Neuroscience and Biobehavioral Reviews, Vol. 16, pp. 131-144, 1992 Printed in the USA. All rights reserved.

0149-7634/92 $5.00 + .00 Copyright .t~ 1992 Pergamon Press Ltd.

Oxytocin and Sexual Behavior C. S U E C A R T E R

Department of Zoology, University of Mao'land, College Park, MD 20742 R e c e i v e d 27 D e c e m b e r 1990 C A R T E R , C. S. Oxytocin and sexual behavior. N E U R O S C I B I O B E H A V REV 16(2) 131-144, 1 9 9 2 . - - T h e n e u r o h y p o p h y s e a l

hormone oxytocin has been implicated in many aspects of reproduction including sexual behavior. This review considers the hypotheses that oxytocin and/or the neural events surrounding the release of oxytocin may have behavioral effects during sexual arousal, orgasm, sexual satiety and other aspects of sociosexual interactions. Oxytocin

Sexual behavior

Arousal

Orgasm

Satiety

IN humans and other primates all components of sexual behavior can be expressed in gonadally inactive individuals with very low levels of steroid hormones (8, 85, 90, 177). However, little is known regarding the neurobiological substrate of the human sexual experience. In the last decade there has been an explosion of new knowledge in the neurosciences. This research has implicated a variety of endogenous chemicals, including hormones and neurotransmitters, in the control of sexual behavior in animals. The present review will describe selected components of the animal and human literature to examine the possibility that neural events surrounding the central release of oxytocin could play a role in sexual behavior. The phenomenology of human sexual behavior and contemporary theories regarding the hormonal control of sexual behavior will be summarized. Direct experimental evidence is not available regarding the role of oxytocin in human behavior. In the absence of such evidence the present review will summarize animal research relevant to the mechanisms responsible for the release of oxytocin and the behavioral effects of oxytocin. The release and actions of oxytocin may be regulated by steroid hormones and a variety of other neurochemicals that also have been implicated in sexual behavior; this research also will be summarized. These observations will be used to generate specific, and admittedly speculative, hypotheses regarding possible roles for oxytocin in the phenomenology of sexual excitement, orgasm, sexual satiety and other aspects of sociosexual behavior.

Human

Species comparisons

ical release from sexually stimulated vasocongestion or myotonia, accompanied by a "subjective perception of a peak of physical reaction to sexual stimuli." The resolution phase was defined as a reverse reaction in which individuals returned through plateau and excitement levels to the unstimulated state. In males and, less predictably, in females the resolution phase also was characterized as a refractory period when sexual stimuli were ineffective in reinitiating the response cycle. Uterine contractions or ejaculatory contractions typically are observed within a few seconds following the onset of the subjective component of orgasm. The subjective experience of orgasm does not lend itself readily to scientific study. For the purpose of this review, however, it is useful to note that the phenomenology of orgasm is described in similar terms by men and women (174). Kinsey and associates noted that "'orgasm in the female matches the orgasm of the male in every physiologic detail except for the fact that it occurs without ejaculation" (85).

Neural Correlates of the Sexual Response A "coital reflex," which is triggered by mechanical stimulation of the urethra, has been identified in rats (33). This reflex was seen following spinal transection in anesthetized and gonadectomized males or females. The reflexive responses recorded were similar in both sexes and resembled those seen during ejaculation but were not elicited in either sex prior to transection of the spinal tract. Although the existence of spinal, sexual reflexes is well documented, little is known regarding the central, neural events responsible for the experiences described during human orgasm. EEG recorded during orgasm shows a "'slowing of the electrical activity with increase in voltage, until there are paroxysmal three per second waves which are mixed with rhythmic alternating muscular discharges" (115). More recently, EEG hemispheric asymmetry has been described during both masturbation (38) and nocturnal penile tumescence (138). Central neural activity could reflect feedback from peripheral reflexes. There are reports, however, that orgasmic experiences are possible in individuals with complete spinal cord lesions (41, 84, 85). Central neural events (normally, but not always, occurring in the context of genital stimulation) presumably are essential for

HUMAN SEXUAL BEHAVIOR

Phenomenology of Human Sexual Behavior and Orgasm Kinsey and associates (85) described human sexual behavior as a pattern of increased muscular tdnsion which may culminate in muscular spasms and concurrent alterations in consciousness; these physical and psychological events were identified as orgasm or the "after-effects" of orgasm. Masters and Johnson (98) partitioned the human sexual response into four phases: excitement, plateau, orgasm and resolution. Excitement was described as an increase in sexual tension. The plateau phase was characterized by an enhancement of sexual tension, including vasocongestion and myotonia. Orgasm was described as a phys-

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the experience of orgasm. Damage to the central nervous system, including epilepsy, can interfere with normal sexual functions (17, 51, 72, 87, 144). Most theories regarding the physiology of orgasm have emphasized peripheral autonomic and neuromuscular events (55, 80, 84, 85, 98, 154). Davidson (41) proposed that two systems were responsible for orgasm. One system, which affects genitopelvic tissues, would participate in seminal emissions or uterine contractions. The second, which acts upon the nervous system, including the cerebral cortex, would account for loss of arousal, altered states of consciousness and other cognitive components of orgasm. In 1980, Davidson hypothesized that a mediating substrate, which he termed "the organ of orgasm," would normally coordinate these systems (41).

Hormones and Sexual Behavior Sex steroids of gonadal origin are not essential for human sexual behavior (8, 43, 84, 85, 90). However, social interactions (177) and specific components of sexual experience may be modulated by gonadal steroid. In general, in most mammals, including nonhuman primates and humans, it appears that estrogens (130,177) and/or androgens (8, 41--44, 128, 139, 141, 155, 156) facilitate sexual behavior, while chronic exposure to progesterone (9, 15, 16, 128) inhibits sexual activity. The effects of various steroid hormones on the capacity to experience orgasm have not been adequately studied. Based primarily on animal research and limited clinical and anecdotal findings in humans (148), it is likely that a variety of nonsteroidal hormones and neurotransmitters influence sexual behavior. The present review will focus on a possible role for one polypeptide, oxytocin. OXYTOCIN

