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Central oxytocin administration has a profound facilitatory effect on the patterning of the milk-ejection reflex in the lactating rat. Lesion and microinjection studies indicate that this action is, in part, mediated via a population of limbic neurones in the bed nuclei of the stria terminalis and ventrolateral septum, which have been shown to possess oxytocin receptors and to be activated by selective oxytocin-receptor agonists in vitro. In vivo electro-physiological recordings reveal that some of these neurones display cyclical activity which is highly correlated to each milk ejection, and are rapidly activated following i.c.v. administration of oxytocin. coincident with the facilitation of milk ejection activity. A hypothetical model is proposed in which this population of limbic neurones serves to gate the activity of a pacemaker which, in turn, coordinates the bursting of hypothalamic magnocellular neurones. The oxytocin innervation of these neurones and their expression of oxytocin receptors increases in the post-partum period, and the resultant enhanced sensitivity leads to a greater facilitatory response during lactation. Inhibitory opioid and noradrenergic inputs which converge on these oxytocin-sensitive neurones may function to switch off the facilitatory circuit during periods of stress. Thus, this population of limbic neurones participates in the regulation of neuroendocrine activity during lactation by providing an appropriate degree of feedback to alter the patterning of the milk-ejection reflex.

Electrical stimulation (35 μA rms/15 s) of the anterior pretectal nucleus (APtN) inhibits the spinal reflex of the tail-flick (TF) to noxious heat in unanaesthetised rats. APtN stimulation also reduces the nociceptive response of spinal dorsal horn neurones in halothane-anaesthetised rats. This study determined if the antinociceptive effects of APtN stimulation depended on neurones in the ventral medulla. Bilateral electrolytic lesions of the ventrolateral medulla, but not the nucleus raphe magnus, reduced by 70% the antinociceptive effect of APtN stimulation in the TF test. In rats anaesthetised with halothane, electrical stimulation of the APtN (single square wave 0.1 msec pulses, 2–20 μA, 1 Hz) excited cells in the ventrolateral medulla. These data suggest a connection between both areas. This connection is futher confirmed by neuroanatomical tract tracing studies in which the retrograde dye Fast Blue was injected into the ventrolateral medulla. Fluorescent cell bodies were found in the APtN. We therefore conclude that the ventrolateral medulla is part of a descending antinociceptive pathway from the APtN.

The bed nuclei of the stria terminalis (BNST) is a target site for the central actions of oxytocin (OT) in promoting behavioural and neuroendocrine responses involved in female reproduction, and binding studies suggest that OT sensitivity may be modulated over the peripartum period. Electrophysiological recordings from brain slices in vitro showed that OT sensitivity of BNST neurones is relatively low in late pregnancy, but is high during lactation. In vivo studies over the immediate peri-partum period revealed that although BNST neurones can be excited by i.c.v. OT at day 22 of pregnancy, there is a 5-10 min delay in their response which is not present in lactation. This delay can be reversed by naltrexone, or lesioning the stria terminalis, and may involve an inhibitory opioid input to the BNST from the amygdala. Examination of the role of steroids in regulating OT responses of BNST neurones showed that oestradiol pre-treatment in late pregnant ovariectomized rats increased OT excitation of BNST neurones in vitro, and a similar result was observed with in vivo recordings. Progesterone also augmented OT excitation of BNST neurones in vitro, but no such effect was observed in vivo. This difference could indicate that an additional effect of progesterone is to potentiate extraneous inhibitory inputs to the BNST, or may reflect the ability of this steroid to suppress OT sensitivity by a direct membrane action. Changes in the response of BNST neurones to OT may have functional implications for the action of central OT in facilitating the neuroendocrine milk-ejection reflex (i.e. increasing milk-ejection frequency), an effect which first appears at around day 3 of lactation. Studies involving steroid treatment of late pregnant ovariectomized rats showed that this facilitatory mechanism can be induced to appear early (i.e. on day 22 of pregnancy) by oestradiol, but not progesterone treatment. Collectively, these results support this view, that the action of OT in the BNST is regulated by the changing levels of steroids towards the end of pregnancy, thereby ensuring appropriate neuroendocrine responses necessary for motherhood.

In the female rat, oxytocin (OT) is recognized for its role in regulating reproductive functions, both as a hormone in the general circulation and as a neurotransmitter in the central nervous system (CNS). As a hormone, OT produces contractions of the pregnant uterus and mammary gland. Its neurotransmitter actions range from the modulation of neuroendocrine reflexes (milk-ejection reflex) to the establishment of complex social and bonding behaviours related to reproduction and care of the offspring. This diversity of effects has led to OT being considered as a coordinating factor, ensuring that the behavioural, physiological and neuroendocrine changes appropriate to lactation are activated at the correct time in the peri-partum period [1,2]. In this respect, expression of OT receptors in some areas of the CNS is modulated by levels of gonadal steroids in the circulation and the sequence of changes of these levels, especially towards the end of gestation. However, some OT receptors are insensitive to changing steroid levels, allowing for differential activation of OT-dependent pathways. The studies reported here concern the pharmacological characterisation of OT receptors in different areas of the CNS (especially in areas displaying contrasting steroid sensitivity); the demonstration that the electrophysiological effect of activation of OT receptors in the limbic system may change during the peripartum period; and the proposal that one of the central actions of OT may be to reduce anxiety levels in the lactating rat.

