Central Oxytocin and Female Sexual Behavior" JACK D. CALDWELLb Brain and Developmental Research Center and Department of Psychiatry School of Medicine University of North Carolina at Chapel Hill Chapel Hill,North Carolina 27599

INTRODUCTION Niles Newton' noted that oxytocin (OXT) is released peripherally during reproductively important events such as coitus, parturition, and nursing. More recently, oxytocinergic cells and cell processes have been observed within the brain.24 OXT has been demonstrated to have direct central effects5-' As more evidence accumulates about the neuroanatomy, neurophysiology, and pharmacology of OXT, the relevance of Newton's original insight is becoming clear: OXT is released not only peripherally but centrally during social and sexual interactions. Evidence also exists that other aspects of OXT systems are changed by reproductive interactions. The development of oxytocinergic systems, particularly those of the rostra1 forebrain, may predispose them to control of the sensory stimuli of interactions. During development a set of neurons that closely resemble oxytocinergic neurons in size and location surround the basal forebrain steroid-concentrating region called the medial preoptic area (MPOA). These cells, along with what are probably a vast set of neuronal projections to other limbic areas, may respond to and then affect the perception of sensory input important for interactions, which, particularly in rodents, include smell and somatosensory information. The MPOA is an important steroid-concentrating region. We have demonstrated previously how estrogen influences a number of OXT cellular dynamics. In this chapter I will discuss how progestins and glucocorticoids affect OXT systems and suggest that OXT might affect central systems influenced by progesterone. In the female, OXT systems within the MPOA respond to the stimuli of sexual interactions, under the influence of steroids, resulting in release of OXT, which then colors the MPOA's subsequent response to such stimuli. One apparent result of OXT release and subsequent alterations in sensory perception is increased receptivity to a male during sexual interactions. This process may also occur in males during sexual activity as evidenced by Hughes et aL8 who demonstrated that CSF OXT levels increased in males during the ejaculatory phase of sexual interaction. If OXT is released centrally during mother-infant interactions, it may serve as the substrate for the bonding that takes place during this encounter. Release of OXT in

'This work was completed with the financial assistance of NICHD HD-06853 and HD-20640. bAddress for correspondence: Jack D. Caldwell, Ph.D., 202 BDRC (CB# 7250), School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7250. 166

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pups during this bonding period might organize synaptic contacts, particularly in brainstem and spinal autonomic nuclei. The appropriateness of these synaptic connections would serve to define responsiveness to interactions in later life. There is extensive oxytocinergic innervation of autonomic nuclei such as the nucleus of the tractus solitarius, dorsal motor nucleus of the vagus, and the intermediolateral nuclei of the spinal ~ o r d .Although ~.~ OXT application to these areas results in activation,' the effect of this interaction and its role in consummatory responses during interactions is not yet understood. This chapter will discuss the possibility that OXT release in these areas is associated with the satisfaction perceived during interactions.