General Features of Oxytocin Oxytocin is a nonapeptide characterized by a six amino acid ring structure with a three amino acid tail (65). Oxytocin is produced primarily in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus (143, 159, 164). Pulses of oxytocin are released into the systemic circulation at the posterior pituitary (neurohypophysis). Arginine vasopressin, which differs from oxytocin by two amino acids, is also produced in the SON and PVN, and is released by the posterior pituitary. Oxytocin and vasopressin are secreted into the circulation in conjunction with their carder proteins (neurophysins) (65). The half-life of peripheral or centrally injected oxytocin is species specific and the half-time for clearance in CSF is approximately 19 minutes in rats (103). Both oxytocin and vasopressin also are released into the central nervous system where they presumably affect neuronal activity (164,176). Oxytocin does not pass easily through the blood-brain barrier, but there is evidence of bidirectional transport of small amounts of oxytocin between the general circulation and cerebrospinal fluid (103). Whether this transport is of biological significance remains uncertain (52,92). The ability of systemically administered oxytocin to reach the central nervous system may help to explain reports (described below) of behavioral changes following peripheral injections of oxytocin. Genes for oxytocin and vasopressin have been isolated and sequenced, and it has been shown that the genes responsible for oxytocin and vasopressin share extensive homologies (65). Pharmacological evidence suggests some overlap of functions between oxytocin and vasopressin. Under physiological conditions the release of oxytocin and vasopressin are often coordinated,

although these hormones can have opposing functions (65).

Localization of Oxytocin Most of the centrally located oxytocin is found in large magnocellular neurons located in the PVN and SON; these cells project to the posterior pituitary gland where oxytocin is stored and secreted into the systemic circulation (10). Smaller, parvocellular cell bodies containing oxytocin also have been identified in the PVN. Oxytocinergic fibers originating in the parvocellular neurons extend into other parts of the nervous system including the caudal brain stem and spinal cord (19, 111, 143, 159,

160, 164). Oxytocin receptors have been identified in a variety of neural tissues, including the ventromedial hypothalamus (VMH), bed nucleus of the stria terminalis (BNST), central amygdala, anterior olfactory nucleus, lateral septum, ventral subiculum, and dorsal motor nucleus of the vagus (60, 65, 164, 171). Patterns of oxytocin receptors and relative concentrations of these receptors are species specific [reviewed (76)]. The functions of these receptors remain to be described (2), but correlational evidence links species differences to patterns of social organization and reproduction (76, 88, 186). Several aspects of oxytocin's action appear to be influenced by steroid hormones, including estrogen, progesterone, and the androgens. Both the gene for oxytocin and oxytocin receptor induction may be regulated by steroid hormones (65). In rats, steroid receptors show a pattern of neuroanatomical distribution that coincides with that of oxytocin in the bed nucleus of the stria terminalis and ventromedial hypothalamus (VMH) (76, 135137). The concentrations of some, but not all, oxytocin receptors are steroid hormone-dependent. A number of studies in rats have documented the steroid dependence of oxytocin receptors within the VMH (75-79, 145, 146, 160, 164). The response of oxytocin receptors to steroid hormones, however, can differ across species. For example, in prairie voles, in which reproduction is highly dependent on chemical communication, oxytocin receptors within the anterior olfactory nucleus are regulated by estrogen in a pattern that correlates with female sexual receptivity. In contrast, in prairie voles manipulations of endogenous or exogenous estrogens did not alter the concentrations of oxytocin receptors within other brain areas including the VMH (186). Oxytocin, the gene for oxytocin expression, and oxytocin receptors also have been found in nonneural tissues (96) including the corpus lutea (71,179) and testis (120). It has been suggested that oxytocin is involved in steroidogenesis (120) and corpus luteum regression (71). Thus, it appears that oxytocin may have regulatory functions at many levels within the hypothalamic-hypophyseal-gonadal axis.

Factors Regulating the Release of Oxytocin Using the rat as a model, factors responsible for the release of oxytocin have been studied extensively in the analysis of mechanisms underlying lactation (175) and parturition (32, 61, 64). In these contexts, breast and genital stimulation are potent releasers of oxytocin and/or the milk ejection reflex. In addition, the release of oxytocin can be induced, even in anesthetized male rats, by light touch, pinch or electrical stimulation of the vagus nerve (161). Olfactory tract stimulation and olfactory stimuli can release oxytocin in some species (77-79). Oxytocin release also can become conditioned, permitting release by cognitive stimuli, at least during lactation (93). In rats, olfactory input also has been implicated in anatomical changes within the

OXYTOCIN AND SEXUAL BEHAVIOR

133

TABLE 1 OXYTOCINLEVELSDURINGMALESEXUALACTIVITY(MEAN + S.E.M, fmol/ml) Sampling Condition

Species

Baseline

Rat Rabbit

9.1 __. 0.8 13.0 - 3.0* 8.6 +--2.1

Human

1.4 --- 0.3

Postejaculation (rain)

Mount and Thrust

19.5 --- 4.0* (Arousal) 2 --- 0.4*

0-5

20

18.3 --- 3.3 45.5 --- 13.0" 46.9 --. 8.5

27.4 +- 4.2

7.3 -- 2.6

30

Ref

14.5 ± 2.0*

(73) (162) (17o) (117)

*Extrapolated from graphed data.

SON that accompany lactation (104, 157, 190). Oxytocin can stimulate its own release in rats (54, 59, 60, 110, 113, 165). Positive feedback of oxytocin may contribute to the pulsatile release which is characteristic of this hormone. Activity in oxytocinergic neurons and the release of oxytocin depends upon the interaction of a variety of other hormones and neurochemicals (175). Steroid hormones, and in particular estrogen and testosterone, may facilitate the activity of the oxytocinergic neurons at many levels, including the induction of oxytocin receptors (77-79, 145, 146); progesterone, in contrast, appears to be inhibitory (129). The opiates, serotonin and gamma aminobutyric acid (GABA), may inhibit the release of oxytocin (13, 14, 160). The catecholamines and acetylcholine are more likely to induce activation in the oxytocinergic system, although this effect may be receptor specific (40,83).

trical activity recorded from cells was synchronized with the spontaneous activity of adjacent neurons, and dye coupling among cells was observed (69, 189-191). Even in virgin female rats, exposure to pups is capable of inducing neuroanatomical changes. Virgin females that cohabitated with pups for several days began to show maternal behavior and exhibited significant increases in several parameters of dendritic morphology within the SON (140). Yang and Hatton (190) also observed in lactating females that electrical coupling in brain slices increased within 10 minutes when electrical stimulation was provided via the lateral olfactory tract. Thus, the potential exists for rapid functional changes within this system following sensory stimulation. This neuronal plasticity, in turn, presumably provides a mechanism for the physiological and environmental regulation of the pulsatile release of oxytocin (11, 95, 175).

