Cort A. Pedersen

Oxytocin activates the postpartum onset of rat maternal behavior in the ventral tegmental and medial preoptic areas.

Oxytocin binding (Bmax) was found to be higher in the ventral tegmental area (VTA) and the medial preoptic area (MPOA) at midparturition compared with Pregnancy Days 15-17 or Postpartum Days 5-7 in rat dams. Pup retrieval and assuming a nursing posture over pups were blocked in parturient dams by infusions of an oxytocin antagonist into the VTA or MPOA and by infusions of a vasopressin (V1) antagonist into the MPOA. These results implicate oxytocin in the VTA and MPOA and vasopressin in the MPOA, as well as a parturition-associated rise in oxytocin binding in these sites in the postpartum activation of maternal behavior.

Oxytocin facilitates the sexual receptivity of estrogen-treated female rats

Oxytocin (OXY) and arginine-vasopressin (AVP) are widely distributed within the brain and have a number of behavioral effects resulting from central administration. We have previously found that central OXY administration accelerated the onset of maternal behavior in ovariectomized (OVXed) estrogen-treated nulliparous rats. We now report that intracerebroventricular (ICV) injections of OXY enhance lordosis behavior in OVXed estrogen-treated rats. After treatment with 0.15, 0.20, or 0.25 micrograms EB IM for three days, OXY (800 ng) infusion ICV on the fourth day produced a significant increase in lordosis behavior between 20 and 90 minutes after administration. Doses of OXY between 0.8 and 5 micrograms injected ICV significantly increased lordosis behavior in animals pretreated with 0.5 micrograms EB for three days. In other OVXed rats treated with 0.5 micrograms EB for three days, ICV injections of 1 micrograms OXY or an equimolar dose of AVP significantly increased lordosis while equimolar doses of ACTH1-10, ACTH4-10, arginine-vasotocin, GnRH and alpha-MSH did not significantly increase lordosis behavior over saline vehicle levels. ACTH1-24 significantly lowered lordosis quotients. We have concluded from these data that central administration of OXY (and possibly AVP) enhance female sexual receptivity. This effect is estrogen dependent, dose related and under our test conditions, specific to OXY and AVP.

Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder.

BACKGROUND This study was designed to examine basal and stress-induced levels of the neuroactive progesterone metabolite, allopregnanolone, in women with premenstrual dysphoric disorder (PMDD) and healthy control subjects. Also, because evidence suggests that allopregnanolone negatively modulates the hypothalamic-pituitary-adrenal axis, plasma cortisol levels were examined. An additional goal was to investigate the relationship between premenstrual symptom severity and luteal phase allopregnanolone levels. METHODS Twenty-four women meeting prospective criteria for PMDD were compared with 12 controls during both the follicular and luteal phases of confirmed ovulatory cycles, counterbalancing phase at first testing. Plasma allopregnanolone and cortisol were sampled after an extended baseline period and again 17 min following the onset of mental stress. Owing to low follicular phase allopregnanolone levels, only luteal phase allopregnanolone and cortisol were analyzed. RESULTS During the luteal phase, PMDD women had significantly greater allopregnanolone levels, coupled with significantly lower cortisol levels, during both baseline and mental stress. Moreover, significantly more controls (83%) showed the expected stress-induced increases in allopregnanolone compared with PMDD women (42%). Premenstrual dysphoric disorder women also exhibited a significantly greater allopregnanolone/progesterone ratio than control subjects, suggesting alterations in the metabolic pathways involved in the conversion of progesterone to allopregnanolone. Finally, PMDD women with greater levels of premenstrual anxiety and irritability had significantly reduced allopregnanolone levels in the luteal phase relative to less symptomatic PMDD women. No relationship between symptom severity and allopregnanolone was observed in controls. CONCLUSIONS These results suggest dysregulation of allopregnanolone mechanisms in PMDD and that continued investigations into a potential pathophysiologic role of allopregnanolone in PMDD are warranted.

Intranasal oxytocin reduces psychotic symptoms and improves Theory of Mind and social perception in schizophrenia

Oxytocin has numerous prosocial and antipsychotic-like effects in animals. Prosocial effects of acute intranasal oxytocin administration have also been reported in human subjects. We conducted a randomized, placebo-controlled trial testing the effects of twice daily intranasal oxytocin treatment for 14 days on psychotic symptoms and social cognition in patients with schizophrenia. PANSS scores declined significantly and several social cognition measures improved significantly or nearly significantly in oxytocin (N=11) but not placebo (N=9) recipients. Our results suggest that, in addition to reducing classic psychotic symptoms, oxytocin may diminish certain social cognition deficits that are not improved by current antipsychotic medications.

