Role of Hippocampal 5-HT1A Receptor and Its Modulation to NMDA Receptor and AMPA Receptor in Depression Induced by Chronic Unpredictable Mild Stress

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,the 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 potentially useful research tools with sufficient validity.The most accepted one is the chronic unpredictable mild stress(CUMS) rodent model,in which rats are chronically and unpredictably subjected to a variety of stressors including immersion in cold water,tail pinch,day and night reversal,and so on.There are several theoretical mechanisms for depression,such as the monoamine neurotransmitter imbalance theory and the neural plasticity theory,but none of them can fully elucidate the formation of depression.Due to the weak and irregular anti-depressant effects of monoamines,glutamate(Glu) and its receptors,especially N-methyl-D-aspartic acid(NMDA) receptors and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid(AMPA) receptors,have gained more attention in recent years.As an important isoform of the 5-hydroxytryptamine(5-HT) receptor,the 1A receptor is highly expressed in the hippocampus.Numerous pharmacological and clinical studies show that the 1A receptor is correlated with the development and therapy of major depressive disorder,anxiety,and drug addiction.The present study investigates the expression and role of the 5-HT receptor 1A(5-HT1AR) and its relationship with NMDA and AMPA receptors in depression induced by CUMS.The CUMS induced depression model was done using Sprague-Dawley rats that were given intra-hippocampal microinjections of drugs.The location of injections was determined by rat brain stereotaxic coordinates.The behavioral observations were conducted by measurement of weight changes,sucrose preference test,open-field test,and tail suspension test.The expression of 5-HT1AR was detected by Western blot,and the expression and phosphorylation of the NMDA and AMPA receptor's subunits were detected by Western blot and ELISA,respectively.The results showed that CUMS rats had depressive-like behavior,lower expression of 5-HT1AR,lower expression and phosphorylation of AMPA receptor subunits(GluR2/3),and higher expression and phosphorylation of NMDA receptor subunits(NR1and NR2B) in the hippocampus in comparison with the CON/SAL group.Microinjection of WAY100635(an antagonist of 5-HT1AR) into the hippocampus of CON/SAL animals resulted in similar animal depressive-like behaviors,as well as similar expression levels and phosphorylation of NMDA and AMPA receptor subunits observed in CUMS/SAL animals.Pretreatment with microinjection of 8-OH-DPAT(an agonist of 5-HT1AR) could rescue CUMS-induced depressive behavior,decrease expression of AMPA receptor subunits(GluR2/3),and increase expression of NMDA receptor subunits(NR1 and NR2B) in the hippocampus.The results suggest that 5-HT may contribute to CUMS-induced depressive-like behaviors via 5-HT1AR,and the antidepressant effect of 5-HT1AR agonists may be mediated by NMDA and AMPA receptors.