Unique Properties of Oxytocinergic Cells

Oxytocin amt Behavior

Oxytocin is released in pulses during labor (61) and before each milk ejection reflex in female rats (175). Both the release of oxytocin and the electrical activity of oxytocinergic cells are pulsatile (95,175). Oxytocinergic neurons display explosive firing patterns 9 to 12 seconds before each milk ejection, and each burst apparently represents the synchronous firing of many neurons. It is assumed that the 9- to 12-second latency represents the time that it takes for oxytocin to be released, carded systemically to the mammary gland and to act on myoepithelial cells of the breast to produce milk ejection. Vasopressin cells within the same nuclei show a phasic, rather than explosive, pattern of electrical activity (95, 132, 163). The morphology of the SON and PVN provides a substrate for the pulsatile release of oxytocin in rats. Ultrastructural analyses of magnocelhilar neurons in the PVN and SON (69, 70, 104, 112-114, 165-169, 172, 173, 189-191)indicate that oxytocin-containing cells occur in clusters, and that these cells are capable of direct neuronal contacts (gap junctions) which could permit synchronous electrical discharges. Astroglial processes normally isolate these cells from eaoh other. Prior to parturition and during lactation, the glial processes are retracted between oxytocinergic cells. Glial withdrawal has not been reported between vasopressinergic cells (69,166). These unisolated, oxytocin-containing cells in lactating or hormone-treated animals show increased cell-cell contact, a large number of double or multiple synapses, and the formation of dendritic bundles. Electrophysiological analyses in rats, including data from brain slices, have provided further evidence for direct contact and synchronous firing among SON cells (68, 163, 191); elec-

Oxytocin, secreted by the posterior pituitary, has powerful contractile effects on smooth muscle such as that found in the uterus and breast. Oxytocin was described first as a "female" reproductive hormone with critical actions in parturition and lactation (153,175). As recently as 1987, Murphy and associates ( l l 7 ) stated that "although men and women have similar concentrations of immunoreactive and bioactive oxytocin in the circulation, cerebrospinal fluid and hypothalamus, oxytocin has no known function in men." A broader role for oxytocin in "interpersonal reproductive acts" including behavior was suggested originally by Newton (118,119), but it is only recently that oxytocin has been implicated directly in behavior [reviewed (2)]. For example, oxytocin may regulate maternal behavior in rats (75, 82, 125-127) and mother-infant bonding in sheep (81-83), adult social bond formation in prairie voles (27, 28, 182), female sexual behavior in rats (5, 21, 66), and male sexual behavior in rats (3, 4, 7, 73, 100, 101, 162). Early reports that milk ejection (or oxytocin release) in women could be induced during orgasm (23) were confirmed using radioimmunoassay (24,58). Recent studies (Table 1) indicate that oxytocin increases slightly during sexual arousal in humans (24,117) and shows a marked increase during the orgasmic (or ejaculatory) phase of sexual behavior in humans, bulls, rams and rabbits (24, 63, 116, 117, 123, 150-152, 170). It has been suggested for several species that contractions in the reproductive tract, caused by peripherally released oxytocin, may facilitate sperm transport (56, 57, 121) and could play a role in sexual satiety in both sexes (24, 41, 73, 97, 162, 187).

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TABLE 2 EFFECTSOF OXYTOCIN(OT) OR OXYTOCINANTAGONIST(OTA) ON MALESEXUALBEHAVIORIN RATS

Drug

Dosage

Site of Administration

Effect on Sexual Behavior

OT OT OT OT OT OTA

1.6-2.5 p,g 200 ng I ng 30 ng 3-9 ng 2.5-50 ng

IV IP ICV ICV PVN ICV

'~ T I" ~" '[' ,~

OTA

10-100 ng

ICV

250-500 ng

ICV

OT

~,

Comments Fewer intromissions to ejaculation Shorter lat. to first ejaculation ~ PEI Penile erection frequency Penile erection frequency Decreased mounts; eliminated most ejaculations Dose-dependent decrease in OT or apomorphine-increased penile erections Increased latency to first mount and intromission and length of PEI

Ref 162 7 3 101 4 3 162

IV = Intravenous; IP = intraperitoneal; ICV = intracerebroventricular; PVN = paraventricular nucleus: PEI = postejaculatory interval prior to resumption of mounting.

OXYTOCINAND SEXUALBEHAVIOR

Sexual Stimulation Sexual arousal and subsequent copulatory behavior can be elicited by a variety of sensory stimuli. For example, somatosensory stimuli play a major role in sexual activity (84, 85, 98). Genital and breast stimulation is particularly powerful in inducing the release of oxytocin (175). In rats, oxytocin also is released by touch (161). Oxytocin release can be regulated by cognitive stimuli and can be conditioned to occur in the absence of direct physical stimulation (62,99). The morphology of cells releasing oxytocin, the release of oxytocin and oxytocin receptors may be affected by steroid hormones (77-79, 145, 146). In addition, tactile sensitivity, including genital sensitivity, may be influenced by hormones (20,89). As described above, steroid hormones influence virtually all aspects of sexual behavior and reproductive function. In addition, various neurotransmitters, neuromodulators and anatomical sites that have been implicated in sexual behavior, also may influence the release or actions of oxytocin [reviewed (65. 67, 82, 83, 175)].