ONTOGENY OF OXYTOCIN SYSTEMS IN THE MEDIAL PREOPTIC AREA Moore9has reviewed evidence that OXT homologues that exist in fish, amphibians, and reptiles are important in the control of reproductive behaviors in those vertebrate classes. There may be a phylogenetically old connection between systems controlling reproductive hormone release and reproductive behaviors that involves OXT or OXTlike peptides in the basal forebrain. Phylogeny and development of the MPOA reveals some intriguing clues to the nature of the oxytocinergic systems in this area. Diffuse cell collections are seen in postolfactory areas in fish, which may be homologous to the MPOA in mammals.'O The post-olfactory location of the MPOA at the juncture between the telencephalon and hypothalamus along with olfactory input into the MPOA via the medial forebrain bundle" may mediate the control by olfaction of pituitary hormone release. The importance of coordinating estrous behaviors with hormonal release leading to ovulation may have resulted in linkage of systems controlling the two in the MPOA. Many of the input fibers for the MPOA, such as the medial forebrain bundle, stria terminalis, and fornix, feed into or pass through the margins of the MPOA. Relatively large oxytocinergic neurons are located at the margins of the MPOA with processes that extend across the incoming fiber bundles. During development the basal forebrain is dominated by three groups of large multipolar cells. These are described by ValverdeIz in mice as being the bed nuclei of the (1) stria terminalis, (2) anterior commissure, and (3) medial forebrain bundle. The size and shape of these cells, identified by Golgi stain, are very similar to the oxytocinergic and vasopressinergic cells of the adult. The location of these bed nuclei cells makes them ideally placed to monitor and/or affect incoming information to the MPOA. The possibility that OXT systems monitor and affect olfactory information in adult rodents is further suggested by the presence of numerous OXT receptors in almost all olfactory system synaptic areas. Autoradiographic evidence has found OXT receptors in the olfactory tubercle, amygdala, hippocampus, and, in some species, cortical regions associated with ~lfaction.'~-'~. We have found OXT receptors in membrane fractions of the olfactory bulb (4.06 fmol/mg protein in pregnant females, using 0.4 nM [I2*I]ornithine vasotocin), olfactory tubercle (2.5 fmol/mg protein in pregnant rats), the amygdala (4.88 fmol/mg protein), and surrounding areas with radioligand assays. Release of OXT into these regions could modulate the perception of smells (and other important sensory information) associated with interactions. Olfaction is a very important sensory component of suckling behavior in pups and maternal and sexual behaviors in adult rodents. As we will see, steroids play an important role in regulating these behaviors, perhaps by controlling OXT release.

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The MPOA has also been demonstrated to respond to the somatic stimuli of mating. Allen et al. I 6 found increased metabolic activity in the MPOA of vaginally stimulated animals. Vaginal stimulation also affects the electrical activity of the ~egi0n.l~ An excellent study by Aou, Oomura, and YoshinatsuI8 on the electrical activity of the MPOA and the ventromedial hypothalamus (VMH) of female macaque monkeys during sexual interactions with a male, demonstrated that during proceptive behaviors 40% of MPOA and VMH cells were active, with MPOA cells mainly inhibited and VMH cells mainly excited. However, during the actual period of sexual contact the number of activated cells increased in the VMH to 56% and in the MPOA to 87%, with MPOA neurons showing considerably more excitation than those in the VMH. Whereas the VMH is clearly very important in the steroid control of estrous behavior initiation, the MPOA may be more relevant in responding to the events and stimuli of sexual intercourse. OXT levels in the MPOA increased in receptive females that were mounted ten times by males, but there was no change in VMH level^.^^^^^ In the MPOA activation of OXT systems may be an important response to sexual stimuli, including somatosensory stimuli such as vaginal distension. The MPOA is an important area for coordinating reproductive behaviors and ovulation under the control of gonadal steroids. Oxytocinergic cells at the margin of the MPOA in groups such as the lateral subcommissural nucleus (LSN), may be activated by increased sensory input into this region to then release OXT, which modulates this input. Processes from these OXT neurons may extend to other important sensory regions, where demonstrated OXT receptors could also control sensory perception. The stimuli of sexual interactions may release OXT within the MPOA and thus influence sensory perception in subsequent interactions.

STEROIDS AND OXYTOCIN RELEASE Several lines of evidence suggest that the MPOA is important in the reproductive cycle of rodents. Numerous cells within the MPOA have been found to bind estradio1.21,22 This area has been shown in rodents to increase progestin receptors in response to e s t r a d i 0 1 . ~Thus, ~ ~ ~ ~cells in this area are capable of responding to the steroids that control female reproductive behaviors and physiology. A population of oxytocinergic neurons in the paraventricular nucleus (PVN) binds estrogen; however, in vivo autoradiography has not revealed OXT cells outside the PVN that bind radiolabeled estrogen.25We have shown that steroids such as estrogen affect OXT-immunoreactive c ~ n t e n t ~and ~ ~ mRNA ~’ levels in areas such as the MPOA,28raising the question of mechanism. It may be that steroids unique to the brain are important for OXT cell functions.29Hagihara et aL30 found a sex-specific P-450 cytochrome in cells of the PVN containing OXT. The topography of this sexspecific cytochrome is almost identical to that of OXT cells (see Jirikowski et suggesting a mechanism for steroid action unique to OXT cells. The presence of estrogen-response elements (EREs) as a promoter for the gene for OXT31*32 suggests an influence of this steroid on OXT cells. However, the fact that radiolabeled estrogen could not be localized in OXT cells outside of the PVN suggests that another steroid activates any EREs that exist in extramagnocellular OXT cells. Thus OXT cells that contain their own unique steroids may be affected by exogenous steroids without actually demonstrating nuclear binding of those exogenous steroids. It is also possible that steroids act on OXT neurons outside of the PVN by nongenomic mechanisms. Jirikowski et al.2’ have suggested that estrogen has nongenomic effects on OXT systems, and Moss and Dudley33have reviewed evidence for such nongenomic

