- Email: [email protected]
Oxytocin inhibits infanticide in female house mice (Mus domesticus)
HORMONES
AND
BEHAVIOR
24,
365-375 (1990)
Oxytocin Inhibits infanticide in Female House Mice (Mm domesticus) MARGARET Institute
of Animal
Behavior,
M. MCCARTHY’
Rutgers-The State University Street, Newark, NJ 07102
of New
Jersey,
101 Warren
Between 60 and 90% of female house mice spontaneously kill unrelated young. A previous report indicated that subcutaneous administration of oxytocin significantly reduced the frequency of infanticide by virgin and pregnant females. However, in this study a distinction could not be made between an action of oxytocin on the CNS versus a secondary effect such as an enhanced release of prolactin by oxytocin. In the current experiment, oxytocin administered intracerebroventricularly was equally as effective at inhibiting infanticide as SC oxytocin. There was no difference in the effectiveness of oxytocin between groups of infanticidal females that were gonadally intact, ovariectomized, or estrogen treated. Pretreatment of infanticidal females with the prolactin inhibitors, bromocriptine and cysteamine, was also without effect on the ability of oxytocin to inhibit infanticide. Last, prolactin-inhibiting drugs had no significant effect on spontaneous parenting behavior by female mice. These data suggest that oxytocin acts directly on the CNS to alter behavior toward pups and that prolactin may not play a role in the maternal behavior of the house mouse. o IWO Academic Press. Inc.
Infanticidal behavior by rodents is now accepted by many as an evolutionarily adaptive response (see Hausfater, Blaffer, and Hrdy, 1984). Between 60 and 90% of virgin male and female wild house mice spontaneously kill unrelated young (Jakubowski and Terkel, 1982; McCarthy and vom Saal, 1986a,b). Wild female house mice bred in the lab continue to kill young after ovariectomy or adrenalectomy (McCarthy, Bare and vom Saal, 1986) and during late pregnancy (McCarthy and vom Saal, 1985) but exhibit normal maternal behavior after parturition. Gonadally intact infanticidal females exhibit a significant reduction in killing behavior after subcutaneous administration of the neurohormone, oxytocin (McCarthy et al., 1986). Centrally acting oxytocin can induce a shortlatency onset of maternal behavior in some strains of rats and under some conditions (Pedersen, Ascher, Monroe, and Prange, 1982; Fahr’ Present address: The Rockefeller University, 1230 York Avenue, New York, NY 10021. 365 OOlS-506XBO $1.50 Copyright 0 I!990 by Academic Press, Inc. All rights of reproduction in any form reserved.
366
MARGARET
M.
MCCARTHY
bath, Morrell, and Pfaff, 1984) but not others (Rubin, Menniti, and Bridges, 1983; Bolwerk and Swanson, 1984; Wamboldt and Insel, 1987), and prior treatment with estrogen is required in order for oxytocin to influence maternal behavior in the rat (Fahrbach et al., 1984). The current experiments were designed to determine (1) if oxytocin inhibits infanticide in female mice by acting peripherally or on the central nervous system, (2) if estrogen treatment affects oxytocin-induced inhibition of infanticide, and (3) since oxytocin enhances release of prolactin (Samson, Lumpkin, and McCann, 1986; Arey and Freeman, 1989), if oxytocin may be influencing infanticidal behavior via an effect on prolactin. Prolactin has been implicated in the control of maternal behavior in the mouse (Voci and Carlson, 1973) and rat (Bridges, DiBiase, Loundes, and Doherty, 1984; Bridges and Dunckel, 1987). METHODS Wild house mice (Mus domesticus) bred in the laboratory for several generations provided the F2-F6 offspring utilized in this study. Additional animals consisted of the offspring produced by matings between wild mice and Swiss Webster mice (CAMM Labs; Wayne, NJ) and the offspring of back-crosses of these hybrids to wild mice. These hybrid crosses resulted in animals with genetic makeups that were 50-75% wild and they were distributed randomly throughout the experimental groups. All animals were pretested for either infanticidal or parental behavior before being used in specific experiments so that there could be no bias in baseline behavior between groups. Matings consisted of a single male and female mouse paired in a polyethylene cage (18 x 29 x 13 cm) with pine shavings in a room maintained at 23°C. The 1ight:dark cycle was lo:14 with lights on at 0800 hr. Purina lab chow and water were available ad lib. Subjects were isolated 1 to 2 days prior to the experiment when they were 75 to 90 days of age. Behavioral testing consisted of placing a lto 3-day-old pup in the corner of the cage and leaving the animals undisturbed for 30 min. After this time the response of the subject was scored as INFANTICIDAL if the pup was found dead or wounded (woundings were rare), PARENT if the pup was found warm and in a nest, and IGNORE if the pup was cold and not in a nest. Care was taken to avoid undue suffering by the pups by keeping the testing period as short as possible and keeping sample sizes low. All animals were pretested for their response to pups and only infanticidal females were used for experiments, with the exception of Experiment 4 in which only parental females were used. All drugs and hormones were purchased from Sigma Chemical Co. (St. Louis, MO).
OXYTOCIN
INHIBITS
INFANTICIDE
367
Experiment 1: Zn.uence of endocrine state on the effect of SC oxytocin. Females were either left gonadally intact or ovariectomized under Metofane anesthesia. Intact animals received oxytocin (7.6 IU = 15.2 pg, in 0.3 cc) or an equal volume of saline subcutaneously (SC). Ovariectomized females were left untreated or injected with SCestradiol benzoate (EB) in oil (10 pg/day for 2 days = short-term; 10 pg/day for 8 days = long-term). After treatment with estrogen and pretesting, infanticidal subjects received saline or oxytocin SC(7.6 IU in 0.3 cc) and were tested for response to pups 40 min postinjection. Experiment 2: Zntracerebroventricular (icv) administration of oxytocin. Gonadally intact females were pretested and infanticidal females were lightly anesthetized with Metofane before being restrained on an adapted rat stereotaxic apparatus. A 2-~1 injection into the lateral ventricle was made using a 25-~1 Hamilton syringe fitted with a 26-gauge stainless steel needle adjusted to approximately 3 mm in length. The injection was made through the skin and cranium and took about 10 sec. Subjects received saline or 0.02 IU (40 ng) oxytocin and both solutions contained india ink. Testing was conducted 20 min postinjection and the subjects exhibited no adverse effects from the anesthesia or the injection at this time. At the completion of the behavioral test, subjects were again anesthetized before being decapitated and the injection site was verified by the presence of the india ink in the ventricle. Sixty percent of the injections were correctly placed in the ventricle and only these animals were included in the analyses. Experiment 3: Effect of oxytocin after inhibition of prolactin. An additional group of infanticidal females was injected ip with the prolactin release inhibitor bromocriptine (0.5, 1.0, or 2.0 mg in 0.5 cc) or the prolactin inhibitor cysteamine (3.0 mg in 0.5 cc). Experimental subjects were then injected SC with oxytocin (7.6 IU) or saline 2.5 hr after bromocriptine and 1 hr after cysteamine. Cysteamine significantly suppresses blood prolactin levels in the mouse by 1 to 2 hr postinjection (Koch and Ehret, 1989; Millard, Sagar, Landis, Martin, and Badger, 1982) and depletes serum prolactin in the rat by 98% when assayed 4 hr after injection (Simpkins, Estes, Millard, Sagar, and Martin, 1983). Bromocriptine disrupts maternal behavior in the hamster 3 hr postinjection (Curran, McCarthy, and Siegel, 1989). Behavioral testing was conducted 40 min after the oxytocin treatment. Therefore, this injection schedule allowed sufficient time for prolactin levels to be suppressed at the time of oxytocin injection, and behavioral testing was conducted at the same time after oxytocin as in Experiment 1. Experiment 4: Effect of prolactin inhibition on parenting behavior. Females that were scored as PARENT on the pretest were injected ip with either bromocriptine (0.5 or 2.0 mg) or cysteamine (1.5, 6.0, or 12.0
368
MARGARET
M.