Facilitation of Male Sexual Behavior Several experiments have indicated that oxytocin can enhance male sexual behavior (Table 2). In 1955, Wilhelmi and associates (181) reported that oxytocin treatment facilitated the spawning reflex in the Killifish (Fundulus heteroclitus). More recent studies have shown evidence of roles for related neurohypophyseal hormones in several nonmammalian species (108). In 1963, Melin and Kihlstr6m (100) observed in rabbits that intravenous administration of oxytocin hastened the onset of an initial ejaculation and increased the number of ejaculations within a fixed (30 minute) test period. Arletti and associates (7) found in rats that both central (intracerebroventricular, ICV, 1 ng) and peripheral (intraperitoneal, IP, 200 ng) injections of oxytocin shortened the latency from first intromission to first ejaculation and the postejaculatory interval leading to the resumption of intromission. [Attempts to elicit sexual behavior in previously nonresponsive male rats were not successful (7)]. Stoneham and associates (162) also found that relatively large intravenous (1.6-12.5 I.tg, IV) injections reduced the number of intromissions preceding ejaculation in male rats. The pharmacology of penile erections in singly-caged rats has

been studied in detail by Argiolas, Gessa and their associates [reviewed (2)]. Although a number of substances can influence penile erections, oxytocin apparently plays a central role in the regulation of these responses. The dose response curve for ICV oxytocin's effects on penile erections is "bell-shaped." Argiolas and Gessa (2) have reported that 5 ng of oxytocin (ICVI is the minimal effective dose, with maximal facilitation of penile erections observed between 10 and 60 rig. Penile erections are most readily induced in males that are primed with either endogenous or exogenous testosterone. Hypophysectomy reduced the behavioral effects of oxytocin in this model, and testosterone replacement partially restored the ability of exogenous oxytocin to facilitate erections. Although secretions from the pituitary-gonadal axis may be permissive in penile erections, these results indicate that hypophyseal oxytocin is not essential. Oxytocin injections directly into the paraventricular nucleus, and to a lesser extent in the hippocampal CA1 field, also produced a dosedependent (3 to 9 ng) increase in penile erections; injections in a variety of other brain regions, including the supraoptic area, lateral septum, preoptic area and ventromedial hypothalamus did not affect penile erections (101). Argiolas and Gessa (2) suggest that low doses of oxytocin may act within the paraventricular nucleus to activate the subsequent release of endogenous oxytocin. Apomorphine and other dopaminergic agonists also can stimulate erections, and Argiolas and Gessa (2) suggest that these behavioral effects are due indirectly to the capacity of dopamine to release oxytocin. Penile erections induced by ICV oxytocin (30 rig), as well as erections induced by apomorphine, were blocked by ICV injections of a potent oxytocin antagonist d(CHz)sTry(Me)-OrnS-vasotocin (OTA) (2,3). The ability of apomorphine to induced erections was blocked by dopaminergic antagonists, although these agents did not interfere with the capacity of oxytocin to induce penile erections. In rats, OTA markedly increased intromission latencies and eliminated ejaculatory behaviors when given at high dosages (25 or 50 ng); a lower dosage of OTA (2.5 ng) eliminated ejaculations in 60 percent of the rats and increased intromission latency in those animals that did eventually ejaculate (41.

hlhibition of Male Sexual Behavior There also is evidence that oxytocin may inhibit male sexual

OXYTOCIN AND SEXUAL BEHAVIOR

behavior [(2), Table 2]. Argiolas and Gessa (2) report that high doses of oxytocin inhibit penile erections. In male rats, Stoneham and associates (162) observed a dose-dependent inhibition of mount and intromission latencies following ICV infusions of oxytocin (250 ng or greater); in this study males that stopped mating emitted ultrasonic vocalizations like those characteristic of the postejaculatory refractory period. The latter study was interpreted as evidence for a possible role for oxytocin in male sexual satiety. We also have observed that oxytocin (300 ng, ICV and 500 ng, IP) can inhibit male sexual behavior in prairie voles (97). Data on a broader range of oxytocin dosages are not available for species other than rats. Hughes and associates (73) produced selective lesions in the lateral and posterior parvocellular PVN, thus eliminating cell bodies which contribute to centrally released oxytocin. These lesions spared the magnocellular regions responsible for the secretion of peripheral oxytocin. Behavioral studies of these animals indicated that lesions in the parvocellular PVN were followed by a more rapid return to sexual activity following ejaculation. These results again are consistent with the hypothesis that oxytocin, and specifically, centrally acting oxytocin, might be part of a neural system responsible for postcopulatory sexual satiety. Oxytocin does not cross the blood-brain barrier (BBB) with ease. Oxytocin does penetrate BBB-free regions of the nervous system, and Ermisch and associates (52) conclude that physiologically effective amounts might reach the nervous system " i f high pharmacological amounts of peptides are injected peripherally." The reported capacity of peripherally administered oxytocin to influence sexual behavior may indicate that some of the behavioral effects of oxytocin are due to direct or indirect actions outside of the BBB. Alternatively, exogenous oxytocin may cross the BBB. Even small amounts of exogenous oxytocin might in turn trigger the release of endogenous peptide (54,110), In summary, the results of several studies in rats suggest the hypothesis that small amounts of centrally administered oxytocin, or somewhat larger dosages of peripherally administered oxytocin, may facilitate the onset or pacing of male sexual behavior. In contrast, centrally administered, larger dosages apparently are more likely to inhibit penile erections and male sexual behavior, possibly creating a physiological state analogous to sexual satiety. The behavioral effects of a broad dose range of oxytocin are available only for penile erections (2). Studies of other components of male sexual behavior, within a consistent paradigm, and using a broader range of dosages, are necessary to examine the above hypotheses. In addition, systematic comparisons are needed of the effects of oxytocin on motivational versus copulatory or reflexive components of behavior. Even less is known regarding the behavioral effects of oxytocin in species other than domestic rats. Data from prairie voles indicate that exogenous oxytocin at relatively high dosages can inhibit male sexual behavior in that species (97), although in voles studies of the behavioral effects of low doses of oxytocin are not yet available. Female Sexual Behavior One of the earliest reports of a behavioral effect for the posterior pituitary hormones in females comes from research showing that vasotocin enhanced the willingness of female frogs to accept male clasping (48). Recent research examining the behavioral effects of oxytocin in females has focused on the capacity of oxytocin to facilitate lordosis in female rats (5, 21, 66, 145, 146). In female rats, the effects of oxytocin are most readily observed following either a sequential treatment with estradiol plus progesterone or in females primed with relatively large amounts