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effects of estrogens. There is evidence that both estrogen and progesterone affect patterns of OXT release (see below), which effects are probably membrane mediated. Progesterone is apparently intricately interlinked with OXT systems in ways that are poorly understood, but are nonetheless probably very important for the control of female sexual behavior. It appears that progesterone can influence OXT release. This was first demonstrated in estrogen-pretreated, ovariectomized (OVXed) rats given progesterone and processed five hours later for OXT immunocytochemistry.l 9 Although mating stimuli had the greatest influence on oxytocinergic perikarya, there was evidence that the addition of progesterone increased the number of OXTimmunostained processes with varicosities in the caudal anterior hypothalamus (AH) and rostra1 VMH. This suggests that progesterone acts to transport OXT out of cell bodies to be released, or that progesterone actually controls OXT release within the MPOA and hypothalamus. Microdialysisis a procedure that may be used to measure release of brain substances into the interstitial space. It involves measuring the constituents of the interstitial compartment that pass through a small dialysis membrane and are collected in the dialysate within the membrane. Because differential osmolarity determines the rate of inflow, it is of some advantage to increase dialysate osmolarity above that found in CSF. In a lactating mother that had had her pups removed at probe implantation, there was no detectable OXT recovery in the MPOA until pups were returned (FIG. 1A). Within 20 minutes of pup reattachment, a peak of recovered OXT was seen, indicating that recovery of OXT in the MPOA is responsive to suckling stimuli. With this technique we have found that estrogen pretreatments increase the overall level of OXT recovered. In one OVXed, estrogen-treated animal, it appeared that OXT was being released in surges (FIG.1B) in the MPOA rather than at a constant rate. This pattern of intermittent release was very similar to that seen in proestrous females (data not shown). In an estrogen-treated animal that was given progesterone immediately before sampling, OXT release in the MPOA was initially suppressed (see FIG.1C) and then released in a very large peak four hours after progesterone injection. It is interesting that the four hours between progesterone injection and OXT surge corresponds to the amount of time it takes for an intramuscular injection of progesterone to facilitate female sexual beha~ior.’~ A similar peak of OXT was seen four hours after progesterone in an animal with a probe in the VMH receiving no estrogen pretreatment (data not shown). In the MPOA vaginal stimulation prolonged the peak of OXT (FIG. ID), which may increase the overall release of OXT. Thus, it appears that (1) OXT can be recovered from areas of the MPOA-AH and VMH, (2) estrogen appears to increase releasable stores of OXT and may precipitate its release in pulses, (3) progesterone releases OXT in a very large peak, which effect may be independent of estrogen, (4) vaginal stimulation appears to extend the duration of the peaks of OXT release. From the microdialysisdata progesterone appears to increase OXT release by acting at the level of the neuronal membrane. The time of the OXT peak corresponds to the time of the effect of progesterone on sexual receptivity. However, the nature of this effect and its relevance to the initiation of sexual behavior is unknown. Some authors have suggested that progesterone may need to be present for OXT to facilitate female sexual r e c e p t i ~ i t y . ~ ~ . ~ ~

PROGESTERONE AND OXYTOCIN IN SEXUAL BEHAVIORS The MPOA may also play an important role in control of the adrenal gland via the pituitary. Glucocorticoids from the adrenal glands have a progestin-like facilitative

