Oxytocin: an emerging regulator of prolactin secretion in the female rat

Abstract

In the female rat, a complex interplay of both stimulatory and inhibitory hypothalamic factors controls the secretion of prolactin. Prolactin regulates a large number of physiological processes from immunity to stress. Here, we have chosen to focus on the control of prolactin secretion in the female rat in response to suckling, mating and ovarian steroids. In all three of these states, dopamine, released from neurones in the mediobasal hypothalamus, is a potent inhibitory signal regulating prolactin secretion. Early research has determined that the relief of dopaminergic tone is not sufficent to account for the full surge of prolactin secretion observed in response to the suckling stimulus, launching a search for possible prolactin-releasing factors. This research has subsequently broadened to include searching for prolactin-releasing factors controlling prolactin secretion after mating or ovarian steroids. A great deal of literature has suggested that this prolactin-releasing factor may include oxytocin. Oxytocin receptors are present on lactotrophs. These oxytocin receptors respond to exogenous oxytocin and antagonism of endogenous oxytocin inhibits lactotroph activity. In addition, the pattern of oxytocin neuronal activity and oxytocin release correlate with the release of prolactin. Here, we suggest not only that oxytocin is stimulating prolactin secretion, but also that prolactin secretion is controlled by a complex network of positive (oxytocin) and negative (dopamine) feedback loops. We discuss the available literature and attempt to describe the circuitry we believe may be responsible for controlling prolactin secretion.

Figure 1

Prolactin is secreted 1) in response to suckling 2) in response to mating and 3) on pro-oestrus evening in response to ovarian steroids (3) (Fig. 1). The suckling of rat pups initiates a surge of prolactin concentration that persists in the lactating rat as long as the suckling stimulus is maintained (4). Prolactin increases within 5 minutes of the suckling stimulus and reaches peak levels by 30 minutes.

Figure 2

Suckling-induced prolactin (PRL) secretion. A) Mean concentration (ηg/mL ±SEM) of serum prolactin in lactating animals 5 days after parturition (n=6) following the infusion of saline or oxytocin antagonist (OTA) (1.25 .g/.Lor 12.5 .g/.L). Upon pup replacement, 12.5 .g/.Lof OTA prevented the suckling-induced rise in prolactin secretion by 20 minutes (two-way ANOVA, followed by Bonferroni’s test

Figure 3

Prolactin secretory rhythm induced by oxytocin. Prolactin secretion in ovariectomized (rats after a single intravenous injection (black arrow) of either oxytocin (solid line) or saline (dotted line with open circles).*Significantly higher prolactin levels for oxytocin-injected animals compared with saline-injected animals (P < 0.05); #Significantly higher prolactin levels for cervically-stimulated animals (dotted line with closed circles) compared with saline-injected animals (P < 0.05). (Adapted from Egli 2006)

Figure 4

Prolactin (PRL) secretory rhythm induced by cervical stimulation (CS). The prolactin secretory rhythm induced by cervical stimulation is blocked by antagonizing peripheral oxytocin receptors. Oxytocin antagonist (OTA) (dotted line) or saline (solid line) in ovariectomizedrats. Values are expressed as mean ηg/mL of prolactin ± SE (n=3-10 serial samples/point). *Significantly lower prolactin levels than corresponding times in saline infused rats (P < 0.05). There was no significant elevation in prolactinsecretion at any time in the oxytocin antagonist-treated group. aStatistical difference from all other time points within the saline infused rats.

Figure 5

Intracerebroventricular (icv) injectionor systemic ovine prolactin (oPRL) administration initiates a daily prolactinsecretory rhythm. Ovariectomizedrats were injected with ovine prolactin or vehicle intracerebroventricular (0.15 %g) (A) or ovine prolactin systemically (15 or 150 %g) (B) at 2200 h of day 0 (arrow). Blood samples were withdrawn during the next 2 days to determine the presence of the prolactindiurnal and nocturnal surges (n = 5–11). Data are presented as mean ± SEM. #, P < 0.05; ###, P < 0.001 vs. vehicle-injected group at the same time point. *P < 0.05; **P < 0.01; ***P < 0.001 vs. basal prolactin on 2100 h of day 1 in the same experimental group.

Figure 6

Oestradiol-induced prolactin (PRL) secretion.Mean concentration (ηg/mL /mL±SEM) of serum prolactin in ovariectomizedanimals treated with oestradiol(n=6) following the infusion of oxytocin antagonist (solid line) or saline (dotted line). A 24 hour infusion of 12.5 /g//Lof oxytocin antagonistattenuated the estradiol-induced prolactinsurge at 1700h, whereas 1.25 /g//Land 3.75 /g//L did not affect the prolactin surge (two-way ANOVA, followed by Bonferroni’s test

Figure 7

Proposed Model. The proposed model for the control of prolactin secretion in the female rat in response to three physiological conditions: suckling, mating stimuli, ovarian steroids. This includes the classical negative dopamine-prolactin feedback loop and the positive oxytocin-prolactin feedback loop. We hypothesize that oxytocin stimulates (+) prolactin secretion triggering a positive feedback loop until a threshold of prolactin secretion is reached to stimulate dopamine release. Dopamine in turn inhibits (-) prolactin secretion. DA=dopamine, OT=oxytocin, PRL=prolactin.