Brief vs. long maternal separations in infancy : contrasting relationships with adult maternal behavior and lactation levels of aggression and anxiety

We compared the effects of daily long (3 h), brief (15 min) or no maternal separation (LMS, BMS, NMS) on postnatal days 2-14 on maternal behavior, aggression and anxiety levels during lactation in adulthood. Animals subjected to LMS received less maternal grooming than animals subjected to BMS. Maternal behaviors, including nursing, pup-grooming (PG) frequency and proportion of total grooming (PG+self-grooming) and nest-building during the immediate postpartum period and on postpartum days 2 and 5 were lower in dams with LMS experience compared to dams with BMS experience. LMS dams attacked male rats placed in their home cages less quickly and less often than did BMS or NMS dams. LMS dams also exhibited more anxiety than BMS dams in the elevated plus maze test. Thus, maternal separation during the postnatal period (or associated changes in the amount of maternal grooming received) affected subsequent adult maternal behavior, aggression and anxiety. The mechanism for this remains to be discovered, however, it seems likely to involve alteration of the development of oxytocin receptors in the brain.

Oxytocin control of maternal behavior. Regulation by sex steroids and offspring stimuli.

The evolution of maternal behavior (MB) revolutionized reproduction. Sustained maternal protection and nurturing of offspring until they were able to fend for themselves allowed a much higher rate of survival. Mothering also permitted a much longer period of brain development and was therefore an essential prerequisite for the evolution of higher intelligence. Species that mother their offspring have dominated every ecological niche in which they dwell. The ever increasingly complex social behavior that has been a major feature of mammalian evolution has probably been built on brain systems that originally evolved to generate MB. The remarkable success of MB as a reproductive behavioral strategy has depended on evolution of mechanisms to assure that maternal responses towards offspring (1) are exhibited only by females that are lactating (i.e., can feed offspring), (2) are not exhibited by females that are not lactating, and (3) are sustained for the prolonged period necessary for offspring to mature despite rapid postpartum dissipation of the hormonal conditions that were necessary for the initial activation of MB. This chapter focuses on the now overwhelming evidence that the neuropeptide oxytocin (OT) is centrally involved in activating MB at the appropriate time as well as on new evidence that OT may play a less essential but significant role in sustaining MB during lactation.

Oxytocin antiserum delays onset of ovarian steroid-induced maternal behavior

We have previously reported that intracerebroventricular (ICV) administration of oxytocin (OXY) produces a significant increase in maternal behavior in ovariectomized (OVXed) rats given a single priming dose of estrogen. Arginine vasopressin (AVP) has a weaker and more delayed but significant facilitating effect on the onset of maternal behavior. Other investigators have demonstrated that prolonged treatment of OVXed nulliparous rats with estrogen and progesterone followed by withdrawal of progesterone shortens the latency of onset of maternal behavior. We hypothesized that ovarian steroids increase the onset of maternal behavior by a central mechanism involving OXY and possibly AVP. To test this nulliparous Sprague Dawley rats were given SC one Silastic capsule containing 4.4 mg of 17 beta-estradiol eight days after OVX and three capsules each containing 40 mg of progesterone ten days after OVX. Progesterone capsules were removed on the 20th day after OVX, 24 hrs before the introduction of three rat pups (1-5 days old). One hr prior to introduction of pups animals received ICV 10 microliters of anti-oxytocin antiserum (AOA), anti-arginine vasopressin antiserum (AVA), anti-neurotensin antiserum (ANA), normal rabbit serum (NRS), AOA + 250 ng OXY or no ICV infusion. Animals receiving AOA displayed significantly less maternal behavior compared to animals receiving NRS, ANA or no ICV infusion over the first two, six and 25 hrs of pup contact. OXY significantly reversed the inhibitory effect of AOA in the first two hrs of pup contact. AVA significantly decreased the onset of maternal behavior compared to ANA or no ICV infusion over the first six hrs of pup contact.