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FIGURE 1. Immunoreactive OXT can be recovered from interstitial fluids in the MPOA-AH and VMH by microdialysis. Microdialysis probes (3 mm long from BAS, Carnegie-Medicin; maximum exclusion size of 20,OOO daltons) implanted into urethane-anesthetized animals. Actual OXT levels were calculated on the basis of percent recovery in vitro for each probe (i.e., pg OXT times the reciprocal of percent recovery = actual pg OXT). In a lactating rat four days postpartum (A) there were no detectable levels of OXT until four pups were returned to the mother; within 20 minutes a peak of OXT appeared (pups had been removed at implantation; dotted lines represent the beginning of 1 M KCI Ringer's infusion). In an OVXed animal given 2 pg of estradiol benzoate (EB) 48 and 24 hours before implantation (B)OXT recovery exhibited peaks and nadirs, suggesting surges of OXT release (dashed lines indicate the beginning of 1 M NaCl Ringer's infusion) in the AH. In another animal with a probe in the MPOA-AH (0 that received the same EB dose above with 500 pg of progesterone immediately before probe implantation, there was a reduction in OXT peak height until four hours after progesterone injection, when there was a large peak of OXT (the high levels of OXT in samples A and B are probably residual OXT from an initial in virro recovery). In the caudal AH (D) vaginal stimulations (each arrow represents five series of four thrusts into the vagina with a 1-ml syringe plunger) resulted in a longer duration, slightly lower, peak of OXT than seen with EB plus progesterone alone.

effect on female receptivity in estrogen-treated animal^.^' Because OXT affects adrenal release of glucoc~rticoids,~~ it is important to determine if central OXT infusions might not facilitate receptivity by augmenting adrenal steroid release. Intracerebral infusions of OXT facilitated sexual receptivity in sham-adrenalectomized (sham-ADXed) animals with subcutaneous cholesterol vehicle pellets but not in sham-ADXed animals with corticosterone pellets (FIG.2A). In ADXed rats, with pellets that released physio-

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FIGURE 2. OXT infused intracerebroventricularly increased receptivity in ADXed animals provided they had corticosterone replacement. In this experiment 69 animals were either shamADXed or ADXed at the time of OVX. At that time all animals received a 100-mgpellet of 25% corticosterone; 75% cholesterol as described by Meyer et ~ 1 to .release ~ ~physiological levels of corticosterone, or 100% cholesterol vehicle. All animals were implanted with bilateral cannulas in the lateral ventricles at the time of OVX. Seven to ten days later, all received 0.5 pg of EB daily for three days and on the fourth day received OXT infusions (50-200 ng/p1 per side) or normal saline vehicle as described in Caldwell et uLZ0OXT infusions significantly (p < 0.05) elevated the maxium increase in LQs in sham-ADXed, cholesterol-implanted animals (FIG.2A; t,, = 2.265 over ranked maximum increases of saline-treated controls). OXT infusions also significantly0, < 0.01) elevated maxium increases in LQs in ADXed rats with 25% corticosterone pellets (FIG. 2 B t,, = 3.54).

logical levels of cortico~terone,~~ OXT significantly increased receptivity (see FIG.2B). ADXed animals with cholesterol vehicle pellets showed no factilitation after OXT infusions. Thus OXT-induced facilitation of receptivity does not depend on glucocorticoid release from the adrenal, since ADXed animals with corticosterone replacement showed receptivity facilitation after OXT. However, it is clear that there is an interaction between OXT and the hypothalamic-pituitary -adrenal axis because corticosterone treatment altered OXT responsiveness even in sham-ADXed animals. Jirikowski and S a p have recently demonstrated the presence of glucocorticoid receptors in a fraction of oxytocinergiccells in the P V N and SON. They also observed cytoplasmic glucocorti-