MCCARTHY
mg). The pup used in the original test remained in the cage with the subject and the response of the female was monitored over the next few hours and recorded at 5 hr postinjection. RESULTS
Experiment
1
Of the adult gonadally intact female mice pretested, 63% were found to be infanticidal (n = 16). Statistical comparison of the posttest response between groups indicates that there was a significant difference in the frequency of killing in the group receiving SC oxytocin as compared to saline-injected controls with fewer oxytocin-treated females exhibiting infanticide (P = 0.046; two-tailed Fisher exact probability, FEP, including correction for probabilities of 0 and 1 females killing). An additional group of ovariectomized females was pretested and 65% were found to be infanticidal. There was a significant difference in the frequency of killing by ovariectomized females after oxytocin injection (n = 11, 18% infanticidal) as compared to saline-injected controls (n = 10, 90% infanticidal, P = 0.026, two-tailed FEP). One hundred percent of ovariectomized females treated with EB (either 2 or 8 days) were infanticidal during the posttest but there was a significant reduction in killing after oxytocin injection (2 days EB; P = 0.026, n = 16; 8 days EB; P = 0.032, n = 9, two-tailed FEP). There was no difference in the degree of the reduction of killing after oxytocin between treatment groups (see Fig. 1). Experiment 2 Infanticidal females receiving icv oxytocin exhibited a significant reduction in the frequency of killing as compared to saline-infused controls (P = 0.034, two-tailed FEP, see Fig. 2). Females receiving icv oxytocin were observed to exhibit increased grooming behavior for approximately 10 min after injection and to move normally about the cage for the remainder of the test period. There were five oxytocin injections that were not into the lateral ventricle and all of these subjects exhibited infanticide postinjection. Experiment 3 Infanticidal females treated with either 1.0 or 2.0 mg bromocriptine were predominantly (80%) scored as IGNORE upon posttesting. This decrease in killing behavior is more likely related to a decrease in motor activity by interference with dopaminergic transmission (Wegener, Schmidt, and Ehret, 1988) rather than an inhibition of infanticide per se. The range of bromocriptine doses chosen was based on the observation that 1.0 mg bromocriptine produced a severe disruption of maternal
OXYTOCIN
Intact Saline (11)
ht&+ Oxytocitl (11)
INHIBITS
Chwiectomized + Oxybxin (11)
369
INFANTICIDE
EETreated + Saline (10
Short-Term ES + Oxytocin
(W
Long-Term EB + Oxytccln (9)
FIG. 1. Influence of endocrine state on the effect of SCoxytocin. Previously infanticidal females exhibited significantly reduced frequency of killing behavior when tested 40 min postinjection (two-tailed Fischer exact probability (n); *P < 0.05). The EB-treated + saline group includes short-term (5) and long-term (5) EB. There was no difference in the effectiveness of oxytocin between groups of females that were gonadally intact, ovariectomized, or estrogen treated.
behavior in the recently parturient hamster 3-5 hr postinjection (Curran et al., 1989). Of the females treated with 0.5 mg bromocriptine, 43% continued to kill postinjection. An additional group of females receiving 0.5 mg bromocriptine followed 2 hr later by oxytocin exhibited an increase in parenting behavior as compared to those receiving only 0.5 mg bromocriptine but this difference was not significant (x2(2) = 5.22). A separate group of infanticidal females was given 3.0 mg cysteamine ip and injected SCwith oxytocin or saline 1 hr later. This dose of cysteamine has been reported to significantly reduce prolactin plasma levels in laboratory mice within 1 hr and it does not interfere with the dopamine system (Millard et al., 1982). There was a significant reduction in the frequency of infanticide and an increase in parenting behavior in the cysteamine-treated group receiving oxytocin as compared to saline controls (x*(2) = 7.25; P < 0.05, see Fig. 3). Experiment 4 Females scored as PARENT received either 0.5 or 2.0 mg bromocriptine ip or 1.5, 6.0, or 12 mg cysteamine. There was no significant
370
MARGARET Cl Parent q
M. MCCARTHY Ignore n lnfanticidal
Vehiie Oxyttin (11) (9) FIG. 2. Intracerebroventricular administration of oxytocin. Previously infanticidal females received oxytocin or saline ICV and were tested 20 min postinjection. There was a significant reduction in the frequency of killing behavior in females receiving oxytocin as compared to those receiving saline (FEP (n); *P = 0.034).
effect of any dose of these prolactin-inhibiting havior up to 5 hr postinjection (see Fig. 4).
drugs on parenting
be-
DISCUSSION Intracerebroventricular administration of oxytocin has been reported to induce short-latency maternal behavior in estrogen-treated rats (Pedersen et al., 1982; Fahrbach et al., 1984) and sheep (Kendrick, Keverne, and Baldwin, 1987). It has been previously reported that oxytocin inhibits infanticide and increases parenting behavior by virgin and pregnant house mice (McCarthy et al., 1986). However, in this study oxytocin was administered peripherally (SC) and although oxytocin can cross the bloodbrain barrier (Mens, Witter, and Van Wimersma Greidanus, 1983), it is not possible to assess whether the behavioral change was due to oxytocin acting on the CNS or the result of secondary effects of oxytocin. In particular, oxytocin can enhance prolactin release from the pituitary (Samson et al., 1986; Arey and Freeman, 1989) and prolactin has been implicated in the control of maternal behavior in mice (Voci and Carlson, 1973) and rats (Bridges et al., 1984). The results reported here indicate that oxytocin acts directly on the CNS to inhibit infanticide and in some instances stimulates maternal
OXYTOCIN 0
Pamnt
0
Ignore
INHIBITS
371
INFANTICIDE
w hlfanncidal
20 10 C Bmfro3iptine l Saline
(74)
Bmmocriptine + Oxybcin WY
Cysteamine + Saline (11)
Cysteamine + Oxytow (10)
3. Effect of oxytocin after inhibition of prolactin. Previously infanticidal females were pretreated with the prolactin inhibitors bromocriptine (0.5 mg) or cysteamine (3 mg) prior to injection with oxytocin or saline. Oxytocin resulted in a significant reduction in the frequency of infanticide in females pretreated with cysteamine as compared to those receiving saline (x’(2) = 7.25, *P < 0.05). FIG.