135

of estradiol alone. Oxytocin is further implicated in lordosis by the recent finding that treatment with an oxytocin antagonist (OTA, given concurrently with progesterone) reduced lordosis behavior in estradiol-treated female rats (185). Oxytocin injections can facilitate lordosis in female rats, and it is generally assumed that this is due to actions of oxytocin within the nervous system. A recent study, however, has reported that facilitative effects of oxytocin were no longer measured after removal of the uterus, leaving open the suggestion that at least some of the effects of oxytocin in female rats are due to feedback from its peripheral actions (107). Oxytocin injections localized to the ventromedial hypothalamus (VMH) did not facilitate lordosis in female rats receiving threshold treatments with estradiol and progesterone. However, in female rats, oxytocin treatments injected into the VMH or ICV were followed by reduced rejection of male advances and increased physical contact with male partners. These results suggest that oxytocin may increase the tolerance of the female rat for tactile stimulation (184,185). In another rodent, the prairie vole, attempts to demonstrate a facilitatory role for oxytocin (ICV or IP) in female sexual behavior have been unsuccessful (187). ICV treatment with 1 to 1000 ng of oxytocin did facilitate contact behaviors and reduce male-directed aggression in estradiol-primed female prairie voles. More recently, Williams and associates (27,182) have demonstrated that the formation of heterosexual social preferences in ovariectomized female prairie voles can be hastened by oxytocin infusion (ICV). These data suggest the possibility that oxytocin could influence sexual behavior indirectly, through actions on afflliative behaviors leading to, or associated with, sexual behavior. In estrous prairie voles, ICV oxytocin at dosages of 300 ng and above produced an immediate and long-lasting inhibition of female sexual behavior. In contrast, peripherally administered high dosages (1 to 10 I.tg) of oxytocin were without behavioral effects in this species (187). Studies of the long-term effects of oxytocin on female sexual behavior in rats have not been reported. The results from studies of the prairie vole indicate that oxytocin can produce inhibitions of female sexual behavior that last well beyond the half-life of the chemical, and suggest the possibility that relatively large pulses of oxytocin, or a refractory state induced by exposure to such pulses, might mediate or signal sexual satiety (187). Davidson (41) also speculated that coitally induced release of oxytocin (24) acting to induce uterine contractions could contribute to sexual satiation in human females. Ventromedial Hypothalamus Recent studies of the central effects of oxytocin and the sex steroids have focused on the VMH. The facilitatory effects of oxytocin on female sexual behavior in rats are usually steroidhormone dependent (21,66). The VMH contains high levels of oxytocin receptors. In both male and female rats, VMH oxytocin receptor levels are steroid-dependent (77-79, 145, 146). In contrast, in prairie voles, at least in females, oxytocin receptors are concentrated in the VMH, but the levels of VMH-oxytocin receptors are not estrogen-dependent (186). There also is no evidence in prairie voles that oxytocin is capable of facilitating or enhancing sexual behavior (187). In both male (97) and female (187) prairie voles, ICV oxytocin injections produce immediate inhibitions in sexual activity. Exposure to large pulses of oxytocin may inhibit sexual behavior, and the inhibitory effects of oxytocin might be either steroid-independent or due to interactions with the inhibitory effects of progesterone. The inhibitory effects of oxytocin might involve receptors in the VMH. How-

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ever, we are not aware of any direct examinations of the role of the VMH or oxytocin in sexual satiety in rats. The VMH has been implicated in a variety of behavioral functions including "motivation" (105,129). ICV oxytocin treatments also inhibit food consumption in rats (6). Destruction to the VMH results in hyperphagia, which has classically been described as a failure of a satiety mechanism. The possibility that the VMH and oxytocin may have a broad role in "motivational" processes, including the reduction of "drives" (105) or integrative or sensory processes regulating behavior deserves further consideration. SPECIES DIFFERENCES

There are several indications of species differences in the neural and behavioral effects of oxytocin. As described above, the relative steroid dependence of VMH oxytocin receptors is species specific (76, 77, 79, 186). Species differences also have been reported in the behavioral effects of steroid hormones. Although estrogen facilitates sexual behavior in both rats and voles, the behavioral effects of progesterone are species specific (25,26). Female rats (15,16) and hamsters (25), but not voles (26), exhibit a biphasic (facilitation followed by inhibition) response to progesterone. Attempts to examine species differences in the behavioral effects of oxytocin also should attend to species differences in behavioral patterns that may correlate with oxytocin release. Data suitable for making quantitative comparisons are not available. There is, however, interspecific variability in mammalian lactational patterns, which may, in turn, correlate with patterns of oxytocin release. As an example of the extreme variations that may occur, prairie vole pups attach almost continually to the maternal nipple, receive extensive maternal care, and presumably receive rather continuous nutrition while the female is in the nest (149). Female rats nurse in discrete bouts throughout the day, while rabbits may enter the nest and deliver milk only once a day (175). Patterns of sexual behavior also show crossspecies variation (46,47). If there are shared neural factors responsible for lactation and sexual behavior, it is possible that these will manifest in correlations among mating patterns and nursing patterns. Male prairie voles may continue to show intermittent sexual behavior over a day or longer (188). Mating in rats typically lasts a few hours (46), while mating in rabbits may be terminated after a single ejaculation (39). Mating systems or social organization also may correlate with the behavioral effects of oxytocin or its pattern of release. Concentrations of oxytocin receptors apparently correlate with monogamy or polygyny in voles and deer mice (76,186). As described above, oxytocin has been implicated in a variety of species-specific behavioral patterns, including pair-bond formation (27, 28, 182), which may contribute to the expression of social systems. These observations suggest the testable hypothesis that interspecific differences in patterns of oxytocin release and action may be reflected in, or perhaps even cause, species differences in patterns of reproductive behavior. SUMMARY

Oxytocin is released following tactile stimulation in rats, and slight elevations have been measured following preejaculatory behaviors including mounting in male rabbits (162) and during sexual arousal in humans (24). Oxytocin is released during ejaculation in several species (Table 1). The results of the studies described here suggest that treatment with relatively low levels of exogenous oxytocin can facilitate or accelerate the onset of

ejaculatory behavior in sexually-active male rats and rabbits. In contrast, large amounts of oxytocin may inhibit sexual behavior. The behavioral actions of oxytocin may be dosage- and/or timedependent. High levels of, or chronic exposure to, oxytocin could have inhibitory effects on sexual behavior, while lower levels or acute treatment may facilitate sexual activity. It has been reported that lesions of the lateral parvocellular PVN reduce the postejaculatory refractory period (73). Since parvocellular neurons project intracerebrally rather than to the neurohypophysis, this finding offers support for the possibility that endogenously released oxytocin also participates in male postcopulatory sexual satiety. Thus, it is possible that endogenously released oxytocin might function to both enhance male sexual arousal or other preejaculatory components of sexual behavior and to later inhibit sexual behavior. The presence of an ejaculatory event permits analogies between sexual activity in human males and other vertebrate species. It is more difficult to draw parallels from studies of female sexual behavior in rodents to the sexual response in human females. Preliminary findings in both voles and rats suggest the possibility that oxytocin might enhance social contact. In addition, the neural actions and behavioral effects of oxytocin may be species specific (76). Experiments examining the effects of oxytocin on motivational, autonomic and/or sensory processes, within a cross-species context, will help to clarify these issues. Additional understanding of potential interactions among steroid hormones and oxytocin is needed, although it is possible that at least some of the behavioral effects of oxytocin are steroid-hormone independent. Research in rats has suggested the VMH as a possible site for behavioral effects of oxytocin (145, 146, 184); however, the behavioral role of VMH oxytocinergic receptors remains to be specified. AUTONOMIC PATHWAYS, SEXUAL BEHAVIOR AND OXYTOCIN RELEASE

