reviews-'.3.
Table 1. Behaviors regulated by oxytocin Behavior
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Effect of o.~ytocin on sexual behavior of animals Unlike humans, the overwhelming majority of animals breed only during certain times of the year, and the expression of sexual behavior is under strict endocrine control. Simply put, male and female animals mate only when circulating steroid hormone levels are at appropriate concentrations. For steroid hormones to influence behavior, they must fundamentally alter neurotransmission in the brain. Numerous studies have clearly established that intracerebral infusion of oxytocin into the hypothalamus facilitates sexual behavior in female rats primed with subthreshold levels of estrogen. There are dense collections of oxytocin receptors in this brain region and their density and binding affinity are increased by estrogen and progesterone. Oxytocin also facilitates male sexual responses in rodent models. Central administration of oxytocin significantly reduces the latency to achieve ejaculation and shortens the post-ejaculatory interval. This effect is even more pronounced in aged male rats and might be related to decreases in circulating testosterone (reviewed in Ref. 2).
Effects of o.~3'tocit7on maternal behavior of animals The expression of normal maternal behavior by rats that have recently given birth also requires a prior period of exposure to estrogen, and exogenous oxytocin can facilitate this response in the virgin or pregnant mouse, rat and ewe. Region-specific changes in oxytocin receptor binding in the brain have been related to the establishment of maternal responsiveness; the natural occurrence of the behavior can be blocked by oxytocin receptor antagonists or antiserum to oxytocin. Oxytocin release at parturition plays an important role in the establishment of maternal behavior in sheep, but also facilitates the development of a selective mother-infant bond (reviewed in Ref. 2).
Effects of o.~3.'tocin on social behal,ior of allimals In trying to understand the significance of oxytocin to human behavior, it is perhaps the role of oxytocin in animal social behavior that is the most intriguing. However, the precise quantification of social behavior in animals is difficult because of the involvement of a collection of related behaviors that includes pair bonding and attachment. One convenient parameter used to assess behaviors related to affiliation is the duration of physical contact between two individuals. For example, continuous infusion of oxytocin into male rats paired with females induced increased durations of physical contact, even in the absence of sexual interactions. In another social rodent species, the prairie vole, oxytocin infusion not only increased physical contact between males and females, but reduced agonistic interactions between them as well4. Futhermore, oxytocin infusions will lead to formation of partner preference for a particular male by female voles; this effect appears to be gender specific because vasopressin modulates pair-bonding in male voles, but not in females5. The complexity of neurotransmitter actions on social behavior is well illustrated by studies in the squirrel monkey, in which the effects of exogenous oxytocin depended on the prior social status of individuals. Dominant males responded to oxytocin administration with increased sexual and aggressive behavior, whereas subordinate males displayed a significant increase in the frequency of associative behaviors such as approaching, touching or huddling with another animal. The fact that dominant animals had serum testosterone titers
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over twice as high as the subordinate males might be a key underlying variable6.
Effects of o.xytocin on stress and anxiety in animals In rodents, oxytocin is a stress hormone in that it is released peripherally in response to both physical and psychological stressors. This stimulated release of oxytocin appears to function, in part, to facilitate the activation of the hypothalamic-pituitary-adrenal axis and increase glucocorticoid release 7. A logical and testable prediction of stress-induced central release of oxytocin is that it functions to ameliorate the symptoms associated with stress, i.e. anxiety. A continuous stress response can ultimately be deleterious and reducing that reaction under appropriate circumstances has substantial advantages. Central administration of oxytocin in male rats has been reported to have an anxiolytic action that is similar to that of the benzodiazepines, and the anxiolytic action of oxytocin in female mice was enhanced by estrogen. Compounds found to have anxiolytic actions in animals are also often effective in animal models of depression, and oxytocin has antidepressant action in two such models: learned helplessness and behavioral despair. In addition, the anti-nociceptive action of oxytocin is consistent with its antidepressant action. Finally, there is evidence in animal models that oxytocin can inhibit the development of opiate tolerance, dependence and self-administration, as well as tolerance to cocaine. Some of these effects appear to be mediated by a neuromodulatory action of oxytocin on dopaminergic neurotransmission in limbic brain regions, which might also be related to the the anxiolytic action of oxytocin in this brain system (reviewed in Ref. 8).
