Suckling-evoked pulsatile release of oxytocin (OT) from the posterior pituitary plays a key role in breastfeeding, which relies on burst-like discharges of OT neurons. To explore cellular mechanisms regulating OT neuronal activity, using lactating rats with pup-deprivation (PD) during postpartum day 1–5, we observed the involvement of prostaglandin, cyclic AMP/protein kinase A (PKA) and hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) signaling pathway in OT neuronal activity. PD gradually reduced lactation efficiency. Intermittent PD (IPD) was largely reversed by intranasally-applied OT (IAO) but not by hypodermically-applied OT. IPD caused involution-like histological changes in the mammary glands, increased hypothalamic OT release but did not influence plasma OT concentrations. In the supraoptic nucleus, IPD increased OT receptor (OTR) expressions in OT neurons as well as Gαq subunit, Gβ subunit and cyclooxygenase 2 (Cox-2). These effects except that on Gβ subunit were reversed by IAO. Notably, IPD increased the expression of catalytic subunit of PKA in the SON, specifically in vasopressin neurons but not in OT neurons. In addition, IPD increased the expression of HCN3. IAO partially reversed these changes in the SON. Lastly, blocking HCN3 blocked excitation and burst firing in OT neurons-evoked by prostaglandin E₂, a key mediator of OT-evoked burst firing; blocking Cox-2 or PKA reduced the molecular association between OTR and HCN3. Thus, there is a prostaglandin-cAMP/PKA–HCN3 pathway in the regulation of OT neuronal activity. PD disrupts lactation performance through uncoupling OTR and PKA-HCN3 signaling. The reversal effect of IAO highlights its therapeutic potential in PD-evoked hypogalactia.

垂体后叶的催乳素催产素（OT）的乳头状搏动释放在母乳喂养中起着关键作用，这依赖于OT神经元的爆发样放电。为了探索调节OT神经元活性的细胞机制，在产后第1至5天使用泌乳剥夺（PD）的哺乳大鼠，我们观察到前列腺素，环状AMP /蛋白激酶A（PKA）和超极化激活的环状核苷酸门控的参与OT神经元活动中的通道3（HCN3）信号通路。PD逐渐降低了泌乳效率。鼻内应用的OT（IAO）可逆转间歇性PD（IPD），但皮下应用的OT不能逆转间歇性PD（IPD）。IPD在乳腺中引起内卷样组织学改变，下丘脑OT释放增加，但不影响血浆OT浓度。在视上核中 IPD增加了OT神经元以及Gαq亚基，Gβ亚基和环氧合酶2（Cox-2）中OT受体（OTR）的表达。除了对Gβ亚基的作用外，这些作用被IAO逆转。值得注意的是，IPD增加了SON中PKA催化亚基的表达，特别是在血管加压素神经元中，而在OT神经元中则没有。另外，IPD增加了HCN3的表达。IAO在SON中部分扭转了这些变化。最后，阻断HCN3阻断了前列腺素E诱发的OT神经元的兴奋和猝发。IPD增加了HCN3的表达。IAO在SON中部分扭转了这些变化。最后，阻断HCN3阻断了前列腺素E诱发的OT神经元的兴奋和猝发。IPD增加了HCN3的表达。IAO在SON中部分扭转了这些变化。最后，阻断HCN3阻断了前列腺素E诱发的OT神经元的兴奋和猝发。_图2是OT诱发的突发射击的关键调解人；阻断Cox-2或PKA会降低OTR和HCN3之间的分子缔合。因此，在OT神经元活性的调节中存在前列腺素-cAMP / PKA-HCN3途径。PD通过解偶联OTR和PKA-HCN3信号传导破坏泌乳性能。IAO的逆转作用突出了其在PD诱发的乳腺减低症中的治疗潜力。