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FIGURE 3. The uterotonic antagonist PPTO-OXT ([Pen’, pMePhe2,The,Om8]-OXT)inhibited the receptivity-facilitatingeffect of progesterone when infused into the MPOA-AH before progesterone. All animals were OVXed and pretested for sensitivity to estrogen and progesterone (see Caldwell et al.”) and then were implanted with bilateral cannulas verified to be in the MPOA-AH. Twenty-seven rats received 0.25 pg of EB daily for three days and on the fourth day were infused with 1 pup1 per side PPTO-OXT or normal saline vehicle immediately before being injected intramuscularly with 250 pg of progesterone (see Caldwell et al. poster contributions to this volume for details). Animals receiving PPTO-OXT in the MPOA-AH had significantly lower mean LQs four J(J < 0.0005) and six hours (p < 0.02) after progesterone than animals receiving saline vehicle (tZ5= 3.82 at four hours, t,, = 2.64 at six hours). Receptivity scores also showed significant reductions after PPTO-OXT infusions (data not shown).

coid receptors in oxytocinergic neurons. Mohr and S ~ h m i t zfound ~ ~ glucocorticoidresponse elements associated with the OXT gene. The nature of the corticosteroneoxytocin interaction is unknown but may be related to the kinds of interactions seen between progesterone and the OXT system. Intracerebroventricular OXT infusions facilitated female sexual receptivity in animals pretreated with estrogen doses from 0.12 to 0.5 pg for three day^.^',^^ The MPOAAH is the most sensitive site for the facilitative effects of OXT.” We demonstrated that simultaneous infusion of a uterotonic antagonist (PPTO-OXT) along with OXT would block the facilitative effects of OXT.43However, we have been unable to block receptivity induced by estrogen plus progesterone treatments when we gave PPTOOXT immediately before testing (unpublished results). Witt and I n ~ edemonstrated l ~ ~ ~ ~ that infusing the uterotonic antagonist ornithine vasotocin (OVTA) before injecting 250 pg of progesterone disrupted receptivity in animals tested four hours later. We recently replicated this unexpected finding by infusing PPTO-OXT directly into the MPOA-AH: OVXed animals were given 0.25 pg of EB daily for three days and on the fourth day were infused with 1 pg/pl per side PPTO-OXT before being injected intramuscularly with 250 pg of progesterone. Animals that received PPTO-OXT exhibited significantly lower mean lordosis quotients (LQs) four hours (p < 0.001) and six hours (p < 0.01) after progesterone (FIG.3). Receptivity scores were also significantly reduced in PPTO-OXT-treated animals (data not shown). It appears PPTO-OXT can block the effect of progesterone on sexual receptivity when given before but not after progesterone. Thus, either OXT receptors must be available for progesterone to facili-

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tate sexual receptivity, or deactivation of OXT receptors may interfere with progesterone receptor binding in the brain. Either case suggests a high degree of OXT-progesterone interaction in control of female sexual behaviors. In summary, corticosterone treatments restore the ability of OXT to facilitate sexual receptivity in ADXed animals while muting that effect in intact animals. A uterotonic antagonist when given centrally before, but not after, progesterone is administered will substantially reduce the ability of progesterone to elevate sexual receptivity. This progesterone/corticosterone-OXT interaction is crucial to sexual behavior and deserves to be elaborated.

EFFECTS OF STEROIDS ON OXYTOCIN RECEPTORS Recently, Jack Elands and c o l l e a g ~ e sconducted ~ ~ * ~ ~ competition studies of brain membrane fractions and concluded that [1251]OVTAcould be used to characterize brain and uterus OXT receptors. We used [1251]OVTA to characterize OXT receptors from the MPOA-AH. We gave OVXed animals sesame oil vehicle, 0.5 pg, or 5 pg of EB daily for three days. The EB treatments result in mean LQs of 3.53 ? 1.7 for 0.5 pg EB and LQ = 81.7 i- 16.4 for 5 pg EB. Scatchard analysis of saturation experiments revealed that OXT receptors in MPOA-AH had significantly (p < 0.02) greater affinity in animals that received 5 pg of EB (F[1,12] = 8.12 versus oil after F[5,12] = 36.9 overall; see FIG. 4A). The density of OXT receptors was significantly (p < 0.05) reduced after a 5-pg dose of EB in membrane fractions from the MPOA-AH but not the mediobasal hypothalamus (Dunnett’s test after ANOVA F [2,6] = 5 . 3 2 , ~< 0.05). In another experiment membrane fractions were again taken from the MPOA-AH. OVXed animals were all given the 5-pg EB dose seen above. Half the animals were then given 500 pg of progesterone, and the other half received sesame oil vehicle four hours before all animals were tested to twenty mounts by sexually active males. In these mated animals, the addition of progesterone resulted in a significant (p < 0.05) increase in OXT receptor density in the MPOA-AH (FIG.4B; Mann-Whitney U test on &,ax from three replications). Therefore, in these mated animals, progesterone increased OXT receptor density without changing affinity. Increasing sexual receptivity with EB treatments increased the affinity of OXT receptors in the MPOA-AH. That we have seen estrogen increase OXT receptor affinity in other experiments (see abstracts) gives us some confidence in this curious effect. It may be that estrogen increases OXT receptor affinity by increasing OXT release as seen above. Shewey and found that the affinity of septa1 vasopressor receptors was greater in heterozygous than in homozygous Brattleboro rats. This is consistent with the theory that increased nonapeptide release increases the affinity of their receptors. In any case, estrogen treatments that enhance sexual receptivity increased OXT receptor affinity, while progesterone treatment resulted in elevated density of OXT receptors. These steroids alter OXT receptor dynamics in different ways that would each increase sensitivity to low concentrations of endogenous OXT.