behavior in the female house mouse. The ability of oxytocin to alter the response to pups does not seem to depend on high levels of prolactin, and spontaneous maternal behavior is not affected by drugs which inhibit prolactin. Prolactin has been reported to alter pup retrieval by the mouse in one study (Voci and Carlson, 1973) but not in another (Koch and Ehret, 1989). Prolactin injections or elevation of prolactin by implantation of ectopic pituitaries decreases the latency to exhibit maternal behavior in the steroid-primed rat (Bridges et al., 1984; Bridges and Dunckel, 1987) and injections of the prolactin-release blocker, bromocriptine, disrupt maternal behavior in the recently parturient hamster (Cut-ran et al., 1989). In the gerbil, increasing plasma levels of prolactin are correlated with an inhibition of infanticide by the male and may be related to the mating-induced inhibition of infanticide in this species (Elwood, 1986). Although not conclusive, the current data support the hypothesis that prolactin is not involved in the regulation of infanticide in female house mice since prior treatment with prolactin-inhibiting drugs had no effect on the oxytocin-induced inhibition of infanticide and no effect on the behavior of spontaneously maternal females.
372
MARGARET
BromMimna 0.5 m g Is)
mw?locriptina 2.0 rng (51
M. MCCARTHY
Cyateamire 1.5mg
Cysteamine 6.0 mg
llol
Ilo/
Cysleamine 12.0 m g m
FIG. 4. Effect of prolactin inhibition on parenting behavior. Previously parental females received varying doses of bromocriptine or cysteamine and remained with the pup. There was no significant effect of drug treatment on spontaneous parenting up to 5 hr postinjection.
Since a high percentage of oxytocin-treated females were scored as IGNORE on the posttest, it could be speculated that oxytocin induces behaviors that are inconsistent with infanticide and thereby inhibits killing behavior indirectly. Previously infanticidal females that received oxytocin icv exhibited increased grooming behavior for approximately 10 min postinjection and moved normally about the cage for the remainder of the test period. In addition, some oxytocin-treated females in this study (Experiment 3) and in a previous study (McCarthy et al., 1986) exhibited a marked increase in parenting behavior which involves the active retrieval of the pup to a nest. Therefore, it does not appear that the effects of oxytocin on infanticide are indirectly due to effects on competing behavioral responses. Oxytocin is synthesized in the hypothalamus and released into the periphery from the posterior pituitary in response to suckling and vaginocervical stimulation (Higuchi, Honda, Fukuoka, Negoro, and Wakabayashi, 1985). In addition, there is a widespread distribution of oxytocin-containing neurons within the brain where it is believed to function as a neurotransmitter (Palkovits, 1984). The concentration of oxytocin and its receptor in the CNS are responsive to circulating steroid levels (Greer, Caldwell, Johnson, Prange, and Pedersen, 1986; de Kloet, Voorhuis, Boschma, and Elands, 1986) and physiological levels of estrogen result in a marked enhancement of oxytocin-receptor binding in the
OXYTOCIN
INHIBITS
INFANTICIDE
373
ventromedial nucleus of the hypothalamus in female rats (Johnson, Corini, Ball, and McEwen, 1989). Oxytocin only successfully induces maternal behavior in rats when they are pretreated with estrogen (Pedersen et al., 1982; Fahrbach et al., 1984). In the present experiment, the endocrine state of the female mouse appeared to have no effect on the ability of oxytocin to inhibit infanticide. There was no significant difference between groups of females that were gonadally intact, ovariectomized, or ovariectomized and estrogen-treated in terms of the behavioral response after oxytocin. This finding can be interpreted as indicating that, (1) a sufficient concentration of oxytocin receptor exists at all times to allow for exogenously administered oxytocin to alter behavior, (2) oxytocin receptors in the CNS of the wild house mouse are not dependent on estrogen, or (3) the doses of oxytocin and estrogen used in this study were not appropriate to reveal a hormone effect on oxytocin-induced inhibition of infanticide. None of these possibilities can be excluded at this time. Nonetheless, the fact that no influence of the endocrine state on the effects of oxytocin could be found in this study does not necessarily imply the lack of a physiologically relevant role for oxytocin in this species. In contrast to males, female wild house mice are particularly impervious to the effects of experience on subsequent infanticide. Male house mice exhibit significantly less infanticide after sexual experience (vom Saal and Howard, 1982, McCarthy and vom Saal, 1986a), cohabitation with a pregnant female (Huck, Soltis, and Coopersmith, 1982; Elwood, 1986), rearing young (Soroker and Terkel, 1988), exposure to young as a juvenile (McCarthy, 1990), and castration (Gandelman and vom Saal, 1975). Female house mice, on the other hand, continue to exhibit infanticide after all these experiences (see McCarthy, 1990) and in fact are most likely to be infanticidal during late pregnancy (McCarthy and vom Saal, 1985). Thus it appears that the only time that female house mice are maternal is when they have delivered their own young, and it is possible that the neuroendocrine event which regulates this change in behavior is the release of oxytocin at parturition and during suckling. Restricting the neural “signal” which turns off infanticidal behavior in female mice to a very discrete event may be an inherently adaptive aspect of this behavior and oxytocin may serve as that signal. Last, an important aspect of the current study is that it involves a change from infanticidal to maternal behavior. Clearly these responses are mutually exclusive yet related. Although oxytocin consistently inhibited infanticidal behavior, it did not always induce maternal behavior. This finding can be taken as evidence for separate mechanisms regulating each response. What precise hormonal and neural factors influence the response of a female mouse toward pups remains to be determined.
374
MARGARET
M. MCCARTHY
ACKNOWLEDGMENTS The author thanks Dr. Sarah Lennington for provision of wild mice and lab space. Helpful comments on the manuscript were contributed by Carol Coopersmith and Dr. Harold Siegel. This is publication 513 from the Institute of Animal Behavior.
