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

Abstract

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 α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor agonists, but not by treatment with N-methykD-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 pre-treatment/cotreatment with specific antagonists of either the NMDA or the AMPA receptor. The SON area or 3 V 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.

Expression of ionotropic glutamate receptor subunit mRNAs in the hypothalamic paraventricular nucleus of the rat

“…In this model, NMDA receptors play a modulatory role, acting to enhance AMPA-induced oxytocin release (Parker and Crowley, 1995). In line with this observation, NMDA receptors appear to be involved in regulating basal excitability of oxytocin neurons but not in generating the bursting discharges associated with lactation (Moos et al, 1997).…”

“…For example, electrophysiological data indicate that glutamate activates all identified neuronal subsets in the PVN (Wuarin and Dudek, 1991;Boudaba et al, 1997). In agreement with this assessment, glutamate infusions into the PVN increase heart rate and blood pressure (Kannan et al, 1989;Martin and Haywood, 1992), increase ACTH secretion (Darlington et al, 1989), increase the release of oxytocin in lactating rats (Parker and Crowley, 1995), and enhance vasopressin release in explant cultures (Sladek et al, 1998). Anatomic studies further support the prominence of glutamate action.…”

Functional, anatomical, and neurochemical differentiation of medial preoptic area subregions in relation to maternal behavior in the mouse

“…Depolarization of oxytocinergic neurons and release of oxytocin can be achieved reliably by injection of a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or kainate receptor agonists, but not by treatment with NMDA alone in the SON (Parker and Crowley, 1993;Nissen et al, 1995). In addition, cotreatment with NMDA and AMPA (using doses that alone did not induce oxytocin release) elicited strong oxytocin release (Parker and Crowley, 1995). The present results suggest that the oxytocinergic neurons in ACN are also insensitive to NMDA alone.…”

N-methyl-D-aspartate receptor subunit NR2B is widely expressed throughout the rat diencephalon: An immunohistochemical study

“…Glu or other EAAs can also increase PVH cell firing rate (Akaishi et al, 1985), affect various mechanisms triggering Fos protein expression (Krukoff et al, 1994;Wan et al, 1994), and also elicit penile erection, grooming, and yawning (Roeling et al, 1991;Melis et al, 1997) as well as feeding behavior (Roeling et al, 1991;Sorrels and Bostock, 1992). Glu, or its receptor agonists, can also regulate breathing (Yeh et al, 1997) and cause oxytocin/vasopressin/adrenocorticotropin release (Darlington et al, 1989;Hattori et al, 1992;Parker and Crowley, 1995). With respect to adrenocorticotropin release, however, Aubry et al (1996) have noted that PVH neurons producing corticotropin-releasing factor did not have detectable NR2B subunit mRNA.…”