OXYTOCIN AS THE SATISFACTION HORMONE Oxytocinergic neurons of the basal forebrain are located in areas suggesting that their origins were in the bed nuclei described by Valverde.’*The perikarya and processes of central OXT-immunostained neurons are at the margins of steroid-sensitiveregions such as the MPOA, anterior hypothalamus, and mediobasal hypothalamus. From this

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FIGURE 4. A 5-pg dose of EB given daily for three days elevated OXT receptor affinity in membrane fractions from the MPOA-AH (A) while in animals receiving the same 5-pg treatment and being mounted twenty times by males, the addition of 500 pg of progesterone increased OXT receptor density in the MPOA-AH. In two separate experiments (three replications each), a range of ['251]ornithinevasotwin from 0.1 to 2 nM was used to generate these Scatchard plots for membrane fractions from microdissected MPOA-AH (see Caldwell et aL poster contributions to this volume for assay details). In OVXed animals a dose of 5 pg of EB daily for three days significantly (p < 0.02) elevated binding affinity (KD= 0.12 nM f 0.01) over the a m i t y (KD = 0.21 nM f 0.01) seen in controls treated with oil vehicle (fl1,12] = 8.12 versus oil after Ff5,12] = 36.9 overall). The density of binding sites ( p a was significantly (p < 0.05) reduced after a 5-pg EB treatment in membrane fractions from the MFQA-AH (for MPOA-AH Dunnett's test after ANOVA Ff2,6] = 5.32, p < 0.05). In another set of OVXed animals (B), all receiving 5 pg of EB for three days, one-half received 500 pg of progesterone, and half received sesame oil vehicle four to five hours before being tested to 20 mounts by sexually active males (for EB only, mean LQ = 71 2 10.88; for animals receiving 500 pg of progesterone, LQ = 100.0 2 0). The animals that received 500 pg of progesterone had a significantly (p < 0.05) higher , of OXT receptors in membrane fractions from the MPOA-AH than those that were injected with oil (Mann-Whitney U on 0, values. density @J

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FIGURE 5. Ovarian steroids and mating stimuli act at several levels in the OXT systems of the lateral subcommissural nucleus (LSN) and MPOA. Estrogen increases OXT levels and OXT mRNA in the LSN as well as increasing released OXT and altering OXT release patterns in the MPOA-AH. Estrogen also increases OXT receptor affinity in the MPOA-AH. Progesterone may also alter OXT release patterns in the MPOA as well as increasing OXT receptor density there. The stimuli of mating, which alter preoptic physiology, also may change OXT release patterns and OXT receptor dynamics. Because OXT infused into the MPOA elevates sexual receptivity,*O one result of the multiple effects on OXT systems in the MPOA may be to increase sexual interactions.