Effects of o.~3'tocin on.feeding and grooming in animals Both peripherally and centrally administered oxytocin reduce feeding, an effect that has led to it being called a 'satiety hormone'. Current theory holds that activation of neurons in the paraventricular nucleus (PVN) that project to the dorsal motor nucleus of the vagus nerve activate inhibitory efferents projecting directly to the gut, which then inhibit gastric motility. Both food and anorexiainducing agents, such as cholecystokinin, induce oxytocin release and reduce food intake, leading to the suggestion that both nausea and satiety activate a common hypothalamic oxytocinergic pathway that controls the inhibition of ingestion 9. Evidence in
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Figure 1. Sites of oxytocin action in humans. Oxytocin acts on multiple organ systems in men and women to regulate various physiological processes. In women, these include the milk let-down response by the smooth muscle of the breast, and uterine contractions; in men, they include contractions of the smooth muscles of the reproductivetract. Oxytocin is also involved in regulationof water balance by the kidneys, and is releasedby central neurons to influence behavior.
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":.,ix Figure 2. The source of oxytocin. Oxytocin is supplied to the posterior pituitary from neurons located in the paraventricular and supraoptic nuclei of the hypothalamus. It is then released from the pituitary into the circulation in response to appropriate stimuli. These same neurons, in addition to accessory oxytocinergic neurons located elsewhere in the brain, project broadly throughout the central nervous system. Receptors for oxytocin are discretely distributed in the brain and, in most mammalian species, are found in the hypothalamus and components of the limbic system. m
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Figure3. (a) Predictedstructureof the humanoxytocinreceptor.The geneencodingthe humanoxytocinreceptorhas beencloned13and encodesa protein withtheseventransmembrane domaintypical s of a G-protein-coupledreceptor. Theaminoacidsmarkedwithatriangleindicatepositionswheresubstitutions canbetoleratedwithoutalteringthe functionalpropertiesof the receptor.(b) Oxytocinreceptorbindingin rat brain, showing thehighestconcentratioofn receptors(red)in theventromedinucleus al of the hypothalamusandamygdala. animal models also suggests that central oxytocin mediates osmolality-related inhibition of appetite for salt, which might impact importantly on the actions of oxytocin as a satiety agenfl °. One of the first consistent behavioral effects reported in animals for central oxytocin administration was a pronounced increase in auto-grooming 11. Subsequent studies indicate that oxytocin increases several aspects of grooming but increases genital grooming more than other components. The ability of oxytocin to facilitate grooming involves activation of dopamine neurotransmission in the mesolimbic pathway and might be the result of direct activation of dopamine neurons in the ventral tegmental area by oxytocin. As discussed above, oxytocin is released in response to stress, and the induction of grooming might be part of a homeostatic mechanism for reducing anxiety. An additional potential function of oxytocin-induced 272
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grooming is the facilitation of pair bonds, whether between mother and infant or between mating partners, by increased transfer of odors between individualsL
