Role of Non-NMDA Receptors in Osmotic and Glutamate Stimulation of Vasopressin Release: Effect of Rapid Receptor Desensitization

Previous studies demonstrated that the increase in vasopressin (VP) release and induction of VPmRNA content by osmotic stimulation was blocked by kynurenic acid, a non-specific antagonist of excitatory amino acid (EAA) receptors. In order to identify the type of EAA receptor involved, perifused explants of the hypothalamo-neurohypophyseal system (HNS) were exposed to a ramp increase in osmolality (40 mOsm over 6  h achieved by increasing NaCl) in the presence and absence of 10  μ m 6,7-dinitroquinoxaline-2,3-dione (DNQX), an antagonist of non- n -methyl-d-aspartate (NMDA) excitatory amino acid receptors. Vasopressin release and VP mRNA content were significantly increased by exposure to the osmotic stimulus. 6,7-dinitroquinoxaline-2,3-dione inhibited osmotically stimulated VP release ( F =16.65, P=0.0008) without significantly reducing basal release. It also prevented the osmotically stimulated increase in VP mRNA content (P<0.05). Although these results implicated glutamate, the primary endogenous ligand for EAA receptors, in the regulation of VP, exogenous glutamate was ineffective in stimulating VP release from HNS explants in either low-Mg²⁺ or Mg²⁺-replete medium. However, blockade of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor desensitization with cyclothiazide (100  μ m ) caused a marked increase in VP release in response to 100  μ m glutamate, and blockade of kainate receptor desensitization with concanavalin A resulted in a small, but significant increase in VP release in response to 1  m m glutamate. These results support a role for non-NMDA receptor activation in osmotic regulation of VP release.