position they may monitor as well as affect sensory input into these regions that are important mediators of reproductive behaviors. These OXT neurons are probably affected themselves by steroids and by the stimuli of mating (see FIG.5). The result of OXT release, across a broad array of inputs, may be to affect the response of the MPOA-AH to such stimuli. This release may also affect the receptors for OXT in this region, which when stimulated alter reproductive behaviors (see FIG.5). The interaction of the infant with the mother is very important in establishing the pattern of future responses in interactive situations in the adult. The responses of the infant to nursing have often been called the building blocks for sexual interactions in adults. Sigmund Freud recognized the psychological connection between suckling and sexual behavior, “It was the child‘s first and most vital activity, his suckling at his mother’s breast . . . that must have familiarized him with this [sexual] pleasure. . . . No one who has seen a baby sinking back satiated from the breast and falling asleep with flushed cheeks and a blissful smile can escape the reflection that this picture persists as a prototype of the expression of sexual satisfaction in later life.”49While Freud’s observation was allegorical and his point rather tangential to the physiological events,

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his observation was perhaps prophetic of the parallel between the autonomic changes surrounding suckling in the infant and those that occur with sexual interactions in adults. The mother-infant interaction appears to serve as a psychological template for later sexual bonding. Newton first suggested that OXT serves as the physiological substrate for this association.’ The release of OXT in major autonomic brain sites, even in young pups, may produce the kind of autonomic responses that Freud saw as the essence of satisfaction. Another set of MPOA-hypothalamus margin cells, that is, those oxytocinergic neurons surrounding blood vessels, play an important role in monitoring and perhaps affecting vascular state and autonomic functions. Control of hypothalamic blood flow may be another mechanism influencing arousal states and orgasm. The presence of OXT at the heart of the mother-infant interaction in the first opportunity to experience satisfaction from a conspecific suggests the importance of OXT in the expression of this feeling. Later experiences with any satisfaction-evoking event may be evaluated against this first response. Indeed a host of memories may be established and recalled according to their association with this feeling. The possibility that OXT is such a “satisfaction” hormone may explain its effects on several widely divergent tests. Such an effect might explain its ability to substitute as a partial replacement for morphine in ameliorating morphine withdrawa1,’O and that its infusion into the appropriate brain area can result in reductions in eating.51If its infusion produced satiety, it may blunt the satisfaction received from a food or water goal and thereby disturb learning processes.52Of course,the increased self-stimulation seen by Scwarzberg el al.53 after central OXT infusions further strengthens the postulate that OXT release results in a positive affect. The best way to parsimoniously incorporate these seemingly divergent effects of OXT is to postulate that its central release is associated with satisfaction.

ACKNOWLEDGMENTS I gratefully acknowledge the leadership and insightful comments of Dr. George A. Mason and the expert assistance of Cheryl A. Walker in compiling the radioligand data for this manuscript. I also thank Ms. Betsy Shambley for her excellent clerical assistance. REFERENCES 1. NEWTON, N. 1978. In Clinical Psychoneuroendocrinology in Reproduction.L. Carenza, P. Pancheri & L. Zichella, Eds.: 411-418. Academic Press. New York.

2. BUIJS,R. M. 1978. Intra- and extrahypothalamic vasopressin and oxytocin pathways in the rat: Pathways to the limbic system, medulla oblongata and spinal cord. Cell Tissue Res. 192: 423-435. 3. Buus, R. M., G. J. DEVRIFS, F. W. VANLEEUWEN & D. F. SWAAB.1983. Vasopressin and oxytocin: Distributionand putative functions in the brain. In The Neurohypophysis: Function and Control, Progress in Brain Research. B. A. Cross & G. Leng, Eds. Vol. 60. 115-122. 4. SOFRONIEW, M. V. & A. WEINDL.1978. Projections from the parvocellar vasopressin and neurophysin-containing neurons of the suprachiasmatic nucleus. Am. J. Anat. 153: 391 430. 5. RAGGENBASS, M., M. DUBOIS-DAUPHIN, S. CHARPAK & J. J. DREIFUSS. 1987. Neurons in the dorsal motor nucleus of the vagus nerve are excited by oxytocin in the rat but not in the guinea-pig.Proc. Natl. Acad. Sci. USA 8 4 3926-3930.

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