A tale of two rhythms: the emerging roles of oxytocin in rhythmic prolactin release

Abstract

Hormone secretion often occurs in a pulsatile manner. In this review, we discuss two rhythms of in vivo prolactin release in female rats and the ongoing research that we and others have performed aiming to understand the mechanisms underlying them. The peptide hormone oxytocin appears to play an important role in both rhythms. One rhythm occurs during the first half of pregnancy, but can also be induced in ovariectomised rats. This is characterised by a circadian pattern with two prolactin surges per day. Two methods for triggering this rhythm are discussed, each utilising a unique physiological pathway that includes oxytocin action, presumably on pituitary lactotrophs. The second rhythm occurs during the oestrous cycle and is characterised by a surge of prolactin on the afternoon of pro-oestrus. We discuss recent findings that oxytocin is more effective at stimulating prolactin release from lactotrophs taken from animals on the afternoon of pro-oestrus than from those of animals on the morning of dioestrus 1, raising the possibility that this hormone plays a physiological role in the regulation of prolactin secretion during the oestrous cycle.

Figure 1

Proposed model for the prolactin rhythm initiated by cervical stimulation (CS) or by oxytocin (OT) injection. Closed arrowheads indicate stimulatory actions, open arrowheads indicate inhibitory actions. The stimulation of dopamine (DA) neurons by prolactin (PRL) has a delay of τ hours. A pulse of vasoactive intestinal polypeptide (VIP) from suprachiasmatic neurons occurs every morning, setting the phase of the prolactin oscillation. The memory, M, is switched on by CS or by PRL.

Figure 2

Numerical simulation of the mathematical model (see (39) for equations). (A) A prolactin rhythm (solid) is initiated by cervical stimulation, as described in Fig. 1. The dopamine neuron activity (dashed) oscillates out of phase with prolactin levels. (B) The cervical stimulation activates oxytocin neurons of the paraventricular nucleus, which oscillate out of phase with prolactin levels due to the inhibitory influence of prolactin on the neurons. (C) The memory is switched on by the cervical stimulation and stays on throughout the simulation. The variables PRL, DA, and OT have all been normalized to facilitate comparison.

Figure 3

Numerical simulation of the mathematical model illustrating the effects of two antagonists on the triggering of the memory for the biphasic circadian prolactin rhythm. (A), (C) Both peripheral oxytocin receptor antagonist (pOTa) and central prolactin antagonist (cPRLa) prevent the rhythm induced by cervical stimulation while the antagonist is present. However, the rhythm emerges once the antagonist has cleared from the system. (B), (D) The prolactin rhythm induced by peripheral oxytocin injection (pOT) is not triggered when the same antagonists are present during the injection.

Figure 4

Comparison of the oxytocin-induced responses in perifused lactotrophs obtained from female rats on the morning of diestrus 1 (open symbols) and the afternoon of proestrus (closed red symbols). (A) Oxytocin application (100 nM for 10 min) evoked a larger prolactin-releasing effect from proestrus cells. Samples were collected every minute. (B) Oxytocin application (100 nM for 2 min) elicited a larger increase in the free intracellular Ca²⁺ concentration, as measured by the fura-2 fluorescence ratio. See (50) for details and a full description of experimental procedures.