1. Functional relationships between the anterior pretectal nucleus (APTN) and nociceptive dorsal horn neurones were investigated electrophysiologically in the anaesthetized rat. The effects of APTN lesions were assessed behaviourally in a model of deafferentation pain. 2. Cells in the dorsal and rostral parts of the APTN were excited orthodromically by electrical stimulation of the ipsilateral dorsolateral funiculus or the contralateral dorsal columns, and by noxious and innocuous cutaneous stimuli. 3. Electrical stimulation of the APTN excited nociceptive lamina I spinal neurones. These cells all projected rostrally in the contralateral dorsolateral funiculus. Identical APTN stimulation also inhibited multireceptive spinal neurones which lay deep in the dorsal horn. These particular cells were shown to project to the brain in the ventrolateral funiculus. 4. It is proposed that noxious stimuli excite spinal lamina I projection neurones which send excitatory axons to the brain, including the APTN. The APTN inhibits deep multireceptive neurones, to reduce the perception of noxious stimuli. The discharge of spinal lamina I neurones, however, will be sustained by the noxious stimulus and by facilitation from the APTN. A sustained descending inhibition of this nature would reduce responses to prolonged injury. 5. The involvement of the APTN in responses to a chronic pain state was examined by comparing the behaviour of animals with bilateral lesions of the APTN with normal controls. Lesions of the APTN strongly enhanced the autotomy behaviour triggered by sectioning of the dorsal roots. 6. These observations support the suggestion that the APTN reduces the debilitating effects of prolonged injury.

Central oxytocin administration has a profound facilitatory effect on the patterning of the milk-ejection reflex in the lactating rat. Lesion and microinjection studies indicate that this action is, in part, mediated via a population of limbic neurones in the bed nuclei of the stria terminalis and ventrolateral septum, which have been shown to possess oxytocin receptors and to be activated by selective oxytocin-receptor agonists in vitro. In vivo electrophysiological recordings reveal that some of these neurones display cyclical activity which is highly correlated to each milk ejection, and are rapidly activated following i.c.v. administration of oxytocin, coincident with the facilitation of milk ejection activity. A hypothetical model is proposed in which this population of limbic neurones serves to gate the activity of a pacemaker which, in turn, coordinates the bursting of hypothalamic magnocellular neurones. The oxytocin innervation of these neurones and their expression of oxytocin receptors increases in the postpartum period, and the resultant enhanced sensitivity leads to a greater facilitatory response during lactation. Inhibitory opioid and noradrenergic inputs which converge on these oxytocin-sensitive neurones may function to switch off the facilitatory circuit during periods of stress. Thus, this population of limbic neurones participates in the regulation of neuroendocrine activity during lactation by providing an appropriate degree of feedback to alter the patterning of the milk-ejection reflex.

In the rat, the synchronous bursting activity of oxytocin neurones associated with the milk-ejection reflex displays important changes during the peri-partum and lactational periods. The most dramatic of these changes is the appearance of a facilitatory response to centrally-administered oxytocin, involving an increase in the frequency and amplitude of bursting in the oxytocin neurones, as well as elevation of their background activity. Studies of rats at different times in the pre- and post-partum period show that this response first appears on day 3 of lactation. Ovariectomy on day 21 of gestation, or treatment with the anti-oestrogen tamoxifen on day 22, does not prevent the appearance of this response. However, ovariectomy and treatment with ovarian steroids for 3 days prior to parturition can dramatically alter the character of the facilitatory response. Oestradiol treatment causes an early (pre-partum) appearance of the facilitatory response, whereas progesterone causes the appearance of an inhibitory response (reduction in milk-ejection frequency) to central oxytocin. A major target for the central effects of oxytocin are the bed nuclei of the stria terminalis (BST) and modulation of the neuronal responses in this region may, in part, underlie the changing facilitatory effects. In vitro recordings indicate that sensitivity of BST neurones to oxytocin is increased between pregnancy and lactation, and oestradiol treatment enhances responsiveness coincident with the appearance of a facilitatory response. Progesterone pre-treatment also increases the ability of BST neurones to respond to oxytocin in vitro (although less than oestradiol), an unexpected result given the absence of oxytocin-induced facilitation of the milk-ejection reflex in late pregnancy or following progesterone treatment in vivo. In vivo recordings of BST neurones suggest that one explanation of this lack of correlation may reside in the presence of a mechanism which attenuates the excitatory response to oxytocin, perhaps serving to prevent premature expression of the facilitatory action of oxytocin. Collectively, these data show that there are dramatic reproductive state and steroid-dependent changes in the central action of oxytocin on the synchronous bursting of magnocellular oxytocin neurones. These changes, which have important consequences for the optimization of bursting in oxytocin neurones, may involve plasticity of transduction mechanisms in the oxytocin-responsive elements of the limbic system.