The role of NR2A- and NR2B-containing NMDA receptors in innate anxiety

Abstract

Anxiety disorders are very common mental health diseases affecting millions of people worldwide and cost billions of dollars in medical care each year. However, the exact biological mechanism underlying the occurrence of anxiety disorders is still not clear. Accumulating studies have shown that N-methyl-D-aspartate (NMDA) type of glutamate receptors (NMDARs) are involved in anxiety disorders in animal models, but the roles of NR2A- and NR2B-containing NMDARs in anxiety disorders remain controversial, and it is completely unknown whether NMDAR-mediated LTP or LTD are involved in anxiety disorders. This project was designed to further investigate the roles of NR2A- and NR2B-containing NMDARs and NMDAR-mediated LTP and LTD in anxiety disorders. The effects of NR2A specific antagonist NVP-AAM077 (1.2mg/kg and 2.4mg/kg), NR2B specific antagonists Ro25-6981 (6mg/kg) and ifenprodil (5mg/kg), and LTD blocking peptides Tat-G1uR2-3Y and Tat-NR2B9c (1.5mumol/kg) were assessed with Elevated Plus-Maze (EPM) and/or modified Novelty Suppressed Feeding (NSF) tests in rats. The effect of bilateral infusion of Ro25-6981 (100muM, 1mu1) into the basolateral amygdaloid nuclei (BLA) was also examined. Our results showed that NVP-AAM077 and LTD-blocking peptides produced no significant effects on innate anxiety both in the EPM and NSF tests. Systemic administration of Ro25-6981 and ifenprodil produced anxiogenic effect, whereas intra-BLA injection of Ro25-6981 produced anxiolytic effect in the EPM test. These results reveal that NR2A-containing NMDARs and NMDAR-mediated LTP are not involved in anxiety disorders, and that NR2B-containing NMDARs play an important role in the development of anxiety disorders through an unknown pathway other than LTD production.