The autonomic nervous system plays a role in milk ejection [reviewed (102, 143, 164)]. It has been known for many years that stress could inhibit milk let down (118), and most of the studies dealing with functional interactions among oxytocin, autonomic processes and milk ejection have focused on the sympathetic nervous system and adrenal. However, oxytocin also influences parasympathetic activity, probably through effects on the central nervous system (143,164). Oxytocin receptors are concentrated in areas that have been implicated in parasympathetic function, such as the dorsal motor nucleus of the vagus and nucleus of the solitary tract (171). The autonomic nervous system regulates genital functions, including vasocongestion in both sexes and, in males, seminal emission and ejaculation. This regulation involves complex interactions between the sympathetic and parasympathetic nervous systems and may involve various neurotransmitters including vasoactive intestinal polypeptide (VIP). Erection and seminal emission require an intact parasympathetic nervous system. Sympathetic innervation of the penis is not essential for the development of erections; however, the sympathetic nervous system apparently influences penile detumescence [reviewed (12)]. Oxytocin also has been implicated in increased seminal emission (56,57), and receptors for oxytocin are found throughout the male reproductive system in rats (96). The peripheral physiology of female sexual responses is not well described. Myoepithelial tissue also is found in the clitoris (22). Genital myoepithelial tissue might share response characteristics with mammary tissue, including responses to oxytocin and the autonomic nervous system.

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Both the psychological and physiological phenomena associated with human sexuality have autonomic components, including not only genital events, but dramatic changes in cardiovascular and respiratory function. Heart rate in humans usually increases during sexual arousal, becomes maximal at orgasm, reaching in some cases rates of 120 to 180 beats per minute, and then drops rapidly during resolution (18, 93, 98). In women, changes in heart rate have been related to the subjective intensity of orgasm (93). As mentioned above, extrahypothalamic oxytocinergic and vasopressinergic fibers project to neural areas associated with autonomic functions (143). Infusions of oxytocin have complex effects on heart rate, suggesting a role for oxytocin in both sympathetic (192) and parasympathetic (133) control of cardiovascular functions. For example, in rats, intrathecal oxytocin produced a gradual increase in heart rate, while peripheral (IV) injection of oxytocin produced an immediate decrease in heart rate and an increase in blood pressure which lasted 5 to 10 minutes (192). Centrally active oxytocin, reaching the level of the spinal cord, might participate in the gradual increase in heart rate that accompanies sexual arousal, while systemically released oxytocin from the posterior pituitary (present following orgasm) might play a role in postcoital bradycardia. Both oxytocin and vasopressin could participate in the coordination of autonomic and behavioral phenomena associated with sexual arousal and orgasm. It is likely that these compounds act within both the central and peripheral nervous system, and affect the sympathetic and parasympathetic control of genital and extragenital responses. Pharmacological studies and the complex neurochemistry of the paraventricular and supraoptic nuclei support the hypothesis that oxytocin and vasopressin interact with each other and a myriad of other neurochemicals to regulate autonomic function (65,164). OTHERNEUROCHEMICALSIMPLICATEDIN SEXUALBEHAVIORANDOXYTOCINRELEASE

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induce or facilitate orgasmic-like sensations [reviewed (148)]. Apomorphine treatment in normal men can stimulate erection (91). In animals, dopaminergic agonists also tend to accelerate or enhance sexual activity. Everitt (53) specifically has implicated dopamine in appetitive versus copulatory components of sexual behavior. These effects are complex and may vary according to the brain region and type of dopamine receptor that is affected (53, 74, 178). Dopamine plays an important role in milk production via its inhibitory effects on prolactin (98). In addition, dopamine may have a facilitatory effect on oxytocin release and mill ejection in rats. Dopamine injections, given centrally, can excite pulsatile oxytocin (and vasopressin) release in rats (109). High dosages of dopamine produce a sustained release of hormones from the posterior pituitary (37). Dopaminergic synapses have been identified in conjunction with oxytocin (19). Dopamine also may inhibit the release of oxytocin, indicating that the interactions among dopaminergic and oxytocinergic processes are complex.

Norepinephrine Norepinephfine plays a role in mate sexual behavior, and alpha-adrenergic receptors have been implicated in this response (34-36). Research in rats suggests that alpha-1 adrenergic receptors facilitate and alpha-2 adrenergic receptors inhibit male sexual behavior. Norepinephrine can act at alpha-adrenergic receptors to activate the release of oxytocin and may inhibit the milk-ejection reflex at beta-adrenergic receptors (175). Both steroid hormones and norepinephrine also have been indirectly implicated in the release of oxytocin (40). The effects of catecholamines are presumably multifaceted and may include interactions with other hormones, neurotransmitters or neuromodulators or their enzymes or receptors. For example, norepinephrine, via alphaadrenergic receptors, can modulate the concentration of estrogen receptors (15,16). Opiates and monoamines also may interact to regulate sexual behavior (50).

Opiates Chronic opioid exposure inhibits various aspects of reproduction, including sexual behavior (1, 131, 180), maternal behavior (79,122), and milk ejection (175). Oxytocin release also is inhibited by the endogenous opiates (13, 14, 94, 147). The endogenous opiates have complex functions and may participate in the fine tuning of behavioral interactions such as those associated with sexual behavior and social bonding (82, 83, 86, 124). An abundance of evidence implicates the endogenous opiates in processes associated with social behavior, tactile sensitivity and pain (50). Acute opiate use has been associated with orgasmic-like experiences, but reports of this association are based upon anecdotes (131,148). There also have been cor~tradictory reports regarding the behavioral effects of opioid antagonists (116,131 ). Murphy and associates (ll6) have recently reported a doubleblind cross-over study of the effects of naloxone infusion on male sexual behavior and concurrent oxytocin release. Naloxone infusion blocked the peripheral release of oxytocin usually present at orgasm. Naloxone-treated men also reported reductions in subjective arousal and reported lower levels of pleasure during orgasm. Murphy and associates suggest that the inhibitory effects of naloxone in their study involve "central nervous system arousal mechanisms."

