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Labour was induced by electrical stimulation of the infundibulum and median eminence in the conscious prepartum rabbit. The stimulus was applied for 20 s through a chronically implanted platinum—rhodium electrode and consisted of 1 mA biphasic pulses at 50/s.

The first visible signs of labour occurred 1·5–3·0 min after stimulation and activity usually ceased within 25 min. This was sometimes sufficient for the delivery of the entire litter. The litters ranged from 5 to 11 pups. Frequently, labour ceased before all the young were expelled, but labour was easily restarted by a further period of stimulation. There were cases in which labour was restarted on more than four occasions before parturition reached completion. Parturition was sometimes left in a suspended state for more than 24 h. The viability of the pups was not adversely influenced by the protracted nature of such parturitions. Stimulation was most effective at inducing labour when applied close to the predicted time of parturition and the treatment was almost totally ineffective when applied more than 48 h before the predicted time. Nest-building was not precipitated by the premature birth of the young and sometimes occurred a day or more after parturition.

The stimulation parameters used for the induction of labour caused large milk-ejection responses when applied to the same animals during lactation. Some of these milk-ejection responses were equal to the release of more than 100 mu. oxytocin.

These results suggest that the rapid expulsion of the pups during natural labour in the rabbit could be the result of a sudden and very large release of oxytocin.

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Negative feedback, in which a hormone directly or indirectly restricts its own release, provides the servo-control observed in many endocrine situations. Such control could apply to oxytocin, for many studies claim that exogenous oxytocin reduces milk production (and ejection) in rats and other species (Carrol, Jacobsen, Kassouny, Smith & Armstrong, 1969; Mena & Beyer, 1969; Kuhn & McCann, 1970; Deis, 1971). In these studies oxytocin has always been given in amounts or in a form which we must now regard as somewhat unphysiological. One milliunit is a physiological dose for a rat and during the prolonged nursing of the rat pulses of this size are released at regular intervals of 5–15 min (Wakerley & Lincoln, 1971; Lincoln, Hill & Wakerley, 1973).

Experiments were conducted to determine whether oxytocin, in low doses, would inhibit or re-modulate the pulsatile release of endogenous oxytocin during suckling. Rats were taken at day 9–10 of

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Stimuli from the cervix and adjacent parts of the reproductive tract have a critical role to play in ovulation, pseudopregnancy and possibly parturition. Appreciable evidence even suggests that stimulation of these regions during coitus may precipitate the release of luteinizing hormone (LH) in those animals which have previously been regarded as spontaneous ovulators. The rat, for example, ovulates to coitus after the spontaneous event has been inhibited by continuous illumination (Dempsey & Searles, 1943) or pharmacological agents such as chlorpromazine (Harrington, Eggert, Wilbur & Linkenheimer, 1966) and pentobarbitone (Everett, 1967). Also, Taleisnik, Caligaris & Astrada (1966) found a dramatic rise in the level of serum LH in the rat within minutes of mating.

Very little is known about the central pathway taken by stimuli from the lower parts of the reproductive tract. Presumably, the stimuli pass to various parts of the diencephalon, since the anterior hypothalamus is involved in ovulation

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The frequency characteristics of the neuronal activity in the hypothalamus, septum and preoptic area of the forebrain were recorded with stereotaxically orientated steel microelectrodes in adult female rats under light urethane anaesthesia.

An exponential type of relationship was observed between the mean discharge rate of units and the frequency with which they were encountered in all areas. Thus, 40–60 % of units had firing rates of less than 1 spike/sec. and only 10–15% had rates exceeding 6/sec. However, units with a mean discharge rate of 2–4/sec. contributed most to the total spike activity. The form of the interspike interval distributions was found to vary with mean firing rate, and the variability of the interspike interval decreased as the firing rate of the unit increased.

The levels of 'spontaneous' activity in the anterior hypothalamic, preoptic and septal areas of rats with light-induced persistent oestrus were lower than those observed after ovariectomy. The administration of 10 μg. oestradiol benzoate/day to the ovariectomized animals depressed the levels of activity towards those observed in the persistently oestrous animals. Reciprocal effects were observed in the lateral hypothalamic area, i.e. decreased activity in the ovariectomized rats.

The results are discussed in relation to unit recording procedures and the feedback effects of oestrogen.

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Unit activity from the hypothalamus and EEG patterns from the cerebral cortex of rats rendered persistently oestrous by exposure to continuous illumination were analysed during the acute infusion of various progesterone preparations.