REFERENCES Arey, B. J., and Freeman, M. E. (1989). Hypothalamic factors involved in the endogenous stimulatory rhythm regulating prolactin secretion. Endocrinology 124, 878-883. Bolwerk, E. L. M., and Swanson, H. H. (1984). Does oxytocin play a role in the onset of maternal behavior in the rat? J. Endocrinol 101, 353-357. Bridges, R. S., DiBiase, R., Loundes, D. D., and Doherty, P. C. (1984). Prolactin stimulation of maternal behavior in female rats. Science 227, 782-784. Bridges, R. S., and Dunckel, P. T. (1987). Hormonal regulation of maternal behavior in rats: Stimulation following treatment with ectopic pituitary grafts plus progesterone. Biol. Reprod. 37, 518-526. Curran, G., McCarthy, M. M., and Siegel, H. I. (1989). Disruption of maternal behavior in the hamster by a prolactin release inhibitor. 19th Conference on Reproductive Behavior. Saratoga Springs, NY. de Kloet, E. R., Voorhuis, D. A. M., Boschma, Y., and Elands, J. (1986). Estradiol modulates density of putative ‘oxytocin receptors’ in discrete rat brain regions. Neuroendocrinology 44, 415-421. Elwood, R. W. (1986). What makes male mice paternal? Behav. Neural Biol. 46, 54-63. Fahrbach, S. E., Morrell, J. I., and Pfaff, D. W. (1984). Oxytocin induction of shortlatency maternal behavior in nulliparous, estrogen-primed female rats. Horm. B&w. 18, 267-286.
Gandelman, R., and vom Saal, F. S. (1975). Pup-killing in mice: The effects of gonadectomy and testosterone administration. Physiol. Behav. 15, 647-651. Greer, E. R., Caldwell, J. D., Johnson, M. F., Prange, A. J., and Pedersen, C. A. (1986). Variations in concentration of oxytocin and vasopressin in the paraventricular nucleus of the hypothalamus during the estrous cycle in rats. Life Sci. 38, 2311-2318. Hausfater, G., and Blaffer Hrdy, S., Eds. (1984). Infanticide: Comparative and Evolutionary Aspects. Aldine, New York. Higuschi, T., Honda, K., Fukuoka, T., Negoro, H., and Wakabayashi, K. (1985). Release of oxytocin during suckling and parturition in the rat. J. Endocrinol. 105, 339-346. Huck, U. W., Soltis, R. L., and Coopersmith, C. B. (1982). Infanticide in male laboratory mice: Effects of social status, prior sexual experience, and basis for discrimination between related and unrelated young. Anim. Behav. 30, 1158-l 165. Jakubowski, M., and Terkel, J. (1982). Infanticide and caretaking in non-lactating Mus musculus: Influence of genotype, family groups and sex. Anim. Behav. 30, 1029-1035. Johnson, A. E., Corini, H., Ball, G. F., and McEwen, B. S. (1989). Anatomical localization of the effects of 17/3-estradiol on oxytocin receptor binding in the ventromedial hypothalamic nucleus. Endocrinology 124, 207-211. Kendrick, K. M., Keveme, E. B., and Baldwin, B. A. (1987). Intracerebroventricular oxytocin stimulates maternal behaviour in the sheep. Neuroendocrinology 46, 56-61. Koch, M., and Ehret, G. (1989). Estradiol and parental experience, but not prolactin are necessary for ultrasound recognition and pup-retrieving in the mouse. Physiol. Eehav. 45, 771-776. McCarthy, M. M. (1990). Short-term early exposure to pups alters infanticide in adulthood in male but not in female wild house mice (Mus domesticus). J. Comp. Psychok 104, 195-197.
OXYTOCIN
INHIBITS
INFANTICIDE
375
McCarthy, M. M., and vom Saal, F. S. (1985). The influence of reproductive state on infanticide by wild female house mice (Mus musculus). Physiol. Behav. 35, 843-849. McCarthy, M. M., and vom Saal, F. S. (1986a). Inhibition of infanticide after mating by wild male house mice. Physiul. Behav. 36, 203-209. McCarthy, M. M., and vom Saal, F. S. (1986b). Infanticide by virgin CF-1 and wild male house mice (MUS musculus): Effects of age, prolonged isolation and testing procedure. Dev.
Psychobiol.
19, 279-290.
McCarthy, M. M., Bare, J. E., and vom Saal, F. S. (1986). Infanticide and parental behavior in wild female house mice: Effects of ovariectomy, adrenalectomy and administration of oxytocin and prostaglandin F,a. Physiol. Behav. 36, 17-23. Mens, W. B. J., Witter, A., and Van Wimersma Greidanus, T. B. (1983). Penetration of neurohypophyseal hormones from plasma into cerebrospinal fluid (CSF): Half-times of disappearance of these neuropeptides from CSF. Brain Res. 262, 143-149. Millard, W. J., Sagar, S. M., Landis, D. M. D., Martin, J. B., and Badger, T. M. (1982). Cysteamine: A potent and specific depletor of pituitary prolactin. Science 217, 452. Palkovits, M. (1984). Distribution of neuropeptides in the central nervous system: A review of biochemical mapping studies. Prog. Neurobiol. 23, 157-189. Pedersen, C. A., Ascher, J. A., Monroe, Y. L., and Prange, A. J., Jr. (1982). Oxytocin induces maternal behavior in virgin female rats. Science 216, 648-650. Rubin, B. S., Menniti, F. S., and Bridges, R. S. (1983). Intracerebroventricular administration of oxytocin and maternal behavior in rats after prolonged and acute steroid pretreatment. Horm. Behav. 17, 45-53. Samson, W. K., Lumpkin, M. D., and McCann, S. M. (1986). Evidence for a physiological role for oxytocin in the control of prolactin secretion. Endocrinology 119, 554-560. Simpkins, J. W., Estes, K. S., Millard, W. J., Sagar, S. M., and Martin, J. B. (1983). Cysteamine depletes prolactin in young and old hyperprolactinemic rats. Endocrino/ogy 112, 1889-1891. Soroker, V., and Terkel, J. (1988). Changes in incidence of infanticidal and parental responses during the reproductive cycle in male and female wild mice Mus muscu/us. Anim. Behav. 36, 1275-1281. Voci, V. E., and Carlson, N. R. (1973). Enhancement of maternal behavior and nest building following systemic and diencephalic administration of prolactin and progesterone in the mouse. J. Camp. Physiol. Psych& 83, 388-393. vom Saal, F. S., and Howard, L. (1982). The regulation of infanticide and parental behavior: Implications for reproductive success in male mice. Science 215, 1270-1272. Wamboldt, M. Z., and Insel, T. R. (1987). The ability of oxytocin to induce short-latency maternal behavior is dependent on peripheral anosmia. Behav. Neurosci. 101, 439441. Wegener, S., Schmidt, W. S., and Ehret, G. (1988). Haloperidol and apomorphine induced changes in pup searching behaviour of house mice. Psychopharmacology 95271-275.