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Behavioral effects of oxytocin in humans Compared with the very active investigation of behavioral effects of oxytocin in rodents, sheep and primates, relatively little data have been collected in humans. A number of difficulties have inhibited studies of oxytocin in humans, including (1) difficulty in obtaining brain tissue, (2) the extremely low basal plasma levels of the hormone and (3) a lack of oxytocin agonists or antagonists that can penetrate the blood-brain barrier. Informative sampling of hormone levels can only be performed in humans by lumbar puncture; this allows access to cerebrospinal fluid (CSF) where levels of oxytocin are higher. Alternatively, administration of pharmacological agents and/or psychophysiological challenges can stimulate secretion of oxytocin into the plasma; this secretion is likely to be a reflection of relative central oxytocin activity, but the relationship of peripheral to central secretion of oxytocin remains to be fully described. Another difficulty in the study of behavioral effects of oxytocin in humans is that behavior in humans is powerfully influenced by nonhormonal factors, particularly cultural expectations. The majority of our informative observations in humans are therefore derived by comparing measures of oxytocin in healthy subjects to measures in subjects with a variety of neuropsychiatric illnesses. Although oxytocin is expected to have behavioral effects in humans analogous to those seen in animals, substantial differences do exist between rats and humans in the regulation, function and neuroanatomical distribution of oxytocin-containing neurons. Initial studies of oxytocin receptor binding in humans differ from receptor binding studies in rats in several respects, including intense receptorbinding in humans in the basal nucleus of Meynert and a lack of oxytocin binding in humans in the hippocampus, amygdala, entorhinal cortex and olfactory bulb 12. However, the human oxytocin receptor has now been cloned ~3 and studies confirm that this 88-residue polypeptide is a typical seven-transmembrane domain, G-proteincoupled receptor (Fig. 3a). The rat oxytocin receptor has also been cloned and the predicted amino acid sequence is 93% identical to the human sequence ~4. Both human and rat oxytocin receptors have multiple transcripts that differ in the length of their 3' untranslated regions and appear to be the product of a single gene. A portion of the 3' untranslated region of the human receptor contains a 30 base-pair (bp) CA repeat polymorphism with two alleles occurring with frequencies of 0.77 and 0.23 in a sample of Caucasians. This polymorphism was also used to map the human oxytocin receptor to chromosome 3p25-3p26 but the functional significance of the polymorphism remains unknown ~5. Unlike rodents, primates (including humans) have a circadian rhythm of oxytocin in the CSF with peak values occuring at midday 16. Neither rodents nor primates have a circadian rhythm of oxytocin in the plasma. Despite these differences in pituitary secretion and differing effects on pituitary adrenocorticotrophic hormone (ACTH) release, oxytocin secretion is stimulated in humans by estrogen, a finding consistent with animal studies. Release of oxytocin into the plasma can be induced by estrogen administration, oral contraceptives and pregnancy. Basal oxytocin levels also rise at the midpoint of the menstrual cycle, at the time of ovulation ~7A8.In addition, women have increased basal plasma oxytocin secretion during labor and lactation, and plasma secretion in response to nipple stimulation
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during pregnancy and the luteal phase of the menstrual cycle ~9.There are some notable species differences with regard to the ability of other stimuli to induce peripheral oxytocin release. In rats, oxytocin release is stimulated in response to a wide variety of stressors, and secretion of ACTH and corticosterone are enhanced in response to oxytocin. By contrast, in humans oxytocin is released in response to relatively few stressors, and oxytocin inhibits, rather than stimulates, ACTH and cortisol secretion 2°. Plasma oxytocin secretion can be stimulated in men and women by hypoglycemia:~--'3,and infusion of angiotensin II (Ref. 24) and apomorphine 2-~.'-6,but not by hypertonic saline infusion -'7 or exercise stress 28. Many of these same stimuli will induce oxytocin release in rats. However, despite these apparent species differences in pituitary secretion of oxytocin, indirect evidence cited below suggests that behavioral effects of oxytocin are similar across species.