Oxytocin and Vasopressin Immunoreactivity in Hypothalamic and Extrahypothalamic Sites in Late Pregnant and Postpartum Rats

This study examines immunoreactive levels of oxytocin (OT) and arginine-vasopressin (AVP) from acid extracts of the paraventricular nucleus (PVN), supraoptic nucleus (SON), anterior commissural nucleus (ACN) and the suprachiasmatic nucleus (SCN) as well as selected extrahypothalamic sites in pregnant or postpartum (PP) rats. Animals are sacrificed between 08.30 and 10.30 h 16 or 22 days after sperm is detected in their vaginal smears or on the morning after parturition. Peptide levels of pregnant or PP animals are compared to levels of ovariectomized (OVXed) rats sacrificed and assayed simultaneously. OT immunoreactive levels in the PVN and SON are significantly elevated in late pregnancy and PP. OT content of the ACN is elevated on day 16, but drops to control levels by day 22 of pregnancy and day 1 PP. Concomitant with the falling OT content in the ACN at the end of pregnancy, samples from the ventral septum have significantly increased OT content on day 1 PP. In extracts including the nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (dMX) OT is also elevated on the day after parturition. AVP levels peak on the day before parturition in all hypothalamic nuclei examined. These increases are significantly greater than in OVXed controls in the PVN and SON. AVP levels in the lateral habenula are elevated both on day 16 of pregnancy and on the first day PP. From these data we conclude that nonapeptide levels are altered across late pregnancy and early postpartum in some hypothalamic synthesis sites and in certain limbic and brainstem sites. We also postulate that OT is transported out of the ACN to extrahypothalamic sites around the time of parturition.

Immunohistochemical localization of oxytocin receptors in human brain

The neuropeptide oxytocin (OT) regulates rodent, primate and human social behaviors and stress responses. OT binding studies employing (125)I-d(CH2)5-[Tyr(Me)2,Thr4,Tyr-NH2(9)] ornithine vasotocin ((125)I-OTA), has been used to locate and quantify OT receptors (OTRs) in numerous areas of the rat brain. This ligand has also been applied to locating OTRs in the human brain. The results of the latter studies, however, have been brought into question because of subsequent evidence that (125)I-OTA is much less selective for OTR vs. vasopressin receptors in the primate brain. Previously we used a monoclonal antibody directed toward a region of the human OTR to demonstrate selective immunostaining of cell bodies and fibers in the preoptic-anterior hypothalamic area and ventral septum of a cynomolgus monkey (Boccia et al., 2001). The present study employed the same monoclonal antibody to study the location of OTRs in tissue blocks containing cortical, limbic and brainstem areas dissected from fixed adult, human female brains. OTRs were visualized in discrete cell bodies and/or fibers in the central and basolateral regions of the amygdala, medial preoptic area (MPOA), anterior and ventromedial hypothalamus, olfactory nucleus, vertical limb of the diagonal band, ventrolateral septum, anterior cingulate and hypoglossal and solitary nuclei. OTR staining was not observed in the hippocampus (including CA2 and CA3), parietal cortex, raphe nucleus, nucleus ambiguus or pons. These results suggest that there are some similarities, but also important differences, in the locations of OTRs in human and rodent brains. Immunohistochemistry (IHC) utilizing a monoclonal antibody provides specific localization of OTRs in the human brain and thereby provides opportunity to further study OTR in human development and psychiatric conditions.

Oxytocin potently enhances novelty-induced grooming behavior in the rat

Intracerebroventricular (i.c.v.) injection of oxytocin was followed by an enhancement of novelty-induced grooming in male and female rats. This effect was dose-dependent, in a dose range of 0.1-10 micrograms. Grooming activity of rats injected i.c.v. with 10 micrograms of oxytocin was 9-fold higher than that of saline-injected controls. The analysis of behavioral element composition revealed an increased occurrence of genital grooming in oxytocin-injected rats. A time-course study revealed a sustained increase in grooming activity of oxytocin-treated rats during 45 min of behavioral testing. Intraperitoneal (i.p.) injection of the dopamine antagonist, haloperidol, totally suppressed oxytocin-enhanced grooming. Furthermore, i.p. injection of the opiate receptor antagonist, naloxone, was followed by an attenuation but not a suppression of grooming enhanced by i.c.v. administration of oxytocin. In addition, a small but significant increase in grooming activity was observed after subcutaneous injection of oxytocin. These results suggest that oxytocin-enhanced grooming behavior involves central mechanisms, e.g. dopamine and opioid transmission in the brain.