Central Stimulation of Oxytocin Release in the Lactating Rat by N-Methyl-D-Aspartate: Requirement for Coactivation through Non-NMDA Glutamate Receptors or the Glycine Coagonist Site

Excitatory amino acid (EAA) neurotransmitters participate in the regulation of secretion of several neuropeptides, including oxytocin (OT), via actions at different receptors. In earlier studies, release of OT could be achieved reliably by injection into the supraoptic nucleus (SON) of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor agonists, but not by treatment with N-methyl-D-aspartate (NMDA) alone. This prompted further examination of the possible role of NMDA receptors in OT release following central coapplication of NMDA and AMPA-site agonists, or of NMDA and agonists active at the glycine coagonist site. The agonists were injected into the right SON, the right paraventricular nucleus (PVN), or into the third ventricle (3V) of nonsuckled lactating rats. Cotreatment with NMDA and AMPA (using doses that alone did not include OT release) elicited a strong OT release in all animals by either the SON or the PVN route, and this was attenuated by pretreatment/cotreatment with specific antagonists of either the NMDA or the AMPA receptor. The SON area or 3V coinjection of NMDA and the NMDA/glycine site agonists glycine or D-serine also induced OT discharges in all animals, while cotreatment in the PVN did not result in uniform OT discharges. This release was potently reduced by cotreatment with the specific NMDA/glycine site antagonist 5, 7-dichlorokynurenate (DCK). L-Serine somewhat increased the frequency of discharge-type response to NMDA, while intra-SON coinjection of L-leucine did not stimulate OT release. D-Serine alone stimulated the release of OT much less than in combination with NMDA, and with no obvious dose dependence. The suckling-induced release of OT was attenuated, but not abolished, by DCK, while PRL release was briefly stimulated by this agent. A physiological role for the NMDA receptor in OT release is clearly supported by these studies. NMDA receptor activation in the lactating rat may result from either an allosteric stimulation by glycine site agonists, or a synergistic interaction with the AMPA/kainate group of excitatory amino acid receptors.