AND
BEHAVIOR
24,
365-375 (1990)
Oxytocin Inhibits infanticide in Female House Mice (Mm domesticus) MARGARET Institute
of Animal
Behavior,
M. MCCARTHY’
Rutgers-The State University Street, Newark, NJ 07102
of New
Jersey,
101 Warren
Between 60 and 90% of female house mice spontaneously kill unrelated young. A previous report indicated that subcutaneous administration of oxytocin significantly reduced the frequency of infanticide by virgin and pregnant females. However, in this study a distinction could not be made between an action of oxytocin on the CNS versus a secondary effect such as an enhanced release of prolactin by oxytocin. In the current experiment, oxytocin administered intracerebroventricularly was equally as effective at inhibiting infanticide as SC oxytocin. There was no difference in the effectiveness of oxytocin between groups of infanticidal females that were gonadally intact, ovariectomized, or estrogen treated. Pretreatment of infanticidal females with the prolactin inhibitors, bromocriptine and cysteamine, was also without effect on the ability of oxytocin to inhibit infanticide. Last, prolactin-inhibiting drugs had no significant effect on spontaneous parenting behavior by female mice. These data suggest that oxytocin acts directly on the CNS to alter behavior toward pups and that prolactin may not play a role in the maternal behavior of the house mouse. o IWO Academic Press. Inc.
Infanticidal behavior by rodents is now accepted by many as an evolutionarily adaptive response (see Hausfater, Blaffer, and Hrdy, 1984). Between 60 and 90% of virgin male and female wild house mice spontaneously kill unrelated young (Jakubowski and Terkel, 1982; McCarthy and vom Saal, 1986a,b). Wild female house mice bred in the lab continue to kill young after ovariectomy or adrenalectomy (McCarthy, Bare and vom Saal, 1986) and during late pregnancy (McCarthy and vom Saal, 1985) but exhibit normal maternal behavior after parturition. Gonadally intact infanticidal females exhibit a significant reduction in killing behavior after subcutaneous administration of the neurohormone, oxytocin (McCarthy et al., 1986). Centrally acting oxytocin can induce a shortlatency onset of maternal behavior in some strains of rats and under some conditions (Pedersen, Ascher, Monroe, and Prange, 1982; Fahr’ Present address: The Rockefeller University, 1230 York Avenue, New York, NY 10021. 365 OOlS-506XBO $1.50 Copyright 0 I!990 by Academic Press, Inc. All rights of reproduction in any form reserved.
366
MARGARET
M.
MCCARTHY
bath, Morrell, and Pfaff, 1984) but not others (Rubin, Menniti, and Bridges, 1983; Bolwerk and Swanson, 1984; Wamboldt and Insel, 1987), and prior treatment with estrogen is required in order for oxytocin to influence maternal behavior in the rat (Fahrbach et al., 1984). The current experiments were designed to determine (1) if oxytocin inhibits infanticide in female mice by acting peripherally or on the central nervous system, (2) if estrogen treatment affects oxytocin-induced inhibition of infanticide, and (3) since oxytocin enhances release of prolactin (Samson, Lumpkin, and McCann, 1986; Arey and Freeman, 1989), if oxytocin may be influencing infanticidal behavior via an effect on prolactin. Prolactin has been implicated in the control of maternal behavior in the mouse (Voci and Carlson, 1973) and rat (Bridges, DiBiase, Loundes, and Doherty, 1984; Bridges and Dunckel, 1987). METHODS Wild house mice (Mus domesticus) bred in the laboratory for several generations provided the F2-F6 offspring utilized in this study. Additional animals consisted of the offspring produced by matings between wild mice and Swiss Webster mice (CAMM Labs; Wayne, NJ) and the offspring of back-crosses of these hybrids to wild mice. These hybrid crosses resulted in animals with genetic makeups that were 50-75% wild and they were distributed randomly throughout the experimental groups. All animals were pretested for either infanticidal or parental behavior before being used in specific experiments so that there could be no bias in baseline behavior between groups. Matings consisted of a single male and female mouse paired in a polyethylene cage (18 x 29 x 13 cm) with pine shavings in a room maintained at 23°C. The 1ight:dark cycle was lo:14 with lights on at 0800 hr. Purina lab chow and water were available ad lib. Subjects were isolated 1 to 2 days prior to the experiment when they were 75 to 90 days of age. Behavioral testing consisted of placing a lto 3-day-old pup in the corner of the cage and leaving the animals undisturbed for 30 min. After this time the response of the subject was scored as INFANTICIDAL if the pup was found dead or wounded (woundings were rare), PARENT if the pup was found warm and in a nest, and IGNORE if the pup was cold and not in a nest. Care was taken to avoid undue suffering by the pups by keeping the testing period as short as possible and keeping sample sizes low. All animals were pretested for their response to pups and only infanticidal females were used for experiments, with the exception of Experiment 4 in which only parental females were used. All drugs and hormones were purchased from Sigma Chemical Co. (St. Louis, MO).
OXYTOCIN
INHIBITS
INFANTICIDE
367
Experiment 1: Zn.uence of endocrine state on the effect of SC oxytocin. Females were either left gonadally intact or ovariectomized under Metofane anesthesia. Intact animals received oxytocin (7.6 IU = 15.2 pg, in 0.3 cc) or an equal volume of saline subcutaneously (SC). Ovariectomized females were left untreated or injected with SCestradiol benzoate (EB) in oil (10 pg/day for 2 days = short-term; 10 pg/day for 8 days = long-term). After treatment with estrogen and pretesting, infanticidal subjects received saline or oxytocin SC(7.6 IU in 0.3 cc) and were tested for response to pups 40 min postinjection. Experiment 2: Zntracerebroventricular (icv) administration of oxytocin. Gonadally intact females were pretested and infanticidal females were lightly anesthetized with Metofane before being restrained on an adapted rat stereotaxic apparatus. A 2-~1 injection into the lateral ventricle was made using a 25-~1 Hamilton syringe fitted with a 26-gauge stainless steel needle adjusted to approximately 3 mm in length. The injection was made through the skin and cranium and took about 10 sec. Subjects received saline or 0.02 IU (40 ng) oxytocin and both solutions contained india ink. Testing was conducted 20 min postinjection and the subjects exhibited no adverse effects from the anesthesia or the injection at this time. At the completion of the behavioral test, subjects were again anesthetized before being decapitated and the injection site was verified by the presence of the india ink in the ventricle. Sixty percent of the injections were correctly placed in the ventricle and only these animals were included in the analyses. Experiment 3: Effect of oxytocin after inhibition of prolactin. An additional group of infanticidal females was injected ip with the prolactin release inhibitor bromocriptine (0.5, 1.0, or 2.0 mg in 0.5 cc) or the prolactin inhibitor cysteamine (3.0 mg in 0.5 cc). Experimental subjects were then injected SC with oxytocin (7.6 IU) or saline 2.5 hr after bromocriptine and 1 hr after cysteamine. Cysteamine significantly suppresses blood prolactin levels in the mouse by 1 to 2 hr postinjection (Koch and Ehret, 1989; Millard, Sagar, Landis, Martin, and Badger, 1982) and depletes serum prolactin in the rat by 98% when assayed 4 hr after injection (Simpkins, Estes, Millard, Sagar, and Martin, 1983). Bromocriptine disrupts maternal behavior in the hamster 3 hr postinjection (Curran, McCarthy, and Siegel, 1989). Behavioral testing was conducted 40 min after the oxytocin treatment. Therefore, this injection schedule allowed sufficient time for prolactin levels to be suppressed at the time of oxytocin injection, and behavioral testing was conducted at the same time after oxytocin as in Experiment 1. Experiment 4: Effect of prolactin inhibition on parenting behavior. Females that were scored as PARENT on the pretest were injected ip with either bromocriptine (0.5 or 2.0 mg) or cysteamine (1.5, 6.0, or 12.0
368
MARGARET
M.