Effects o[ o.~ytocin on sexual behavior in humans There have been several reports that plasma oxytocin secretion is increased during sexual stimulation and arousal, and that it peaks during orgasm in both men and women, leading to the suggestion that oxytocin plays a role in generating sexual arousal and orgasmzg. The intensity of muscular contractions during orgasm correlated with oxytocin plasma level. Men who took naloxone (an opioid antagonist) before sexual self-stimulation had reductions in both oxytocin secretion and the degree of arousal and pleasure during orgasm -~°. Oxytocin was an effective treatment for impotence in one male subject 3~ and a case study reported enhanced sexual arousal and enhanced intensity of orgasm in a woman during intranasal administration of oxytocin. The response could be elicited only while the subject was taking daily doses of an oral contraceptive with estrogenic and progestogenic actions (levonorgestrel) 3-'. Because intranasal oxytocin administration in these cases is unlikely to cross the blood-brain barrier, enhanced sexual arousal and sexual response might occur through direct effects on sexual organs or sensory nerve sensitivity. This possibility has been confirmed as a potential mechanism by studies in the rat. A peak in plasma oxytocin secretion at ovulation combined with high estrogen levels at midcycle could contribute to the increased sexual interest noted in women at midcycle in some studies 33.
Effects of o.~ytocin on maternal behavior in humans Although effects of centrally administered oxytocin on maternal behavior have been clearly demonstrated in animal studies, it is not possible to perform similar investigations in humans. A few studies have compared maternal behavior in lactating and non-lactating postpartum women, on the assumption that lactating women experience higher central secretion of oxytocin. Results suggest that breastfeeding within 1 h of birth, when oxytocin levels are very high, causes long-lasting enhancement of bonding and interactive behavior between the mother and her infant -~4.-~-~.
Effects of o.~ytocin on stress and anxiet3, in humans Indirect evidence that oxytocin reduces anxiety and stress in humans also comes from studies of lactating women. Compared with postpartum women who bottle-feed their infants, lactating women had reduced hormonal responses to exercise stress 36 and had lower heartrate responses to hearing a baby's cry. In addition, women with panic disorder can experience a relief of symptoms during lactation, and the panic disorder tends to relapse after weaning 37, as does their de-
pression 38. Reduced stress responsivity during lactation is adaptive for the mother and infant because stress and anxiety can impair maternal caretaking and reduce release of oxytocin and milk during suckling. Stress and anxiety also exacerbate the experience of pain. Consistent with the analgesic effects of oxytocin in rats, intrathecal administration of oxytocin relieved acute and chronic low back pain. Interestingly, CSF oxytocin levels were elevated in patients with chronic low back pain, perhaps as a compensatory response to the painful condition 39.
Role of oxytocin in neuropsychiatric disorders Obsessive-compulsive disorder ( OCD) Increased oxytocin levels in CSF have been noted in the large subgroup of patients with obsessive-compulsive disorder (OCD) who do not have a history of tic disorders. In this group, symptom severity correlated with oxytocin levels4°. Excessive grooming is often a component of OCD, and exogenous oxytocin induces high levels of self grooming in animals. Notably, puberty and pregnancy - periods of increased gonadal steroid secretion - are associated with a heightened risk for onset of OCD. It is possible that gonadal steroids activate oxytocin receptors during these periods.
Eating disorders Oxytocin release in response to a meal, which has been noted in a number of different animals, does not seem to occur in humans. There has been one report of increased basal oxytocin levels in obese individuals, with a reduction in oxytocin levels after surgical gastric banding and the subsequent restriction of caloric intake. Conversely, in women with anorexia nervosa, CSF levels of oxytocin are reduced during the starvation phase of the illness and return to normal as the patients increase their food intake 41. Plasma oxytocin responses to stimulation with estrogen and hypoglycemia are also reduced in underweight anorectic women, and normalize with weight restoration 42. Reduced brain and plasma levels of oxytocin during the 'starvation phase' of the illness might contribute to the symptom profile of anxiety, loss of libido, amenorrhea and increased activation of the hypothalamic-pituitary-adrenal hormonal stress axis. In patients with Prader-Willi syndrome (a severe disorder characterized by an extreme appetite for food, obesity, hypogonadism, mental retardation and hypogenitalism), investigators found a 42% decrease in the number of hypothalamic neurons producing oxytocin; these cells also had smaller cell volumes than hypothalamic oxytocin-producing cells in unaffected controls 43.