Infusion of 400 μg. of progesterone in either 0·1 ml. propylene glycol or ethanol caused dramatic changes in the spike activity of many hypothalamic units and precipitated a reproducible change in the EEG pattern. The infusion invariably caused a prolonged synchronization of the EEG, lasting 30–40 min. (i.e. an EEG pattern of large-amplitude slow waves). In addition, a period of high-amplitude high-frequency EEG waves occurred 2–4 min. after the infusion. These EEG changes were usually concurrent with any changes which occurred in the spike activity of hypothalamic units. Similar changes were observed after the infusion of the control materials, i.e. 0·1 ml. of propylene glycol or ethanol. The inclusion of progesterone did not produce changes in brain activity which were substantially different from the control infusions.

Infusion of up to 400 μg. of progesterone in propylene glycol or ethanol did not change the specific response of hypothalamic units to probing the vaginal parts of the cervix. On the other hand, this treatment frequently abolished the non-specific response (i.e. a response which is related to the period of EEG arousal) of these units for a period of 10–30 min. after infusion. The loss of the non-specific response appeared to be associated with an increase in the intensity of stimulus necessary to cause EEG arousal. This change in arousal threshold was caused, at least in part, by the action of the carrier agents.

The infusion of up to 400 μg. of progesterone in a microcrystalline form in saline caused changes in the activity of many units in the anterior hypothalamus and adjacent regions; both excitatory and inhibitory effects were observed. However, every one of these prominent changes in unit activity was associated with a prolonged period of synchronized EEG. There was no evidence to suggest that progesterone was having any selective action on the hypothalamus.

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The responses of septal, preoptic and hypothalamic neurones to pain, cold, changes in ocular illumination and probing of the cervix were recorded in adult female rats under light urethane anaesthesia. Responses in rats with light-induced persistent oestrus were compared with those obtained after ovariectomy, and after ovariectomy with oestrogen treatment.

The majority of units in the lateral hypothalamic area were excited by pain, cold and cervical stimuli, whereas in the lateral septal area most were inhibited. The numbers of units in the anterior hypothalamic and preoptic areas that displayed excitation to these stimuli were approximately equal to those showing inhibition.

The time-course of the responses to pain, cold and cervical stimuli of most hypothalamic and septal units closely corresponded to that of the associated EEG activation (frontal cortex), suggesting that they were non-specific arousal effects. Other responses, usually of brief duration, were not correlated with EEG changes.

Endogenous and exogenous oestrogen increased the percentage of units in the lateral and anterior hypothalamic areas that were inhibited by the pain, cold and cervical stimuli, and decreased the number in the lateral septal area. Oestrogen enhanced the responsiveness of preoptic units to the cervical stimulus, but depressed their responsiveness to pain and cold.

Hypothalamic units inhibited by the pain stimulus had mean 'spontaneous' firing rates of 4–5 spikes/sec. and those which were excited had rates of 1–2/sec.

Light-sensitive units were found mainly in the lateral septal and anterior hypothalamic areas. The usual form of the response was a brief 'on-off' or 'off-on' discharge.

The results are discussed in relation to the central nervous control of ovulation.

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A method is described for making extracellular recordings of the spontaneous activity of single hypothalamic neurones in unanaesthetized, freely moving, lactating rats using chronically implanted micro-wire electrodes. Extracellular recordings taken from individual neurones were maintained for periods of between 1 and 12 days. These records were not affected by any normal movement of the animal. As several micro-wires were implanted into each animal it was possible to make simultaneous recordings from several different hypothalamic sites in the same animal. Some recordings were identified as those from magnocellular neurones in the paraventricular nucleus on the basis of antidromic invasion after electrical stimulation of the neurohypophysis.

Milk ejection in response to the prolonged sucking of ten or more pups was intermittent, and individual milk ejections recurred at intervals of 2–10 min throughout each period of nursing. The rise in intramammary pressure at milk ejection was associated with a vigorous extensor response from the pups. This was monitored by radar to provide an index of milk ejection in the unanaesthetized rat.

Eleven antidromically identified neurones were recorded through 321 milk ejections. Eight of these neurones displayed a transient (2–6 s) and very substantial acceleration in discharge at the time predicted for oxytocin release, i.e. 10–12 s before milk ejection. The background discharge of these cells was 0·1–2·6 action potentials/s; this increased to 16–50 action potentials/s during the brief period of accelerated activity. Twenty-five neurones were studied during 365 milk ejections in rats which did not have a stimulating electrode implanted in the neurohypophysis. Thirteen of these neurones displayed a burst of high frequency discharge before each milk ejection, similar to that described for the antidromically identified neurones. Two of the non-responsive cells displayed a phasic pattern of discharge, characteristic of vasopressinergic neurone discharge recorded in anaesthetized rats.

These observations of putative oxytocinergic neurones in unanaesthetized, freely moving rats are identical with those previously made on anaesthetized rats, and establish that the high frequency burst of electrical activity displayed by magnocellular neurones some 10–12 s before milk ejection is responsible for oxytocin release under normal physiological circumstances.