MCCARTHY
mg). The pup used in the original test remained in the cage with the subject and the response of the female was monitored over the next few hours and recorded at 5 hr postinjection. RESULTS
Experiment
1
Of the adult gonadally intact female mice pretested, 63% were found to be infanticidal (n = 16). Statistical comparison of the posttest response between groups indicates that there was a significant difference in the frequency of killing in the group receiving SC oxytocin as compared to saline-injected controls with fewer oxytocin-treated females exhibiting infanticide (P = 0.046; two-tailed Fisher exact probability, FEP, including correction for probabilities of 0 and 1 females killing). An additional group of ovariectomized females was pretested and 65% were found to be infanticidal. There was a significant difference in the frequency of killing by ovariectomized females after oxytocin injection (n = 11, 18% infanticidal) as compared to saline-injected controls (n = 10, 90% infanticidal, P = 0.026, two-tailed FEP). One hundred percent of ovariectomized females treated with EB (either 2 or 8 days) were infanticidal during the posttest but there was a significant reduction in killing after oxytocin injection (2 days EB; P = 0.026, n = 16; 8 days EB; P = 0.032, n = 9, two-tailed FEP). There was no difference in the degree of the reduction of killing after oxytocin between treatment groups (see Fig. 1). Experiment 2 Infanticidal females receiving icv oxytocin exhibited a significant reduction in the frequency of killing as compared to saline-infused controls (P = 0.034, two-tailed FEP, see Fig. 2). Females receiving icv oxytocin were observed to exhibit increased grooming behavior for approximately 10 min after injection and to move normally about the cage for the remainder of the test period. There were five oxytocin injections that were not into the lateral ventricle and all of these subjects exhibited infanticide postinjection. Experiment 3 Infanticidal females treated with either 1.0 or 2.0 mg bromocriptine were predominantly (80%) scored as IGNORE upon posttesting. This decrease in killing behavior is more likely related to a decrease in motor activity by interference with dopaminergic transmission (Wegener, Schmidt, and Ehret, 1988) rather than an inhibition of infanticide per se. The range of bromocriptine doses chosen was based on the observation that 1.0 mg bromocriptine produced a severe disruption of maternal
OXYTOCIN
Intact Saline (11)
ht&+ Oxytocitl (11)
INHIBITS
Chwiectomized + Oxybxin (11)
369
INFANTICIDE
EETreated + Saline (10
Short-Term ES + Oxytocin
(W
Long-Term EB + Oxytccln (9)
FIG. 1. Influence of endocrine state on the effect of SCoxytocin. Previously infanticidal females exhibited significantly reduced frequency of killing behavior when tested 40 min postinjection (two-tailed Fischer exact probability (n); *P < 0.05). The EB-treated + saline group includes short-term (5) and long-term (5) EB. There was no difference in the effectiveness of oxytocin between groups of females that were gonadally intact, ovariectomized, or estrogen treated.
behavior in the recently parturient hamster 3-5 hr postinjection (Curran et al., 1989). Of the females treated with 0.5 mg bromocriptine, 43% continued to kill postinjection. An additional group of females receiving 0.5 mg bromocriptine followed 2 hr later by oxytocin exhibited an increase in parenting behavior as compared to those receiving only 0.5 mg bromocriptine but this difference was not significant (x2(2) = 5.22). A separate group of infanticidal females was given 3.0 mg cysteamine ip and injected SCwith oxytocin or saline 1 hr later. This dose of cysteamine has been reported to significantly reduce prolactin plasma levels in laboratory mice within 1 hr and it does not interfere with the dopamine system (Millard et al., 1982). There was a significant reduction in the frequency of infanticide and an increase in parenting behavior in the cysteamine-treated group receiving oxytocin as compared to saline controls (x*(2) = 7.25; P < 0.05, see Fig. 3). Experiment 4 Females scored as PARENT received either 0.5 or 2.0 mg bromocriptine ip or 1.5, 6.0, or 12 mg cysteamine. There was no significant
370
MARGARET Cl Parent q
M. MCCARTHY Ignore n lnfanticidal
Vehiie Oxyttin (11) (9) FIG. 2. Intracerebroventricular administration of oxytocin. Previously infanticidal females received oxytocin or saline ICV and were tested 20 min postinjection. There was a significant reduction in the frequency of killing behavior in females receiving oxytocin as compared to those receiving saline (FEP (n); *P = 0.034).
effect of any dose of these prolactin-inhibiting havior up to 5 hr postinjection (see Fig. 4).
drugs on parenting
be-
DISCUSSION Intracerebroventricular administration of oxytocin has been reported to induce short-latency maternal behavior in estrogen-treated rats (Pedersen et al., 1982; Fahrbach et al., 1984) and sheep (Kendrick, Keverne, and Baldwin, 1987). It has been previously reported that oxytocin inhibits infanticide and increases parenting behavior by virgin and pregnant house mice (McCarthy et al., 1986). However, in this study oxytocin was administered peripherally (SC) and although oxytocin can cross the bloodbrain barrier (Mens, Witter, and Van Wimersma Greidanus, 1983), it is not possible to assess whether the behavioral change was due to oxytocin acting on the CNS or the result of secondary effects of oxytocin. In particular, oxytocin can enhance prolactin release from the pituitary (Samson et al., 1986; Arey and Freeman, 1989) and prolactin has been implicated in the control of maternal behavior in mice (Voci and Carlson, 1973) and rats (Bridges et al., 1984). The results reported here indicate that oxytocin acts directly on the CNS to inhibit infanticide and in some instances stimulates maternal
OXYTOCIN 0
Pamnt
0
Ignore
INHIBITS
371
INFANTICIDE
w hlfanncidal
20 10 C Bmfro3iptine l Saline
(74)
Bmmocriptine + Oxybcin WY
Cysteamine + Saline (11)
Cysteamine + Oxytow (10)
3. Effect of oxytocin after inhibition of prolactin. Previously infanticidal females were pretreated with the prolactin inhibitors bromocriptine (0.5 mg) or cysteamine (3 mg) prior to injection with oxytocin or saline. Oxytocin resulted in a significant reduction in the frequency of infanticide in females pretreated with cysteamine as compared to those receiving saline (x’(2) = 7.25, *P < 0.05). FIG.