Depression Pederson has speculated that diminished oxytocin release or insensitivity to oxytocin might occur during depression and contribute to activation of the hypothalamic-pituitary-adrenal stress axis. He bases this hypothesis on a report in primates that repeated exposure to uncontrollable stress decreased oxytocin blood levels and that dexamethasone administration, which suppresses hypothalamicpituitary-adrenal axis activation, increased oxytocin secretion. A 23% increase in the number of oxytocin-producing cells in the hypothalamus was detected by immunocytochemistry in postmortem samples from patients with depression 44. The increased detection of oxytocin-producing neurons might be the result of decreased release of the neuropeptide or might reflect a higher rate of oxytocinergic activity in these patients. 273
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The outstandingquestions • Do oxytocin and/or oxytocin analogs have anxiolytic effects in humans? • Does steroid hormone modulation of oxytocin binding occur in the human brain and does this induce gender differences in normal behavior? • Are gender differences in neuropsychiatric illnesses related to hormonal modulation of oxytocin? • Are polymorphisms in the gene encoding the oxytocin receptor, or polymorphisms in genes that regulate the oxytocin receptor, associated with particular psychiatric illnesses? • Will nonpeptide oxytocin agonists and antagonists have beneficial effects in humans with some neuropsychiatric illnesses?
Schizophrenia
In light of oxytocin-induced activation of social behaviors in animals, impairments in the function of oxytocin or its receptor could be hypothesized to play a role in the profound social deficits that occur in autism and schizophrenia. Increased oxytocin and oxytocin neurophysin have been found in the plasma and CSF of schizophrenic patients in some, but not all, studies 4-~.46.This finding is not easy to interpret, but might represent a compensatory increase in oxytocin secretion in the context of impaired oxytocin-receptor function. Alzheimer's
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There has been speculation that oxytocin might play a role in Alzheimer's disease because pre-clinical studies in animals suggest that oxytocin impairs memory functions. Tissue levels of oxytocin were increased in the hippocampus and temporal cortex of patients with Alzheimer's disease 47, while the number of hypothalamic cells expressing oxytocin were normal in two other sets of patients with Alzheimer's disease 48.49. Studies of oxytocin levels in the CSF of patients with Alzheimer's disease have produced mixed results. Interestingly, the nucleus basalis of Meynert in the basal forebrain, which is the major nucleus for cortical cholinergic neurons and degenerates in Alzheimer's disease, is also one of the densest concentrations of oxytocin receptors in humans ~2. Future directions Animal models have proved critical in elucidating the mechanisms of neurohormonal regulation of complex behaviors. Attempting to determine a 'cause and effect' relationship between a neurochemical and social behavior in humans would be virtually impossible without the guidelines and directions set by basic research in animals. This has been particularly true in the case of oxytocin and the regulation of social behaviors. In future years, new techniques should lead to further substantial advances in our understanding of how oxytocin modulates complex multivariate behaviors in humans and animals. Nonpeptide oxytocin agonists and antagonists that can enter the brain should become available for use in acute and long-term studies. In addition, these compounds could be labeled to allow imaging of brain oxytocin-receptor populations at baseline and in a variety of other conditions. Investigations into the signal transduction pathways regulated by oxytocin will be informative, and genetic research might reveal changes in the genes encoding and regulating oxytocinreceptor function in any of a number of psychiatric illnesses, such as 1
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those characterized by anxiety, social deficits, abnormal eating, memory problems or substance abuse. In turn, this information might yield clues to the development of new treatments for these illnesses. Administration of these compounds to humans will help to clarify the importance of oxytocin in determining expression of many of the behaviors suggested by animal studies of oxytocin; these include sexual function, affiliation, aggression, anxiety, eating and grooming. In addition, chronic administration of nonpeptide oxytocin angonists and antagonists might provide relief of symptoms for patients with a variety of psychiatric disorders, including anxiety, autism, eating disorders, drug abuse and aggression. Oxytocin agonists might also prove beneficial for patients with sexual dysfunctions. References
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