Abstract: Stressors markedly influence central neurochemical and hormonal processes and thus play a pivotal role in the occurrence of depressive illnesses. As the center for stress response and the potential target for stressful provocation, hippocampus is becoming a focus in depression research. Although a large number of behavioral paradigms have been proposed as animal models of depression, only a few are considered as potentially useful research tools with sufficient validity. The most accepted one is chronic unpredictable mild stress rodent model, in which rats were subjected chronically and unpredictably to a variety of stressors including immersion in cold water, tail pinch, day and night reversed and so on. There are several theoretic mechanisms for depression, such as monoamine neurotransmitter imbalance theory, neural plasticity theory, but none of them can fully elucidate the formation of depression. Due to weakness of the antidepressant-like effect of monoamines, glutamate (Glu) and its receptors, especially N-methyl-D-aspartic acid (NMDA) receptor, and neuropeptides such as neuropeptide Y (NPY), substance P (SP), are drawing closer attention in recent years. Here, we are attempted to explore the interaction between Glu/NMDA receptor and SP/neurokinin 1 (NK1) receptor in chronic unpredictable mild stress (CUMS)-induced depression.
CUMS-induced depression model was established in 250~300g weighted 90-day old Sprague-Dawley rats. Intrahippocampal microinjection of NK1 receptor antagonist CP-96345, NMDA receptor agonist NMDA or NMDA receptor antagonist MK-801 was performed under stereotaxic guide cannula. The body weight of rats was weighed on the 1st, 7th, 14th, and 21st days during the experiment. The behavioral conducts were observed by means of sucrose consumption test, open field test and tail suspension test. The substance P (SP) and glutamate (Glu) content in hippocampus were separately determined by High performance liquid chromatography (HPLC). One-way ANOVA, LSD and repeated measures in SPSS were used in datum analysis.
Our data suggest that CUMS significantly induced the depressive-like behaviors in animals and the content of SP and Glu in hippocampus had increased significantly. Microinjection of NMDA into hippocampus resulted in similar animal depressive-like behaviors and an increased SP content compared to the CON/SAL group. Intrahippocampal injections of CP-96345 or MK-801 had effectively improved the depression-like behaviors induced by CUMS, and the elevation of SP level in hippocampus was attenuated in MK-801 injection, whereas Glu level remained unchanged in CP-96345 injection.
Our results imply that hippocampal NMDA receptor may contribute to chronic stress induced depressive-like behaviors via SP-NK1 receptor pathway, of which, chronic stresses can induce excessive release of Glu which consequently increases the synthesis and release of SP through over-activation of NMDA receptor, ultimately, over-released SP aberrantly activates its NK1 receptor.

Key words: chronic unpredictable mild stress, depression, hippocampus, N-methyl-D-aspartic acid receptor, substance P