behavior in the female house mouse. The ability of oxytocin to alter the response to pups does not seem to depend on high levels of prolactin, and spontaneous maternal behavior is not affected by drugs which inhibit prolactin. Prolactin has been reported to alter pup retrieval by the mouse in one study (Voci and Carlson, 1973) but not in another (Koch and Ehret, 1989). Prolactin injections or elevation of prolactin by implantation of ectopic pituitaries decreases the latency to exhibit maternal behavior in the steroid-primed rat (Bridges et al., 1984; Bridges and Dunckel, 1987) and injections of the prolactin-release blocker, bromocriptine, disrupt maternal behavior in the recently parturient hamster (Cut-ran et al., 1989). In the gerbil, increasing plasma levels of prolactin are correlated with an inhibition of infanticide by the male and may be related to the mating-induced inhibition of infanticide in this species (Elwood, 1986). Although not conclusive, the current data support the hypothesis that prolactin is not involved in the regulation of infanticide in female house mice since prior treatment with prolactin-inhibiting drugs had no effect on the oxytocin-induced inhibition of infanticide and no effect on the behavior of spontaneously maternal females.
372
MARGARET
BromMimna 0.5 m g Is)
mw?locriptina 2.0 rng (51
M. MCCARTHY
Cyateamire 1.5mg
Cysteamine 6.0 mg
llol
Ilo/
Cysleamine 12.0 m g m
FIG. 4. Effect of prolactin inhibition on parenting behavior. Previously parental females received varying doses of bromocriptine or cysteamine and remained with the pup. There was no significant effect of drug treatment on spontaneous parenting up to 5 hr postinjection.
Since a high percentage of oxytocin-treated females were scored as IGNORE on the posttest, it could be speculated that oxytocin induces behaviors that are inconsistent with infanticide and thereby inhibits killing behavior indirectly. Previously infanticidal females that received oxytocin icv exhibited increased grooming behavior for approximately 10 min postinjection and moved normally about the cage for the remainder of the test period. In addition, some oxytocin-treated females in this study (Experiment 3) and in a previous study (McCarthy et al., 1986) exhibited a marked increase in parenting behavior which involves the active retrieval of the pup to a nest. Therefore, it does not appear that the effects of oxytocin on infanticide are indirectly due to effects on competing behavioral responses. Oxytocin is synthesized in the hypothalamus and released into the periphery from the posterior pituitary in response to suckling and vaginocervical stimulation (Higuchi, Honda, Fukuoka, Negoro, and Wakabayashi, 1985). In addition, there is a widespread distribution of oxytocin-containing neurons within the brain where it is believed to function as a neurotransmitter (Palkovits, 1984). The concentration of oxytocin and its receptor in the CNS are responsive to circulating steroid levels (Greer, Caldwell, Johnson, Prange, and Pedersen, 1986; de Kloet, Voorhuis, Boschma, and Elands, 1986) and physiological levels of estrogen result in a marked enhancement of oxytocin-receptor binding in the
OXYTOCIN
INHIBITS
INFANTICIDE
373
ventromedial nucleus of the hypothalamus in female rats (Johnson, Corini, Ball, and McEwen, 1989). Oxytocin only successfully induces maternal behavior in rats when they are pretreated with estrogen (Pedersen et al., 1982; Fahrbach et al., 1984). In the present experiment, the endocrine state of the female mouse appeared to have no effect on the ability of oxytocin to inhibit infanticide. There was no significant difference between groups of females that were gonadally intact, ovariectomized, or ovariectomized and estrogen-treated in terms of the behavioral response after oxytocin. This finding can be interpreted as indicating that, (1) a sufficient concentration of oxytocin receptor exists at all times to allow for exogenously administered oxytocin to alter behavior, (2) oxytocin receptors in the CNS of the wild house mouse are not dependent on estrogen, or (3) the doses of oxytocin and estrogen used in this study were not appropriate to reveal a hormone effect on oxytocin-induced inhibition of infanticide. None of these possibilities can be excluded at this time. Nonetheless, the fact that no influence of the endocrine state on the effects of oxytocin could be found in this study does not necessarily imply the lack of a physiologically relevant role for oxytocin in this species. In contrast to males, female wild house mice are particularly impervious to the effects of experience on subsequent infanticide. Male house mice exhibit significantly less infanticide after sexual experience (vom Saal and Howard, 1982, McCarthy and vom Saal, 1986a), cohabitation with a pregnant female (Huck, Soltis, and Coopersmith, 1982; Elwood, 1986), rearing young (Soroker and Terkel, 1988), exposure to young as a juvenile (McCarthy, 1990), and castration (Gandelman and vom Saal, 1975). Female house mice, on the other hand, continue to exhibit infanticide after all these experiences (see McCarthy, 1990) and in fact are most likely to be infanticidal during late pregnancy (McCarthy and vom Saal, 1985). Thus it appears that the only time that female house mice are maternal is when they have delivered their own young, and it is possible that the neuroendocrine event which regulates this change in behavior is the release of oxytocin at parturition and during suckling. Restricting the neural “signal” which turns off infanticidal behavior in female mice to a very discrete event may be an inherently adaptive aspect of this behavior and oxytocin may serve as that signal. Last, an important aspect of the current study is that it involves a change from infanticidal to maternal behavior. Clearly these responses are mutually exclusive yet related. Although oxytocin consistently inhibited infanticidal behavior, it did not always induce maternal behavior. This finding can be taken as evidence for separate mechanisms regulating each response. What precise hormonal and neural factors influence the response of a female mouse toward pups remains to be determined.
374
MARGARET
M. MCCARTHY
ACKNOWLEDGMENTS The author thanks Dr. Sarah Lennington for provision of wild mice and lab space. Helpful comments on the manuscript were contributed by Carol Coopersmith and Dr. Harold Siegel. This is publication 513 from the Institute of Animal Behavior.