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A. S. McNeilly and D. W. Lincoln

To investigate the role of the pineal gland in the long-term suppression of gonadotrophin secretion induced by prolactin, the effects of pinealectomy were studied in adult male rats with hyperprolactinaemia produced by the transplantation of two pituitary glands under the kidney capsule.

Pinealectomy had no effect on basal levels of LH, FSH or prolactin. The presence of pituitary transplants induced a significant twofold increase in prolactin levels and a prolonged suppression in both LH and FSH. These changes were not affected by pinealectomy. Castration resulted in a similar rise in plasma levels of LH and FSH in rats with and without pituitary transplants. In control rats this rise in LH and FSH was reduced by testosterone-containing silicone elastomer implants (s.c) of 10 mm in length and delayed by implants of 30 mm. These rises in LH and FSH were significantly delayed (10-mm implant) or abolished (30-mm implant) in rats with pituitary transplants indicating an increase in sensitivity of the hypothalamic-pituitary axis to the negative feedback effects of testosterone in these animals compared to controls. These responses were not affected by pinealectomy.

These results suggest that the pineal gland is not involved in the mechanism whereby pituitary grafts, possibly through their secretion of prolactin, cause long-term suppression of gonadotrophin secretion.

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Antidromically-identified paraventricular (PV) neurones were studied in the anaesthetized rat during milk ejection (ME) evoked by the natural stimulus provided by the suckling young. An intermittent pattern of ME was observed, though the ME interval was slightly longer (10–20 min) in the doe during unit recording than in unoperated or conscious animals (5–15 min). PV neurones displayed a steady background of spike discharge in both the non-lactating rat and lactating rat during suckling. The firing rates ranged from 0 to 9·4 spikes/s and were exponentially distributed with 32% of the units firing at <1 spike/s. Phasic patterns of discharge were seen in 18% of the units.

Fifty-eight per cent of the PV units displayed a stereotyped and explosive acceleration in spike activity some 15–20 s before the rise in intramammary pressure at ME. The peak firing rate during this brief (2–4 s) response was in the range of 24–84 spikes/s. A prominent after-inhibition was then displayed by these responsive units, though this second component of the response was variable in duration (7–56 s). The electrical activity of the remaining units, including all the cells with phasic discharge, was not correlated with ME.

There was no apparent change in the intensity of the suckling stimulus at the time of PV activation, i.e. 15–20 s before ME. Secondly, the activity of the PV neurones was not influenced by the rise in the intramammary pressure and the increased sucking of the pups at the time of ME. Simulation of an individual ME was obtained with both 1 mu. exogenous oxytocin, i.v., and electrical stimulation of the neurohypophysis (50 pulses/s for 4 s). The latencies to ME ranged from 7–14 s and 11–23 s, respectively.

In conclusion, an explosive increase in the electrical activity of PV neurones precipitates the release of oxytocin at ME.

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A. M. Naylor, D. W. F. Porter, and D. W. Lincoln


Stress interferes with the normal secretion of LH and FSH from the anterior pituitary gland and therefore exerts a deleterious effect on reproductive function. Evidence suggests that the stress-induced disruption of gonadal function is due to a central action of corticotrophin-releasing factor (CRF) to inhibit the release of LHRH into the hypophysial-portal circulation. The following studies were undertaken to investigate further the role of CRF in regulating gonadotrophin release in the sheep and to determine whether central administration of this peptide can alter the secretion of other hormones (e.g. prolactin and cortisol) known to be released under conditions of stress.

In contrast to other species, injection of CRF into the third ventricle of the sheep brain caused a dose-related stimulation of LH secretion. The pulse frequency and mean levels of LH were increased significantly following central administration of CRF. In contrast to this effect, central administration of CRF did not alter the plasma concentration of FSH but caused a marked and dose-related stimulation of prolactin and cortisol secretion. The stimulatory effect of CRF on prolactin secretion was reversed by i.v. administration of the opioid antagonist naloxone, suggesting that endogenous opioid peptides mediate the central effect of CRF on the release of prolactin, but not cortisol.

In conclusion, these data demonstrate that administration of CRF causes a dose-related stimulation of LH and prolactin release from the anterior pituitary gland and cortisol from the adrenal gland. In the case of prolactin, endogenous opioid peptides are likely to mediate this response. The observations concerning LH are the opposite of those reported for the rat and the monkey where CRF caused a prolonged inhibition of gonadotrophin secretion. This suggests that a species difference may exist or, alternatively, the stimulatory effect of CRF on LH secretion in the sheep may be similar to the increase in LH secretion reported in rats and monkeys subjected to short-term handling or restraint stress.

Journal of Endocrinology (1990) 124, 117–125