Dopamine There are anecdotal reports that the intravenous use of stimulants, such as amphetamines, which release catecholamines, may

GABA Oxytocin release is tonically inhibited by gamma-aminobutyric acid (GABA). GABAergic innervation has been implicated in the timing of glial retraction that is believed to regulate the pulsatile release of oxytocin (167). GABA also may inhibit sexual behavior, at least in rats (129,130). The possibility exists that shared mechanisms underlie these observations.

Other Neurochemicals The neurochemistry of sexual behavior is complex and beyond the scope of this review. Various neurotransmitters and brain regions that have been implicated in sexual behavior (45, 49, 139) appear to have relatively parallel functions in the regulation of oxytocin release and milk ejection (175). HYPOTHESESREGARDINGTHE ROLEOF OXYTOCININ SEXUALBEHAVIOR Oxytocin has been implicated in many aspects of sexual behavior. Circumstantial evidence suggests the general hypothesis that relationships exist among the neural events associated with the release of oxytocin and those associated with orgasm. The coordinated central, spinal and peripheral release of oxytocin makes this hormone a particularly attractive candidate for a role in the mediation of the sequential events in the sexual behavior. In the absence of evidence to the contrary, multiple functions for oxytocin are hypotbesized. At this stage in our understand-

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ing of the behavioral effects of oxytocin, these hypotheses are admittedly untested and highly speculative. The broad behavioral actions of the steroid hormones offer precedent for the possibility that oxytocin may have multiple behavioral actions. The following hypotheses are drawn primarily from studies of laboratory animals. Based on species differences in behavior and reproductive functions, and again on precedent from the steroid hormones, we also anticipate species differences in the behavioral effects of oxytocin. It is assumed here that all effects of oxytocin are present within the context of other hormones and neurotransmitters.

paraventricular and/or supraoptic nuclei). Transition from the plateau stage to the experience of orgasm in humans might be triggered by neurochemical events that specifically induce the pulsatile release of oxytocin. In their studies of penile erection, Argiolas and Gessa (2) have provided evidence for a positive feedback of oxytocin within the paraventricular nucleus. Additional studies of sexual behavior, which take into account the research on neuroanatomical events during oxytocin release (69, 104, 114), may provide insights into the plausibility of this hypothesis.

Hypothesis 3 SPECIFIC HYPOTHESES

Oxytocin could participate at several levels in the sexual response: 1) The initial central release of relatively small amounts of oxytocin might prime or stimulate preorgasmic sexual activity. 2) The initial release of oxytocin also might initiate a subsequent pulsatile release of endogenous central and/or peripheral oxytocin. 3) The pulsatile release of oxytocin could play a direct and/or indirect role in the experience of orgasm. 4) Physiological events following the release of oxytocin, including transitory central depletion of oxytocin and/or the aftermath of exposure to high levels of central and/or peripheral oxytocin might constitute components of sexual satiety or the postorgasmic refractory state. 5) Sex differences in oxytocinergic activity and steroid hormones might contribute to sex differences in sexual responsivity or patterns of sexual satiety.

Hypothesis 1 Small amounts of oxytocin or initial exposure to oxytocin could facilitate precopulatory events, including sexual arousal or excitement. Initial release of oxytocin could be facilitated by sexually arousing stimuli including nongenital touch (161), genital or breast stimulation, and cognitively conditioned events (175). Vasopressin, which increases measurably during sexual arousal (117), also might participate in the events leading to orgasm or other aspects of sexual behavior (45). Oxytocin release has been measured after mounting in rabbits (170) and prairie voles (Winslow, Williams, Hastings, Insel and Carter, unpublished data). Carmichael and associates (24) reported gradual increases in peripheral oxytocin during self-stimulation in both men and women, and a slight increase in oxytocin was measured in men during the excitement phase of the sexual response cycle by Murphy and associates [(117): Table 1]. A more recent report from Murphy (116), however, does not show increases in peripheral levels of oxytocin in samples taken after arousal to the point of erection (prior to self-stimulation). Methodological differences or individual differences may explain these results. It is possible that different paradigms were differentially stressful, possibility contributing to the preorgasmic release of oxytocin under some, but not all, test conditions. In addition, the relationship between central and peripheral oxytocinergic events during male sexual behavior remains undescribed. Hypothesis 1 focuses on central neural events associated with the release of oxytocin, although research on this problem, at least in males, has been limited to studies measuring serum levels of oxytocin.

Hypothesis 2 Oxytocin, released centrally during early stages of sexual excitement could, through positive feedback, prime the nervous system to permit a larger, pulsatile release of oxytocin. Among the events leading to the pulsatile release of oxytocin might be a coupling of oxytocinergic neurons (presumably within the

When adequate priming has been achieved, electrical coupling among oxytocin-producing cells would be possible (69). The pulsatile release of oxytocin might in turn influence electrical activity within the central nervous system, which could be manifest as measurable changes in EEG, "altered states of consciousness" and other behavioral and autonomic events described above (38, 41, 85, 89). It is interesting to note that, in the context of milk ejection in rats, Wakerley and associates (176) report that centrally administered oxytocin produced synchronization of the cortical EEG. After milk ejection, which was facilitated by this treatment, desynchronization of the EEG was observed. Because milk ejection can occur in some cases without changes in the EEG, these authors suggest that cortical EEG reflects "'an underlying common control and not part of the direct regulation of the milk ejection reflex." The peripheral release of oxytocin might coordinate the phenomenology of orgasm with contractions of the male and female reproductive tracts and, thus, facilitate sperm transport. Failure to achieve adequate priming due to interference with this process at one or more levels could be associated with anorgasmia. The ability to achieve orgasm, or variability in the subjective experience of orgasm, could reflect variability in the release of oxytocin or other neural events including those responsible for or associated with the release of oxytocin. A variety of neurochemical processes support the pulsatile release of oxytocin; drugs, stress or other processes that interfere with the release of oxytocin might inhibit sexual excitement. For example, endogenous opiates (endorphins), GABA or progesterone could inhibit, or selectively permit the release of, both oxytocin and sexual excitement/orgasm. Events associated with the release of oxytocin, for example, catecholaminergic activity, might play a role in the release of oxytocin and/or in the subjective or rewarding experience of orgasm. Peripheral autonomic events coordinated in part by the release of oxytocin, could produce changes in heart rate, blood pressure, and respiration which would be experienced as components of sexual arousal and orgasm.