REFERENCES Arey, B. J., and Freeman, M. E. (1989). Hypothalamic factors involved in the endogenous stimulatory rhythm regulating prolactin secretion. Endocrinology 124, 878-883. Bolwerk, E. L. M., and Swanson, H. H. (1984). Does oxytocin play a role in the onset of maternal behavior in the rat? J. Endocrinol 101, 353-357. Bridges, R. S., DiBiase, R., Loundes, D. D., and Doherty, P. C. (1984). Prolactin stimulation of maternal behavior in female rats. Science 227, 782-784. Bridges, R. S., and Dunckel, P. T. (1987). Hormonal regulation of maternal behavior in rats: Stimulation following treatment with ectopic pituitary grafts plus progesterone. Biol. Reprod. 37, 518-526. Curran, G., McCarthy, M. M., and Siegel, H. I. (1989). Disruption of maternal behavior in the hamster by a prolactin release inhibitor. 19th Conference on Reproductive Behavior. Saratoga Springs, NY. de Kloet, E. R., Voorhuis, D. A. M., Boschma, Y., and Elands, J. (1986). Estradiol modulates density of putative ‘oxytocin receptors’ in discrete rat brain regions. Neuroendocrinology 44, 415-421. Elwood, R. W. (1986). What makes male mice paternal? Behav. Neural Biol. 46, 54-63. Fahrbach, S. E., Morrell, J. I., and Pfaff, D. W. (1984). Oxytocin induction of shortlatency maternal behavior in nulliparous, estrogen-primed female rats. Horm. B&w. 18, 267-286.
Gandelman, R., and vom Saal, F. S. (1975). Pup-killing in mice: The effects of gonadectomy and testosterone administration. Physiol. Behav. 15, 647-651. Greer, E. R., Caldwell, J. D., Johnson, M. F., Prange, A. J., and Pedersen, C. A. (1986). Variations in concentration of oxytocin and vasopressin in the paraventricular nucleus of the hypothalamus during the estrous cycle in rats. Life Sci. 38, 2311-2318. Hausfater, G., and Blaffer Hrdy, S., Eds. (1984). Infanticide: Comparative and Evolutionary Aspects. Aldine, New York. Higuschi, T., Honda, K., Fukuoka, T., Negoro, H., and Wakabayashi, K. (1985). Release of oxytocin during suckling and parturition in the rat. J. Endocrinol. 105, 339-346. Huck, U. W., Soltis, R. L., and Coopersmith, C. B. (1982). Infanticide in male laboratory mice: Effects of social status, prior sexual experience, and basis for discrimination between related and unrelated young. Anim. Behav. 30, 1158-l 165. Jakubowski, M., and Terkel, J. (1982). Infanticide and caretaking in non-lactating Mus musculus: Influence of genotype, family groups and sex. Anim. Behav. 30, 1029-1035. Johnson, A. E., Corini, H., Ball, G. F., and McEwen, B. S. (1989). Anatomical localization of the effects of 17/3-estradiol on oxytocin receptor binding in the ventromedial hypothalamic nucleus. Endocrinology 124, 207-211. Kendrick, K. M., Keveme, E. B., and Baldwin, B. A. (1987). Intracerebroventricular oxytocin stimulates maternal behaviour in the sheep. Neuroendocrinology 46, 56-61. Koch, M., and Ehret, G. (1989). Estradiol and parental experience, but not prolactin are necessary for ultrasound recognition and pup-retrieving in the mouse. Physiol. Eehav. 45, 771-776. McCarthy, M. M. (1990). Short-term early exposure to pups alters infanticide in adulthood in male but not in female wild house mice (Mus domesticus). J. Comp. Psychok 104, 195-197.
OXYTOCIN
INHIBITS
INFANTICIDE
375
McCarthy, M. M., and vom Saal, F. S. (1985). The influence of reproductive state on infanticide by wild female house mice (Mus musculus). Physiol. Behav. 35, 843-849. McCarthy, M. M., and vom Saal, F. S. (1986a). Inhibition of infanticide after mating by wild male house mice. Physiul. Behav. 36, 203-209. McCarthy, M. M., and vom Saal, F. S. (1986b). Infanticide by virgin CF-1 and wild male house mice (MUS musculus): Effects of age, prolonged isolation and testing procedure. Dev.
Psychobiol.
19, 279-290.
McCarthy, M. M., Bare, J. E., and vom Saal, F. S. (1986). Infanticide and parental behavior in wild female house mice: Effects of ovariectomy, adrenalectomy and administration of oxytocin and prostaglandin F,a. Physiol. Behav. 36, 17-23. Mens, W. B. J., Witter, A., and Van Wimersma Greidanus, T. B. (1983). Penetration of neurohypophyseal hormones from plasma into cerebrospinal fluid (CSF): Half-times of disappearance of these neuropeptides from CSF. Brain Res. 262, 143-149. Millard, W. J., Sagar, S. M., Landis, D. M. D., Martin, J. B., and Badger, T. M. (1982). Cysteamine: A potent and specific depletor of pituitary prolactin. Science 217, 452. Palkovits, M. (1984). Distribution of neuropeptides in the central nervous system: A review of biochemical mapping studies. Prog. Neurobiol. 23, 157-189. Pedersen, C. A., Ascher, J. A., Monroe, Y. L., and Prange, A. J., Jr. (1982). Oxytocin induces maternal behavior in virgin female rats. Science 216, 648-650. Rubin, B. S., Menniti, F. S., and Bridges, R. S. (1983). Intracerebroventricular administration of oxytocin and maternal behavior in rats after prolonged and acute steroid pretreatment. Horm. Behav. 17, 45-53. Samson, W. K., Lumpkin, M. D., and McCann, S. M. (1986). Evidence for a physiological role for oxytocin in the control of prolactin secretion. Endocrinology 119, 554-560. Simpkins, J. W., Estes, K. S., Millard, W. J., Sagar, S. M., and Martin, J. B. (1983). Cysteamine depletes prolactin in young and old hyperprolactinemic rats. Endocrino/ogy 112, 1889-1891. Soroker, V., and Terkel, J. (1988). Changes in incidence of infanticidal and parental responses during the reproductive cycle in male and female wild mice Mus muscu/us. Anim. Behav. 36, 1275-1281. Voci, V. E., and Carlson, N. R. (1973). Enhancement of maternal behavior and nest building following systemic and diencephalic administration of prolactin and progesterone in the mouse. J. Camp. Physiol. Psych& 83, 388-393. vom Saal, F. S., and Howard, L. (1982). The regulation of infanticide and parental behavior: Implications for reproductive success in male mice. Science 215, 1270-1272. Wamboldt, M. Z., and Insel, T. R. (1987). The ability of oxytocin to induce short-latency maternal behavior is dependent on peripheral anosmia. Behav. Neurosci. 101, 439441. Wegener, S., Schmidt, W. S., and Ehret, G. (1988). Haloperidol and apomorphine induced changes in pup searching behaviour of house mice. Psychopharmacology 95271-275.