Hypothesis 4 Several authors have suggested that oxytocin might be involved in sexual "satiety." Oxytocin injections, especially in large dosages, can inhibit sexual activity in rodents (97, 162, 170). Elevations in peripheral oxytocin or the aftermath of exposure to large oxytocin pulses might be experienced as a physical state such as that which follows orgasm. Exposure to a large pulse or high levels of oxytocin also might inhibit subsequent oxytocin release or otherwise alter the function of cells that release or respond to oxytocin. Hughes and associates (73) found that lesions to the parvocellular PVN, which spared the ability of the magnocellular elements to produce peripheral oxytocin, were associated with a more rapid resumption of sexual activity following ejaculation.

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This study implicates intracerebral oxytocin in sexual satiety, since the peripheral release of oxytocin remained intact. The PVN also is rich in other behaviorally active chemicals (143) and the specificity of the effects of these lesions remains to be demonstrated. In general, research on sexual behavior has focused on its induction and relatively little is known regarding the naturally occurring events responsible for terminating sexual activity. Repeated sexual experience is usually associated with a transient reduction in subsequent sexual behavior (or sexual satiety). Time (a refractory period) might be required for the repletion of coitally released oxytocin. Other neural events, including the release of various hormones and neurotransmitters with potential inhibitory effects, also could be responsible for sexual satiety. A variety of other chemicals including, for example, serotonin, opiates (49, 50, 116, 131, 139) and vasopressin (106,158), may participate in the inhibition of sexual behavior and/or in sexual satiety. Patterns of sexual behavior and satiety are species specific (25, 187, 188). The neurochemistry of these events also may differ among species.

Hypothesis 5 Oxytocin released during or after coitus could influence the development of subsequent social attachments. Research in prairie voles (27,187) and rats (184) has shown that intracranial injections of oxytocin produce increases in social contact. Keverne and his associates (81-83) have implicated oxytocin in filial attachment in sheep. The release of oxytocin during sexual behavior also could function to reinforce social bonds between sexual partners. Recent data from prairie voles, a species that develops male-female pair bonds, suggest that either sexual experience or oxytocin treatment may facilitate subsequent social bond formation (27),

H3pothesis 6 Sex and/or species difference in oxytocin and differential effects of steroid hormones could modulate sex differences, species differences and individual differences in sexual responses. Oxytocinergic functions can differ among individuals and between males and females (142). In particular, there are sex differences in the stress-related release of oxytocin (29-31). In addition, steroid hormones modulate the release of oxytocin and oxytocin receptors. Oxytocin (109) and steroids (112) also have direct effects on glial morphology in rats and, thus, may influence the pulsatile release of oxytocin. These findings suggest a substrate that could explain, in part, interspecific differences, sex differences, individual differences and within-individual variations in sexual responsivity.

pulses are not readily measured in human serum, especially in samples from men (142). Thus, the finding that oxytocin is released during orgasm in both sexes has stimulated interest in the possible functions of this hormone. The behavioral effects of manipulations of central oxytocin in humans remain to be described. Oxytocin (Syntocinon, Sandoz Pharmaceuticals) has been administered intranasally as an aid to lactation, although little is known regarding the behavioral effects of such treatments. Intranasal or peripheral administration of oxytocin could be used in controlled studies to examine the behavioral effects of this hormone in normal or sexually dysfunctional men or women. Several of the hypotheses proposed here could be examined indirectly through correlational studies of variations in human sexual function and dysfunction, such as those that occur during the menstrual cycle, lactation, aging and during hormone-replacement therapies. For example, there are indications that lactation can inhibit sexual behavior in human females (134). Assessment of the behavioral effects of lactation on human behavior will require a much more detailed individual analysis of patterns of lactation and oxytocin release than is available in the current literature. Animal research examining the role of oxytocin in sexual behavior is ongoing in several laboratories. The hypotheses described above, suggesting that low levels of or initial increases in oxytocin may facilitate, while high levels or prolonged exposure to oxytocin may inhibit male sexual behavior in rats, were derived from data scattered among several studies. Support for this hypothesis comes from recent unpublished studies of penile erections by Argiolas and Gessa [cited in (21]. Additional studies are needed to compare, within a consistent animal model, the broader behavioral effects of different dosages, modes of administration, and so forth of oxytocin. Animal models would be particularly useful to examine potential effects of oxytocin on motivational versus ejaculatory processes in sexual behavior. Behavioral effects of oxytocin extend beyond copulatory behavior and may influence processes such as social bond formation (27, 28, 81-83, 182), aggression (187) and social dominance (183), which could in turn influence sexual behavior. Animal research is also needed to examine the possible behavioral effects of vasopressin and interactions among vasopressin, oxytocin and other behaviorally active neurochemicals. Differences and similarities between the sexes and among species may be particularly valuable in providing insights into the behavioral effects of oxytocin. In the absence of directly relevant research, the hypotheses presented here remain largely untested. Relationships between oxytocin and sexual behavior may be due to direct actions of oxytocin or could be indirectly mediated by other central neural events that influence both oxytocinergic activity and sexual behavior. ACKNOWLEDGEMENTS

Summao, and Critique As described above, most of the research implicating oxytocin in sexual behavior has appeared within the last decade. At present, the published research relating oxytocin to human sexual behavior is limited in scope and is primarily correlational (24, 116, 117, 123). Aside from its release during birth (31) and lactation (175), oxytocin levels are low in humans and oxytocin

I am grateful to the following for the generous contribution of ideas, suggestions, and references which have been invaluable in the development of this paper: Stephen Porges. Diane Witt. Tom lnsel, Jessie Williams, Julian Davidson, Barry Keverne, Stafford Lightman, Glenn Hanon. Jack Caldwell, AI Johnson, Elaine Hull and two anonymous reviewers. Research described here as contributions from my laboratory was supported by NSF (BNS 87197481.

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